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"reach", "pmid": "18803326", "text": "Consequently, GTPase activating proteins (GAPs) such as neurofibromin are required to enhance the intrinsic GTPase activity of Ras proteins and thereby inactivate these small G-proteins.", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "coords": [ [ 14, 40 ], [ 108, 114 ] ], "raw_text": [ "GTPase activating proteins", "GTPase" ], "raw_grounding": [ { "TEXT": "GTPase activating proteins", "FPLX": "GAP", "GO": "GO:0005096", "NCIT": "C17298" }, { "FPLX": "GTPase", "NCIT": "C16650", "ECCODE": "3.6.5", "TEXT": "GTPase" } ] }, "prior_hash": 10945081091335363, "prior_uuids": [ "86c24300-9313-4ce5-8649-6bb334884d7b" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 17, "stmt_hash": 5094065187720124, "belief": 0.5309418930057913, "source_counts": { "reach": 17 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "18803326", 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true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "2121370", "DOI": "10.1016/0092-8674(90)90150-D", "TRID": 11908084 }, "source_hash": 7721435147745865194 }, { "source_api": "reach", "pmid": "23875798", "text": "These substitutions disrupt guanine nucleotide binding and cause a reduction in intrinsic and GAP induced GTPase activity, resulting in Ras remaining in the active state.", "annotations": { "found_by": "Positive_early_activation", "agents": { "coords": [ [ 94, 97 ], [ 106, 112 ] ], "raw_text": [ "GAP", "GTPase" ], "raw_grounding": [ { "FPLX": "GAP", "GO": "GO:0005096", "NCIT": "C17298", "TEXT": "GAP" }, { "FPLX": "GTPase", "NCIT": "C16650", "ECCODE": "3.6.5", "TEXT": "GTPase" } ] }, "prior_hash": 5745432201711080, "prior_uuids": [ "88b67927-887b-4f75-86a6-033ed574206d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 17, "stmt_hash": 5094065187720124, "belief": 0.5309418930057913, "source_counts": { "reach": 17 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "23875798", "PMCID": "PMC4115674", "DOI": "10.1146/ANNUREV-GENOM-091212-153523", "MANUSCRIPT_ID": "NIHMS604870", "TRID": 19520275 }, "source_hash": -2242505018197223775 }, { "source_api": "reach", "pmid": "21396583", "text": "These proteins are activated by GEFs, including SOS1, which promote release of GDP, and inactivated by GAPs, which accelerate the intrinsic GTPase activity.", "annotations": { "found_by": "Positive_activation_syntax_5_verb", "agents": { "coords": [ [ 103, 107 ], [ 140, 146 ] ], "raw_text": [ "GAPs", "GTPase" ], "raw_grounding": [ { "TEXT": "GAPs", "FPLX": "GAP", "GO": "GO:0005096", "NCIT": "C17298" }, { "FPLX": "GTPase", "NCIT": "C16650", "ECCODE": "3.6.5", "TEXT": "GTPase" } ] }, "prior_hash": -28117045840249118, "prior_uuids": [ "0daa8527-060c-4366-bebb-aec0fbf9446e" ], "indranet_edge": { "residue": null, "position": null, 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(CeGAP) may be a promiscuous GAP, which not only stimulates the GTPase of nematode and human Rho, but also that of human H-Ras and Rab3a [138].", "annotations": { "found_by": "Positive_activation_syntax_5_verb", "agents": { "coords": [ [ 166, 169 ], [ 201, 207 ] ], "raw_text": [ "GAP", "GTPase" ], "raw_grounding": [ { "FPLX": "GAP", "GO": "GO:0005096", "NCIT": "C17298", "TEXT": "GAP" }, { "FPLX": "GTPase", "NCIT": "C16650", "ECCODE": "3.6.5", "TEXT": "GTPase" } ] }, "prior_hash": 5745432201711080, "prior_uuids": [ "67f652fc-a179-458e-9d39-77da69d67243" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 17, "stmt_hash": 5094065187720124, "belief": 0.5309418930057913, "source_counts": { "reach": 17 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "7626654", "DOI": "10.1016/0304-419X(95)00003-X", "TRID": 22272333 }, "source_hash": -2711319475805173701 }, { "source_api": "reach", "pmid": "8246952", "text": "The GTPase activity of p21ras is stimulated by GTPase activating proteins (GAPs) such as p120GAP and the product of the neurofibromatosis 1 gene, which may negatively regulate p21 function.", "annotations": { "found_by": "Positive_activation_syntax_2_verb", "agents": { "coords": [ [ 47, 73 ], [ 4, 10 ] ], "raw_text": [ "GTPase-activating proteins", "GTPase" ], "raw_grounding": [ { "FPLX": "GAP", "GO": "GO:0005096", "NCIT": "C17298", "TEXT": "GTPase-activating proteins" }, { "FPLX": "GTPase", "NCIT": "C16650", "ECCODE": "3.6.5", "TEXT": "GTPase" } ] }, "prior_hash": 12573493633034605, "prior_uuids": [ "db32c9f1-30a5-47a2-9372-a51ef7ca7ee0" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 17, "stmt_hash": 5094065187720124, "belief": 0.5309418930057913, "source_counts": { "reach": 17 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "8246952", "PMCID": 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1957420694551316024 }, { "source_api": "sparser", "pmid": "23082153", "text": "In an attempt to elucidate the mechanism of SecPH inhibition of cofilin phosphorylation by ROCK activated LIMK2, we postulated that SecPH might prevent LIMK2 from interacting with ROCK.", "annotations": { "prior_hash": 33631737726925445, "agents": { "raw_text": [ "ROCK", "LIMK2" ], "raw_grounding": [ { "FPLX": "ROCK", "IP": "IPR015008", "TEXT": "ROCK" }, { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" } ] }, "prior_uuids": [ "181399b3-5460-4297-b8d7-7ab3ce2a6dd3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 10, "stmt_hash": 33631737726925445, "belief": 1, "source_counts": { "reach": 2, "sparser": 8 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 3132644128448748575 }, { "source_api": "sparser", "pmid": "23082153", "text": "SecPH 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WT mice (XREF_FIG).", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "coords": [ [ 8, 11 ], [ 47, 50 ] ], "raw_text": [ "LTG", "Nf1" ], "raw_grounding": [ { "TEXT": "LTG", "HGNC": "11930", "UP": "O43557", "EGID": "8740" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "Nf1", "EGID": "4763" } ] }, "prior_hash": 477062704726590, "prior_uuids": [ "7424ba45-a0d3-4b49-86f0-a2b63cd038a4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 1, "stmt_hash": -17033490012754483, "belief": 0.16574388091545011, "source_counts": { "reach": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "25917366", "PMCID": "PMC5603719", "DOI": "10.1038/MP.2015.48", "MANUSCRIPT_ID": "NIHMS899788", "TRID": 2831460 }, "source_hash": 7470089904333945744 } ], "id": "7424ba45-a0d3-4b49-86f0-a2b63cd038a4", "matches_hash": "-17033490012754483" }, { "type": "Activation", "subj": { "name": 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associated with local mast cell proliferation.", "annotations": { "found_by": "Positive_early_activation", "agents": { "coords": [ [ 81, 91 ], [ 101, 110 ] ], "raw_text": [ "Fas ligand", "apoptosis" ], "raw_grounding": [ { "UP": "P48023", "HGNC": "11936", "TEXT": "Fas ligand", "EGID": "356" }, { "GO": "GO:0006915", "MESH": "D017209", "TEXT": "apoptosis" } ] }, "prior_hash": 15194844016064692, "prior_uuids": [ "618d4711-b578-48e9-ad90-1e3870e2dc79" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 9, "stmt_hash": 15194844016064692, "belief": 1, "source_counts": { "reach": 9 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "15039234", "PMCID": "PMC1615352", "DOI": "10.1016/S0002-9440(10)63233-6", "TRID": 2432191 }, "source_hash": 6353971422458879334 }, { "source_api": "reach", "pmid": "15039234", "text": "Here, we show that Nf1 deficient mast cells have reduced surface Fas antigen 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Nf1 renders mast cells resistant to Fas ligand mediated apoptosis, WT, Nf1 +/- and Nf1 -/- BMMCs were cultured in kit-L (100 ng/ml) for 72 hours and then stimulated with recombinant Fas ligand (100 ng/ml) or vehicle control for 16 hours.", "annotations": { "found_by": "Positive_early_activation", "agents": { "coords": [ [ 71, 81 ], [ 91, 100 ] ], "raw_text": [ "Fas ligand", "apoptosis" ], "raw_grounding": [ { "UP": "P48023", "HGNC": "11936", "TEXT": "Fas ligand", "EGID": "356" }, { "GO": "GO:0006915", "MESH": "D017209", "TEXT": "apoptosis" } ] }, "prior_hash": 15194844016064692, "prior_uuids": [ "88d7b2e2-d9b0-49b5-9f20-ac92ea977377" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 9, "stmt_hash": 15194844016064692, "belief": 1, "source_counts": { "reach": 9 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "15039234", "PMCID": "PMC1615352", "DOI": 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increased apoptosis in Schwann cell tumors.", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "coords": [ [ 0, 4 ], [ 25, 38 ] ], "raw_text": [ "Rac1", "proliferation" ], "raw_grounding": [ { "UP": "P63000", "HGNC": "9801", "EGID": "5879", "TEXT": "Rac1" }, { "GO": "GO:0008283", "MESH": "D049109", "TEXT": "proliferation" } ] }, "prior_hash": -13490133292393347, "prior_uuids": [ "cb2ba6d5-9e03-48dc-8b67-3ee55530983d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 5, "stmt_hash": -13490133292393347, "belief": 1, "source_counts": { "reach": 5 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "23045281", "PMCID": "PMC3542412", "DOI": "10.1038/ONC.2012.374", "MANUSCRIPT_ID": "NIHMS392997", "TRID": 14485144 }, "source_hash": 6742330681333206720 }, { "source_api": "reach", "pmid": "22431917", "text": "Thrombospondin 2 regulates cell proliferation induced by Rac1 redox dependent signaling.", "annotations": { "found_by": "Positive_activation_syntax_2_verb", "agents": { "coords": [ [ 57, 61 ], [ 27, 45 ] ], "raw_text": [ "Rac1", "cell proliferation" ], "raw_grounding": [ { "UP": "P63000", "HGNC": "9801", "EGID": "5879", "TEXT": "Rac1" }, { "GO": "GO:0008283", "MESH": "D049109", "TEXT": "cell proliferation" } ] }, "prior_hash": -13490133292393347, "prior_uuids": [ "3865eb84-a55a-4f23-b183-40f36b9d5068" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 5, "stmt_hash": -13490133292393347, "belief": 1, "source_counts": { "reach": 5 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "22431917", "PMCID": "PMC3306254", "DOI": "10.1593/NEO.111600", "TRID": 4328638 }, "source_hash": -4506817993214991543 }, { "source_api": "reach", "pmid": "28934903", "text": "Results Pharmacological inhibition of RAC1 could significantly inhibit the proliferation of both RT4 cells and human NF2 associated primary schwannoma cells by inducing apoptosis.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "coords": [ [ 38, 42 ], [ 75, 88 ] ], "raw_text": [ "RAC1", "proliferation" ], "raw_grounding": [ { "UP": "P63000", "HGNC": "9801", "EGID": "5879", "TEXT": "RAC1" }, { "GO": "GO:0008283", "MESH": "D049109", "TEXT": "proliferation" } ] }, "prior_hash": -13490133292393347, "prior_uuids": [ "02519097-cbc3-43c8-9360-4482c61e1f91" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Activation", "evidence_count": 5, "stmt_hash": -13490133292393347, "belief": 1, "source_counts": { "reach": 5 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "28934903", "DOI": "10.1080/01616412.2017.1376494", "TRID": 7449998 }, "source_hash": 4034681990762795827 }, { "source_api": "reach", "pmid": "28934903", "text": "Reduced RAC1 activity inhibits cell 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phospho-specific antibody against Hpo\u2019s autophosphorylation site (T195) ( xref ).", "annotations": { "prior_hash": 25947443425104565, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ "2c897fee-ca45-4a9b-aa4c-aed7157c5250" ] }, "text_refs": { "PMID": "24012335", "PMCID": "PMC3835333", "DOI": "10.1016/J.CELL.2013.08.025", "PII": "S0092-8674(13)01019-2", "MANUSCRIPT_ID": "NIHMS526293", "TRID": 26758113 }, "source_hash": 4631525784258590954 }, { "source_api": "sparser", "pmid": "20159598", "text": "RNAi knockdown of kbr not only resulted in a decrease of Yki S168 phosphorylation ( xref ), but also a decrease of Hpo kinase activity ( xref ), as measured by a phospho-specific antibody against Hpo\u2019s autophosphorylation site ( xref ).", "annotations": { "prior_hash": 25947443425104565, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ 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dimerization and translocation into the nucleus to directly drive gene expression needed for cell proliferation [ xref \u2013 xref ].", "annotations": { "prior_hash": -14522752266105373, "agents": { "raw_text": [ "STAT3" ], "raw_grounding": [ { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "32297fee-d034-41f9-aaae-ccaf193c4fb7" ] }, "text_refs": { "PMID": "28427224", "PMCID": "PMC5458238", "DOI": "10.18632/ONCOTARGET.15912", "TRID": 8283188 }, "source_hash": -6748717752838579101 } ], "id": "32297fee-d034-41f9-aaae-ccaf193c4fb7", "matches_hash": "-14522752266105373" }, { "type": "Autophosphorylation", "enz": { "name": "AURKA", "db_refs": { "UP": "O14965", "TEXT": "Aurora A", "HGNC": "11393", "EGID": "6790" } }, "belief": 0.6566337937959456, "evidence": [ { "source_api": "sparser", "pmid": "23934191", "text": "The reported interaction and functional cooperation of LIMK1 and 2 with Aurora A led us to explore the effect of LIMK inhibition with 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PI3K-AKT and JAK-STAT3 pathways than in sporadic GISTs, and the near absence of neurofibromin expression. xref , xref Mitotic recombination or other genetic mechanisms resulting in the loss of wild-type allele and NF1 heterozygosity may be the key molecular event underlying GIST development in NF-1 patients. xref , xref There are no clear data about their imatinib sensitivity, but in vitro data suggest that NF-1-related GISTs are not well controlled by imatinib, similarly to wild-type GISTs in general. xref ", "annotations": { "prior_hash": -19783848488741483, "agents": { "raw_text": [ "KIT" ], "raw_grounding": [ { "TEXT": "KIT", "HGNC": "6342", "UP": "P10721", "EGID": "3815" } ] }, "prior_uuids": [ "70360975-b021-434f-a921-0066e8d5c6ca" ] }, "text_refs": { "PMID": "23776354", "PMCID": "PMC3681166", "DOI": "10.2147/TACG.S7191", "TRID": 21211699 }, "source_hash": -6879811156285457154 } ], "id": "70360975-b021-434f-a921-0066e8d5c6ca", "matches_hash": "-19783848488741483" }, { "type": 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xref ) are dissociated by treatment of cells with antagonists of hyaluronan-CD44 interaction, we determined whether o-HA also affect interactions between CD44 and BCRP or Pgp.", "annotations": { "found_by": "INTERACT", "prior_hash": 242479948789150, "agents": { "raw_text": [ "hyaluronan", "CD44" ], "raw_grounding": [ { "CHEBI": "CHEBI:16336", "HMDB": "HMDB0002061", "CAS": "9004-61-9", "TEXT": "hyaluronan" }, { "UP": "P16070", "HGNC": "1681", "EGID": "960", "TEXT": "CD44" } ] }, "prior_uuids": [ "7fe09fc7-7e2c-4cfc-bf4a-65ffea128311" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 20, "stmt_hash": -26653286010578551, "belief": 0.8809103757638806, "source_counts": { "sparser": 16, "reach": 4 }, "internal": true } }, "text_refs": { "PMID": "19470767", "PMCID": "PMC3655760", "DOI": "10.1158/0008-5472.CAN-09-0143", "MANUSCRIPT_ID": "NIHMS463086", "TRID": 26276482 }, "source_hash": -5677116828658733881 }, { "source_api": "sparser", "pmid": "19470767", "text": "The o-HA reduced secreted hyaluronan in a dose-dependent fashion, with almost complete inhibition at 10 to 100 \u00b5g/mL ( xref ), amounts found previously to inhibit drug resistance and signaling events downstream of hyaluronan-CD44 interactions ( xref , xref , xref ).", "annotations": { "found_by": "INTERACT", "prior_hash": 242479948789150, "agents": { "raw_text": [ "hyaluronan", "CD44" ], "raw_grounding": [ { "CHEBI": "CHEBI:16336", "HMDB": "HMDB0002061", "CAS": "9004-61-9", "TEXT": "hyaluronan" }, { "UP": "P16070", "HGNC": "1681", "EGID": "960", "TEXT": "CD44" } ] }, "prior_uuids": [ "882c7269-d3ba-4bf2-911c-c12aa015503d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 20, "stmt_hash": -26653286010578551, "belief": 0.8809103757638806, "source_counts": { "sparser": 16, "reach": 4 }, "internal": true } }, "text_refs": { "PMID": "19470767", "PMCID": "PMC3655760", "DOI": "10.1158/0008-5472.CAN-09-0143", 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10(-6) M 1,25[OH]2VD3 unregulated Myt1 mRNA from 6 h to 24 h and Wee1 mRNA from 12 to 48 h.", "annotations": { "MeSHAnatomy": { "bronchoalveolar lavage fluid": true }, "bel": "complex(a(CHEBI:calcitriol), p(HGNC:VDR)) increases act(p(HGNC:VDR), ma(tscript))", "agents": { "raw_text": [ null, null ], "raw_grounding": [ { "CHEBI": "CHEBI:17823", "DRUGBANK": "DB00136", "CAS": "32222-06-3", "CHEMBL": "CHEMBL846", "MESH": "D002117", "HMDB": "HMDB0001903", "PUBCHEM": "5280453" }, { "HGNC": "12679", "UP": "P11473", "MESH": "D018167", "EGID": "7421" } ] }, "prior_uuids": [ "0e6fdcc7-5989-43e9-abfd-707a1fad10bc", "fa3bef0c-8233-45c9-90fa-cf763169cc79" ], "prior_hash": 3568607530906916, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 59, "stmt_hash": 3568607530906916, "belief": 0.9597747808558853, "source_counts": { "reach": 54, "bel": 5 }, "internal": true } }, "epistemics": { "direct": false }, "context": { "location": { "name": "Cell Nucleus", 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"annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ "CPT", "NF1" ], "raw_grounding": [ { "TEXT": "CPT", "CHEBI": "CHEBI:27656", "PUBCHEM": "24360", "MESH": "D002166", "DRUGBANK": "DB04690", "CHEMBL": "CHEMBL65", "CAS": "7689-03-4" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "dbd632fe-8697-4c1b-8202-94d2feee8eee" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 5, "stmt_hash": 13936841039412363, "belief": 0.26320124795810673, "source_counts": { "sparser": 5 }, "internal": true } }, "text_refs": { "PMID": "35024939", "TRID": 34384989, "DOI": "10.1007/S00439-021-02429-2" }, "source_hash": -4091085672966643678 }, { "source_api": "sparser", "pmid": "35024939", "text": "In NF1-CPT patients, when the results from earlier reports and the present study were combined, 66.7% of them showed somatic NF1 inactivation in PA tissues other than germline inactivation.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ "CPT", "NF1" ], "raw_grounding": [ { "TEXT": "CPT", "CHEBI": "CHEBI:27656", "PUBCHEM": "24360", "MESH": "D002166", "DRUGBANK": "DB04690", "CHEMBL": "CHEMBL65", "CAS": "7689-03-4" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "0da56229-dac7-4b97-b175-fba6bf115785" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 5, "stmt_hash": 13936841039412363, "belief": 0.26320124795810673, "source_counts": { "sparser": 5 }, "internal": true } }, "text_refs": { "PMID": "35024939", "TRID": 34384989, "DOI": 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] }, "prior_uuids": [ "4530719f-1706-45fc-9f72-ebb71d3c1af3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 5, "stmt_hash": 13936841039412363, "belief": 0.26320124795810673, "source_counts": { "sparser": 5 }, "internal": true } }, "text_refs": { "PMID": "35024939", "TRID": 34384989, "DOI": "10.1007/S00439-021-02429-2" }, "source_hash": 728310113629721386 }, { "source_api": "sparser", "pmid": "35024939", "text": "Up to 84% of patients with congenital pseudarthrosis of the tibia (CPT) present with neurofibromatosis type 1 (NF1) (NF1-CPT).", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ "CPT", "NF1" ], "raw_grounding": [ { "TEXT": "CPT", "CHEBI": "CHEBI:27656", "PUBCHEM": "24360", "MESH": "D002166", "DRUGBANK": "DB04690", "CHEMBL": "CHEMBL65", 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greater improvement in adaptive coping compared to HEP-NF from baseline to post-intervention and baseline to 6 months (M difference = 0.29; 95% CI 0.13-0.46; p\u2009<\u20090.001; M difference = 0.25; 95% CI 0.07-0.33; p\u2009=\u20090.005); there were no other between-group differences amongst the remaining resilience factors.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.3711367051960603, "HGNC:15598": 0.1151189758312338, "MESH:D017121": 0.11046581452441855, "MESH:D022781": 0.11202788013828577, "PUBCHEM:74689": 0.09622789005627648, "ungrounded": 0.19502273425372516 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": 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"type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.3711367051960603, "HGNC:15598": 0.1151189758312338, "MESH:D017121": 0.11046581452441855, "MESH:D022781": 0.11202788013828577, "PUBCHEM:74689": 0.09622789005627648, "ungrounded": 0.19502273425372516 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ "0ff29922-2f5a-491d-a584-be2fbf1e058b" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 10657297313150414, "belief": 0.250155140548582, "source_counts": { "sparser": 12 }, "internal": true } }, "text_refs": { "PMID": "37440099", "TRID": 36880708, "DOI": "10.1007/S11060-023-04389-1" }, "source_hash": -8612484881556064956 }, { "source_api": "sparser", "pmid": "37378983", "text": "In this randomized clinical trial of 3RP-NF vs HEP-NF, benefits from 3RP-NF and HEP-NF were comparable after treatment, but at 12 months from baseline, 3RP-NF was superior to HEP-NF on all primary and secondary outcomes.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.31565084473366467, "HGNC:15598": 0.12112740641187039, "MESH:D017121": 0.11555423601859041, "MESH:D022781": 0.11725026591707355, "PUBCHEM:74689": 0.10575048574871482, "ungrounded": 0.2246667611700863 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", 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{ "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.31565084473366467, "HGNC:15598": 0.12112740641187039, "MESH:D017121": 0.11555423601859041, "MESH:D022781": 0.11725026591707355, "PUBCHEM:74689": 0.10575048574871482, "ungrounded": 0.2246667611700863 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ "7ae071aa-be89-4f78-8452-0811f5cdb6d3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 10657297313150414, "belief": 0.250155140548582, "source_counts": { "sparser": 12 }, "internal": true } }, "text_refs": { "PMID": "37378983", "TRID": 36819327, "DOI": "10.1001/JAMANETWORKOPEN.2023.20599" }, "source_hash": -5514139996363878653 }, { "source_api": "sparser", "pmid": "37378983", "text": "001; HEP-NF, 6.4; 95% CI, 4.6-8.3; P\u2009<\u2009.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.31565084473366467, "HGNC:15598": 0.12112740641187039, "MESH:D017121": 0.11555423601859041, "MESH:D022781": 0.11725026591707355, "PUBCHEM:74689": 0.10575048574871482, "ungrounded": 0.2246667611700863 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ "614128f0-c48e-4241-a5af-da2cea12ed47" ], "indranet_edge": { 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"source_api": "sparser", "pmid": "38409461", "text": "Secondary analysis of a fully-powered RCT of a mind-body program (Relaxation Response Resiliency Program for NF; 3RP-NF) versus an educational program (Health Enhancement Program for NF; HEP-NF) among 228 adults with NF.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "adeft": [ null, { "CHEBI:CHEBI:28304": 0.40474717210232547, "HGNC:15598": 0.10579076031322264, "MESH:D017121": 0.10633563357574387, "MESH:D022781": 0.10085344337571109, "PUBCHEM:74689": 0.0879312616961759, "ungrounded": 0.1943417289368212 } ], "raw_text": [ "HEP", "NF" ], "raw_grounding": [ { "TEXT": "HEP", "CHEBI": "CHEBI:28304", "CHEMBL": "CHEMBL1909300", "CAS": "9005-49-6", "DRUGBANK": "DB01109" }, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ 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"prior_uuids": [ "addc59b2-76a0-47e5-a8e4-18f22d5f3458" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 2313828052545414852 }, { "source_api": "sparser", "pmid": "33414453", "text": "Here, we demonstrate that pyridoxal-5\u2032-phosphate phosphatase/chronophin (PLPP/CIN) dephosphorylated NF2-S10 site as well as cofilin-S3 site.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "217ebed3-bbc3-45b0-91fd-854f112477e3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 1652258242677868659 }, { "source_api": "sparser", "pmid": "33414453", "text": "Furthermore, NF2-S10 phosphorylation, but not NF2 protein and S518 phosphorylation levels, showed an inverse proportional relationship with PSD95 protein level with linear correlation coefficients of \u22120.7367 within control siRNA- and NF2 siRNA-treated groups under post-KA conditions ( t (26) \u2009=\u20095.555, p \u2009<\u20090.0001; Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "31e38427-1f3e-426e-a750-008a196c56a4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -7240055712678925866 }, { "source_api": "sparser", "pmid": "33414453", "text": "The Mdm2 protein level showed a direct proportional relationship with NF2-S10 phosphorylation after KA treatment (linear correlation coefficients, 0.542; t (26) \u2009=\u20093.289, p \u2009=\u20090.003; Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "0e2193a8-f5d2-492a-b565-de809b43f901" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 9162142445441964503 }, { "source_api": "sparser", "pmid": "33414453", "text": "Thus, it is plausible that PLPP/CIN-mediated NF2-S10 dephosphorylation would affect the inhibitory effect of Mdm2 on PSD95 protein level.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "2c5ba396-0400-4ab0-adcc-16b4639f4479" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 2831229758959839291 }, { "source_api": "sparser", "pmid": "33414453", "text": "Regarding the effects of NF2 knockdown on cofilin activity and F-actin contents, our findings suggest that NF2 down-regulation and/or PLPP/CIN-mediated NF2-S10 dephosphorylation may facilitate seizure intensity and its progress through F-actin instability independent of cofilin-mediated actin dynamics.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "db4a24c0-e119-4d14-80e6-c910ef81382a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 1963769714693988915 }, { "source_api": "sparser", "pmid": "33414453", "text": "The F-actin contents also showed a direct proportional relationship with NF2-S10 phosphorylation level (linear correlation coefficients, 0.7977; t (54) \u2009=\u20099.72, p \u2009<\u20090.001; Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "479d4e6b-5f4a-4a98-aa25-104954b6c96f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -7651345173190022763 }, { "source_api": "sparser", "pmid": "33414453", "text": "However, PLPP/CIN over-expression and its deletion selectively affected NF2-S10 phosphorylation under physiological- and post-KA conditions.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "d6790a91-bcfb-4ce8-b03d-8a5795d0e594" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 8989774171445520430 }, { "source_api": "sparser", "pmid": "33414453", "text": "Therefore, our findings suggest that PLPP/CIN may be a counterpart of PKAc for NF2-S10 phosphorylation.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "59d75237-be5d-42af-9970-c1f09ea54c69" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 5982653380276199490 }, { "source_api": "sparser", "pmid": "33414453", "text": "Considering the data obtained from PLPP/CIN Tg mice, these findings indicate that PLPP/CIN deletion may abolish NF2-S10 dephosphorylation in response to KA, in spite of the lower NF2-PKAc binding and PKAc activity than WT mice, and that PKAc phosphorylation may correlate to seizure intensity.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "fd458939-5dd0-4d8e-9f63-5c2a7638ef80" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 785078093226120212 }, { "source_api": "sparser", "pmid": "33414453", "text": "PLPP/CIN deletion enhanced NF2-S10 phosphorylation induced by KA without altering its expression and S518 phosphorylation ( F (3,24) \u2009=\u2009105.4, p \u2009=\u20090.007, one-way ANOVA, n \u2009=\u20097, respectively; Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "e045e213-29f2-475d-a7f6-04404d3c8c75" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -6755470606641976391 }, { "source_api": "sparser", "pmid": "33414453", "text": "However, PLPP/CIN deletion increased NF2-S10 phosphorylation to ~1.52-fold of WT mice level under physiological condition ( t (12) \u2009=\u20096.86, p \u2009=\u20090.00002, Student\u2019s t -test, n \u2009=\u20097, respectively; Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "001114b8-a17c-4d1e-b89d-0c449fca1080" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -7404434428335890297 }, { "source_api": "sparser", "pmid": "33414453", "text": "Regardless of the roles of AKT, p53 and NEDD4-2 in seizure activity, our findings suggest that PLPP/CIN-mediated NF2-S10 dephosphorylation may increase KA-induced seizure activity by enhancing F-actin instability and Mdm2-mediated PSD95 degradation (Fig. xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "30539b5e-8c82-4c23-9b48-ad5a65374eec" ], "indranet_edge": { 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"Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -8506400099957886292 }, { "source_api": "sparser", "pmid": "33414453", "text": "The present study also demonstrates that following KA injection NF2 protein level and NF2-S10 phosphorylation showed an inverse and a direct proportional relationship with the Mdm2 protein level in the presence of PLPP/CIN, respectively.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "80d597c3-7789-4d49-8216-f90f6ec65ce4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 0.2848774077490388, "source_counts": { "sparser": 33 }, "internal": true } }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 8709445160678729844 }, { "source_api": "sparser", "pmid": "33414453", "text": "Thus, it is plausible that NF2 itself and/or NF2-S10 phosphorylation would directly affect AKT-mediated Mdm2-S166 phosphorylation.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 31907438446354969, "agents": { "raw_text": [ "S10", "NF2" ], "raw_grounding": [ { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "9f48b8f7-c700-4fd0-b5de-e00e4b473130" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 33, "stmt_hash": -21810619402844857, "belief": 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A cell-penetrant version of this peptide (t-CNRP1) inhibited CaV2.2 and NaV1.7 currents in Nf1 -edited neurons.", "annotations": { "found_by": "INTERACT", "prior_hash": -7978190915495679, "agents": { "raw_text": [ "syntaxin 1A", "CaV2.2", "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CaV2.2", "HGNC": "1389", "UP": "Q00975", "EGID": "774" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "8b2a22f4-bcdc-4154-a558-4aa57db02564" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 4, "stmt_hash": -7978190915495679, "belief": 0.3109877912073009, "source_counts": { "sparser": 4 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 4283301123416126959 }, { "source_api": "sparser", "pmid": "28767512", "text": "Our work also identifies a novel tool\u2013the CRMP2-derived aptamer CNRP, which is capable of uncoupling CRMP2\u2019s interactions with neurofibromin, syntaxin 1A, and Cav2.2.", "annotations": { "found_by": "INTERACT", "prior_hash": -7978190915495679, "agents": { "raw_text": [ "syntaxin 1A", "Cav2.2", "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "Cav2.2", "HGNC": "1389", "UP": "Q00975", "EGID": "774" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "a5e63cf3-c6e9-4e70-b6b7-504cc4fc8d14" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 4, "stmt_hash": -7978190915495679, "belief": 0.3109877912073009, "source_counts": { "sparser": 4 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 2204136014152474680 }, { "source_api": "sparser", "pmid": "28767512", "text": "These results suggest that targeting CRMP2 interactions with neurofibromin, syntaxin 1A and Cav2.2 is beneficial for nociceptive pain behaviors in a rat model of HIV-SN.", "annotations": { "found_by": "INTERACT", "prior_hash": -7978190915495679, "agents": { "raw_text": [ "syntaxin 1A", "Cav2.2", "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "Cav2.2", "HGNC": "1389", "UP": "Q00975", "EGID": "774" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "acc5f095-c33e-4d50-a247-9919ad4160b9" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 4, "stmt_hash": -7978190915495679, "belief": 0.3109877912073009, "source_counts": { "sparser": 4 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -2220569484430837535 } ], "id": "c4693620-8888-44ed-bbd5-34301f3c47c9", "matches_hash": "-7978190915495679" }, { "type": "Complex", "members": [ { "name": "STX1A", "db_refs": { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" } }, { "name": "DPYSL2", "db_refs": { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } } ], "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "28767512", "text": "This mechanism suggests that CRMP2\u2019s interaction with syntaxin 1A might be a therapeutic target for pain management because this interaction directly controls neurotransmitter release.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "da4b1341-a604-494f-96b1-1249399696e6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -6106669429739181110 }, { "source_api": "sparser", "pmid": "28767512", "text": "A possible explanation for this could be that the loss of interaction between CRMP2 and syntaxin 1A may result in relocalization of syntaxin 1A to other protein partners, for instance TRPV1/TRPA1 xref or ATP receptors (eg, P2X, P2Y). xref , xref Facilitating these interactions would promote the trafficking of these channels/receptors to the plasma membrane where they are active, thus explaining the increased number of neurons responding to the constellation pharmacology triggers.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "a450852a-f630-4032-af17-9e10c41bec77" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -3977962028985944226 }, { "source_api": "sparser", "pmid": "28767512", "text": "Here, targeting CRMP2/neurofibromin interaction disrupted CRMP2\u2019s interaction with syntaxin 1A, a protein involved in synaptic vesicle docking and neurotransmitter release. xref , xref , xref Of importance, intrathecal administration of the peptide reversed mechanical allodynia and/or thermal hyperalgesia in experimental models of inflammatory, postsurgical, and neuropathic pain.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "4e7b2c8b-8713-46b5-bcea-7b3d943cdcbc" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 2901837566786603887 }, { "source_api": "sparser", "pmid": "28767512", "text": "Excitingly, as there is precedence for development of drugs against synaptic vesicle proteins with the development of levetiracetam targeting the synaptic vesicle protein SV2A, xref our findings support future efforts aimed at targeting the CRMP2\u2013 syntaxin 1A interaction for pain curbing drugs.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "8a2d190d-2c23-4461-8864-8e3293570ad6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -162204355816958197 }, { "source_api": "sparser", "pmid": "28767512", "text": "Neurofibromin inhibits CRMP2 interactions with syntaxin 1A.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "2ce79b79-34cd-40f0-bfaf-3366a7cc32f7" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 2973516069926884225 }, { "source_api": "sparser", "pmid": "28767512", "text": "These results show that the previously unknown interaction between CRMP2 and syntaxin 1A is regulated by neurofibromin and that it can be inhibited using t-CNRP1.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "a148f079-d015-4533-97d0-16bf1c91f589" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 4183909850458080590 }, { "source_api": "sparser", "pmid": "28767512", "text": "This suggested that the same region of CRMP2 can interact with either neurofibromin or syntaxin 1A. In NF1, the CRMP2/neurofibromin interaction is decreased (because of decreased expression of neurofibromin), and we found that deletion of neurofibromin increases CRMP2\u2019s interaction with syntaxin 1A. Thus, we conclude that the augmented interaction between CRMP2 and syntaxin 1A is responsible for increased Cav2.2 currents and increased CGRP release in NF1.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "0e3905ac-25a1-487c-8c47-88d100ec5fdd" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -512843990186157202 }, { "source_api": "sparser", "pmid": "28767512", "text": "We then tested CRMP2 binding to syntaxin 1A by coimmunoprecipitation ( xref ).", "annotations": { "found_by": "BINDING", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "66ba735d-ec28-43de-bb18-5094aa63dd23" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -7266667346177488147 }, { "source_api": "sparser", "pmid": "29655575", "text": "One possibility is via CRMP2\u2019s interaction with syntaxin 1A. We previously reported that t-CNRP1 inhibits the CRMP2/syntaxin 1A interaction [11].", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "c5c8fb8b-d742-4ed6-a4e5-f3a810025585" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -8483651117567340546 }, { "source_api": "sparser", "pmid": "28767512", "text": "The release of the neuropeptide CGRP by presynaptic terminals from small-diameter sensory neurons is known to be a major mediator of pain signaling. xref Activity of the N-type Ca 2+ channel has been directly linked to CGRP release in nerve terminals, xref , xref and controlling this channel\u2019s interaction with CRMP2 has proven efficient in inhibiting CGRP release from sensory neurons. xref , xref Furthermore, Cav2.2-dependent neurotransmitter release relies on syntaxin 1A recruitment. xref , xref Our data suggest that t-CNRP1 inhibits Cav2.2 by uncoupling of CRMP2 and syntaxin 1A interaction.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "ad3e11a2-7535-4d92-b9fa-ea1f862549be" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 1085573089755376803 }, { "source_api": "sparser", "pmid": "30915713", "text": "More precisely, hyperalgesia developed by the rats was\ndependent on the CRMP2-neurofibromin interface that regulated CRMP2\ninteraction with Syntaxin1A [ xref , xref ].", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "Syntaxin1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "Syntaxin1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "55a076c1-aac3-4411-8535-5d994406f9fd" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -1321606580568101219 }, { "source_api": "sparser", "pmid": "29655575", "text": "Also, CRMP2\u2019s interaction with syntaxin 1A, which is augmented when CRMP2\u2019s interaction with neurofibromin is lost (Moutal, et al., 2017e), could aid in docking of synaptic vesicles directly to these channels.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "f655b191-04e7-494c-842b-e1342834bf3e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -4733075024123079795 }, { "source_api": "sparser", "pmid": "29655575", "text": "Also, CRMP2\u2019s interaction with syntaxin 1A, which is augmented when CRMP2\u2019s interaction with neurofibromin is lost ( xref ), could aid in docking of synaptic vesicles directly to these channels.", "annotations": { "found_by": "INTERACT", "prior_hash": -27676153738821615, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "825a09cd-b55b-45e8-9b6f-5c6980c3ea4f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 13, "stmt_hash": -27676153738821615, "belief": 1, "source_counts": { "sparser": 13 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 5972989463975780739 } ], "id": "6659652f-4439-40d0-9e28-3e41b68687d3", "matches_hash": "-27676153738821615" }, { "type": "Complex", "members": [ { "name": "STX1A", "db_refs": { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" } }, { "name": "DPYSL2", "db_refs": { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } }, { "name": "NF1", "db_refs": { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } } ], "belief": 0.14707024723768614, "evidence": [ { "source_api": "sparser", "pmid": "28767512", "text": "This suggested that the same region of CRMP2 can interact with either neurofibromin or syntaxin 1A. In NF1, the CRMP2/neurofibromin interaction is decreased (because of decreased expression of neurofibromin), and we found that deletion of neurofibromin increases CRMP2\u2019s interaction with syntaxin 1A. Thus, we conclude that the augmented interaction between CRMP2 and syntaxin 1A is responsible for increased Cav2.2 currents and increased CGRP release in NF1.", "annotations": { "found_by": "INTERACT", "prior_hash": 7869776206374426, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "6ecb1637-aed6-4849-af83-4b735a892503" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 2, "stmt_hash": 7869776206374426, "belief": 0.14707024723768614, "source_counts": { "sparser": 2 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -512843990186157202 }, { "source_api": "sparser", "pmid": "29655575", "text": "Our work also identified the CRMP2-derived peptide CNRP1, which uncoupled CRMP2\u2019s interactions with neurofibromin, syntaxin 1A, as well as CaV2.2.", "annotations": { "found_by": "INTERACT", "prior_hash": 7869776206374426, "agents": { "raw_text": [ "syntaxin 1A", "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "syntaxin 1A", "HGNC": "11433", "UP": "Q16623", "EGID": "6804" }, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "fa749a76-95cd-4f74-8491-0dcfdd16188c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 2, "stmt_hash": 7869776206374426, "belief": 0.14707024723768614, "source_counts": { "sparser": 2 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", 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directly interact, with the possibility that Merlin sequesters YAP in the cytosol, preventing it from trans-activating expression.", "annotations": { "found_by": "INTERACT", "prior_hash": 14996307744338073, "agents": { "raw_text": [ "YAP", "Merlin" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" }, { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "3b11eea4-6766-4e4c-ab5e-1cf77e1fdcc4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 14996307744338073, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "25255738", "PMCID": "PMC4236251", "DOI": "10.1002/AJMG.A.36754", "MANUSCRIPT_ID": "NIHMS623607", "TRID": 18159510 }, "source_hash": 6789564521198283310 }, { "source_api": "sparser", "pmid": "25893302", "text": "Studies in human meningioma tumors and in paired cell lines\u2014KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells\u2014demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 14996307744338073, "agents": { "raw_text": [ "YAP", "merlin" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "3012f0ac-1f45-4733-9582-be631e7894a4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 14996307744338073, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "25893302", "PMCID": "PMC4615258", "DOI": "10.1038/ONC.2015.125", "MANUSCRIPT_ID": "NIHMS672877", "TRID": 20517466 }, "source_hash": 2935752291006317050 }, { "source_api": "sparser", "pmid": "18725387", "text": "Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1.", "annotations": { "found_by": "INTERACT", "prior_hash": 14996307744338073, "agents": { "raw_text": [ "YAP1", "Merlin" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP1" }, { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "aedf6bc5-e3f3-4ced-b924-6d6407661cad" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 14996307744338073, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "18725387", "DOI": "10.1093/CARCIN/BGN200", "TRID": 11690207 }, "source_hash": -5254620154782712437 }, { "source_api": "sparser", "pmid": "18953429", "text": "Merlin Loss Is Associated with an Increase in YAP Protein\nExpression In Drosophila, merlin controls cell proliferation and\napoptosis by signaling through the Hippo pathway and its effector\nprotein Yorkie, the ortholog of YAP [16,18].", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 14996307744338073, "agents": { "raw_text": [ "YAP", "Merlin" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" }, { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "a734b93c-43ff-48b4-b68d-4c40d294378d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 14996307744338073, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "18953429", "PMCID": "PMC2570596", "DOI": "10.1593/NEO.08642", "TRID": 20402649 }, "source_hash": 3544534685417776500 }, { "source_api": "reach", "pmid": "25893302", "text": "Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct.", "annotations": { 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"text": "This study provides the first evidence for an important tumor inhibitory effect of KAT2B in CCA through regulation of NF2-YAP signaling and suggests that this signaling cascade may be therapeutically targeted for CCA treatment.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ "YAP", "NF2" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" }, { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "f00a9fb3-8014-4b8e-8499-3b372ef37d4e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": 14996307744338073, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "38641672", "TRID": 38077385, "DOI": 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led to the first FDA-approved drug for NF1-PN and has changed management of these tumors, allowing for systemic therapy rather than reliance on only a surgical modality.", "annotations": { "found_by": "BIO-COMPLEX", "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ "PN", "NF1" ], "raw_grounding": [ { "TEXT": "PN", "HGNC": "16953", "EGID": "10631", "UP": "Q15063" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "96afae33-b32e-4b7a-a1fc-077b9185e231" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 14, "stmt_hash": 865313453706124, "belief": 0.23948227575115033, "source_counts": { "sparser": 14 }, "internal": true } }, "text_refs": { "PMID": "35759947", "TRID": 35134401, "DOI": "10.1016/J.PEDIATRNEUROL.2022.06.003" }, "source_hash": 7131046038880288524 }, 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"HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } } ], "belief": 1, "evidence": [ { "source_api": "reach", "pmid": "30274822", "text": "The SPRED1, a putative tumor suppressor and an important interacting gene with NF1, binds to neurofibromin, through an interaction between the EVH1 and the GRD domains.", "annotations": { "found_by": "binding1b", "agents": { "coords": [ [ 4, 10 ], [ 93, 106 ] ], "raw_text": [ "SPRED1", "neurofibromin" ], "raw_grounding": [ { "UP": "Q7Z699", "HGNC": "20249", "TEXT": "SPRED1", "EGID": "161742" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 19057687467458003, "prior_uuids": [ "19c4376b-55af-4d3e-9e6d-3c5f59704517" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "species": { "name": null, "db_refs": { "TAXONOMY": "76720" } }, "type": "bio" }, "text_refs": { "PMID": "30274822", "PMCID": "PMC6197713", "DOI": "10.1016/J.EBIOM.2018.09.039", "PII": "S2352-3964(18)30397-9", "TRID": 29414461 }, "source_hash": -2842797898496258185 }, { "source_api": "trips", "pmid": "26635368", "text": "These data clearly demonstrate that SPRED1 inhibits the Ras-ERK pathway by recruiting neurofibromin to Ras through the EVH1-GRD interaction, and this study also provides molecular basis for the pathogenic mutations of NF1 and Legius syndrome.", "annotations": { "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "neurofibromin" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "NCIT": "C102822", "EGID": "161742" }, { "TEXT": "neurofibromin", "UP": "P21359", "HGNC": "7765", "NCIT": "C17412", "EGID": "4763" } ] }, "prior_uuids": [ "1e144614-6581-43de-a3dd-d69fa2b54fca" ], "indranet_edge": { "residue": null, 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that mutations in SPRED1(EVH1) could cause Legius syndrome due to an inability to form the NF1-SPRED1 complex ( xref ).", "annotations": { "found_by": "BIO-FORM", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "61596231-2979-4069-94e8-1359a8d8b3d2" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 3446703062804358063 }, { "source_api": "reach", "pmid": "30274822", "text": "Recent works characterizing the association between NF1 and SPRED1 uncovered specific essential regions in the N and C terminal regions of the RAS-GAP domain that are required for their interaction [11, 22].", "annotations": { "found_by": "binding11", "agents": { "coords": [ [ 52, 55 ], [ 60, 66 ] ], "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "UP": "Q7Z699", "HGNC": "20249", "TEXT": "SPRED1", "EGID": "161742" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "NF1", "EGID": "4763" } ] }, "prior_hash": 19057687467458003, "prior_uuids": [ "ec9f94d5-3ef4-4c59-899c-8928455bbc47" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005886" } }, "species": { "name": null, "db_refs": { "TAXONOMY": 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affinity between NF1 and SPRED1, suggesting that these NF1 residues individually do not contribute significantly to NF1-SPRED1 interaction ( xref and xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "5acc8a7e-f518-45d6-8218-e623ab4e16f5" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 2917660842027293026 }, { "source_api": "sparser", "pmid": "32697994", "text": "The neurofibromin-SPRED1 interaction interface provides a rationale for mutations observed in Legius syndrome.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "neurofibromin" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "e3edb3b8-6632-479e-816f-a60226073da6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 5264246488069926722 }, { "source_api": "sparser", "pmid": "32697994", "text": "Most of the missense mutations observed in the SPRED1(EVH1) domain are located on the NF1-SPRED1 interface ( xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "112ab93b-a971-4de0-903c-dd0bf77ba3ed" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": -8324830711143758264 }, { "source_api": "reach", "pmid": "30274822", "text": "Much like NF1, SPRED1 is a negative regulator of Ras and MAPK signaling and acts by binding to neurofibromin inducing it 's localization in the plasma membrane, which subsequently down-regulates Ras-GTP levels [46].", "annotations": { "found_by": "binding1b", "agents": { "coords": [ [ 15, 21 ], [ 91, 104 ] ], "raw_text": [ "SPRED1", "neurofibromin" ], "raw_grounding": [ { "UP": "Q7Z699", "HGNC": "20249", "TEXT": "SPRED1", "EGID": "161742" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 19057687467458003, "prior_uuids": [ "7fe1db50-38e5-452a-b848-0f4c3a5ff791" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005886" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "76720" } }, "type": "bio" }, "text_refs": { "PMID": "30274822", "PMCID": "PMC6197713", "DOI": "10.1016/J.EBIOM.2018.09.039", "PII": "S2352-3964(18)30397-9", "TRID": 29414461 }, "source_hash": 4967392712348505056 }, { "source_api": "sparser", "pmid": "32697994", "text": "However, the structural details of the SPRED1-NF1 complex and the effects of the pathogenic mutations observed in Legius syndrome on SPRED1\u2019s interaction with NF1 remain to be clarified.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "ae2f3adf-a478-4f76-bc89-01007fb229e0" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, 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}, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": -3789110547304493774 }, { "source_api": "sparser", "pmid": "32697994", "text": "SPRED proteins share significant sequence similarity in the EVH1 domain, and most of the EVH1 residues involved in SPRED1-NF1 interaction are conserved among them ( xref and xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", "NF1" ], "raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "c01ad9f2-4554-4aa9-8b29-4ac4f259e98a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { 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"raw_grounding": [ { "TEXT": "SPRED1", "HGNC": "20249", "UP": "Q7Z699", "EGID": "161742" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "9b0c2d89-7c1d-4703-a341-d795c17b4d99" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 61, "stmt_hash": 19057687467458003, "belief": 1, "source_counts": { "reach": 12, "trips": 3, "sparser": 45, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 4097898324268773806 }, { "source_api": "sparser", "pmid": "32697994", "text": "We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 19057687467458003, "agents": { "raw_text": [ "SPRED1", 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it was reported that CRMP2 binds to voltage-gated calcium channels, particularly N-type (Cav2.2), and regulates calcium influx through these channels. xref , xref , xref That Cav2.2 currents were increased in sensory xref and hippocampal xref neurons from mice with a haploinsufficiency of Nf1 suggests that the CRMP2\u2013neurofibromin protein complex could be a determinant of Cav2.2 currents.", "annotations": { "found_by": "BINDING", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "184307ce-87d6-41d5-8612-d4c196686259" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": 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function is unclear.", "annotations": { "found_by": "binding_syntax_24_noun", "agents": { "coords": [ [ 151, 164 ], [ 184, 189 ] ], "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "cab03e7f-ce66-46bb-b1fe-f5d14d823624" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "cell_type": { "name": null, "db_refs": { "CL": "CL:0000101" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10116" } }, "type": "bio" }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -1652019854398169683 }, { "source_api": "reach", "pmid": "29655575", "text": "Here, we tested if targeting the CRMP2 and neurofibromin interaction in Nf1 edited in sensory neurons could reverse ion channel dysregulation, sensory neuron excitability, and hyperalgesia.", "annotations": { "found_by": "binding7a", "agents": { "coords": [ [ 33, 38 ], [ 39, 52 ] ], "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "cb93924c-034c-4861-80ad-d74722ab397f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { 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"annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "6f7aff6e-1663-4bb4-9f50-5efbc10ef305" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -3162564620976155830 }, { "source_api": "reach", "pmid": "29655575", "text": "In this platform, neurofibromin interacts with CRMP2 to prevent recruitment of syntaxin 1A and CaV2.2, thus leading to block of CGRP and a reduction in pain behaviors.", "annotations": { "found_by": "binding13", "agents": { "coords": [ [ 18, 31 ], [ 47, 52 ] ], "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "6d718a2b-3a2c-4ac2-a45b-cb414fad7138" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0016020" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10116" } }, "type": "bio" }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -8096314273747804003 }, { "source_api": "sparser", "pmid": "18313395", "text": "CDK5, a kinase that regulates CRMP-2 in axonal outgrowth, was required for the interaction between neurofibromin and CRMP-2.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP-2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP-2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "efeaa350-e2f4-40fa-bb20-b2b040dc8426" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "18313395", "DOI": "10.1016/J.BBRC.2008.02.095", "TRID": 483849 }, "source_hash": 3116839492906003470 }, { "source_api": "sparser", "pmid": "28767512", "text": "Two recent proteomics approaches identified collapsin response mediator protein 2 (CRMP2) as a novel target of neurofibromin. xref , xref As CRMP2 is a major regulator of Cav2.2 xref , xref , xref and interacts with neurofibromin, xref , xref we targeted the CRMP2 neurofibromin interaction as a novel approach to control Cav2.2 function.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "ff08ae66-ab3e-49e7-92c1-572172e2188b" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": 2399469339410431073 }, { "source_api": "sparser", "pmid": "28809766", "text": "A strong convergence of signaling pathways for neurofibromin and CRMP2 was suggested by findings that neurofibromin directly binds to CRMP2, as well as, indirectly modulates the kinases that phosphorylate CRMP2. xref We recently showed a direct positive effect of CRMP2 on calcium channel trafficking in sensory neurons. xref Thus, CRMP2 interaction with neurofibromin may be a novel mechanism for regulating phosphorylated CRMP2 levels in sensory neurons and, in turn, directing Ca 2+ channel trafficking and activity ( xref ).", "annotations": { "found_by": "BINDING", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", 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}, "prior_hash": 325259531219378, "prior_uuids": [ "f04abbeb-0b93-4835-8809-66d076d19b42" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "18313395", "DOI": "10.1016/J.BBRC.2008.02.095", "TRID": 483849 }, "source_hash": -7227538730906389835 }, { "source_api": "sparser", "pmid": "29655575", "text": "The CRMP2-neurofibromin interaction likely regulates CRMP2 functions by ( i ) modifying CRMP2\u2019s post-translational state ( xref ; xref ) and ( ii ) controlling CRMP2\u2019s interactome [33].", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "ce6f4353-d80b-4175-b634-6fee1e869e2f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 7680477899668574742 }, { "source_api": "sparser", "pmid": "29655575", "text": "The functional association of neurofibromin and CRMP2 was reported to be essential for neuronal cell differentiation; lack of expression or abnormal regulation of neurofibromin resulted in impaired function of neuronal cells ( Lin and Hsueh, 2008 ;Patrakitkomjorn, et al., 2008).", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "565d292b-b748-47f0-96e2-ddf3692f55ec" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -5873380749386771366 }, { "source_api": "reach", "pmid": "18313395", "text": "Immunoprecipitation immunoblotting analysis confirmed the interactions between neurofibromin and CRMP-2 and CRMP-4, but not CRMP-1, in rat brain.", "annotations": { "found_by": "binding11", "agents": { "coords": [ [ 79, 92 ], [ 97, 103 ] ], "raw_text": [ "CRMP-2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP-2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "13320613-e664-4fa0-b210-c9856c053e27" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "18313395", "DOI": "10.1016/J.BBRC.2008.02.095", "TRID": 483849 }, "source_hash": 5444511777963011811 }, { "source_api": "sparser", "pmid": "30915713", "text": "Neurofibromin,\nthe protein encoded by NF1 , interacts with CRMP2 and\nregulates its phosphorylation during neuronal polarity establishment [ xref ].", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "Neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "Neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "410b1b34-9650-435c-ade3-41b3208b1702" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": 9158387733400072320 }, { "source_api": "sparser", "pmid": "28767512", "text": "And although it was previously reported that CRMP2 binds to neurofibromin, xref the functional consequence of a connection between a CRMP2/neurofibromin interaction and a CRMP2/Cav2.2 interaction is an open question, despite reports that Cav2.2 mRNA and currents are increased in sensory neurons with reduced neurofibromin levels. xref , xref We hypothesized that the CRMP2/neurofibromin interaction could be preventing CRMP2 from interacting with protein partners involved in Cav2.2 trafficking and that t-CNRP1 could inhibit these interactions.", "annotations": { "found_by": "BINDING", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "31271721-bdf5-4ce3-93a3-712c44ff1bba" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -5955889937924025494 }, { "source_api": "sparser", "pmid": "28767512", "text": "The rationale for probing for the phosphorylated forms of CRMP2 was guided by previous reports of the CRMP2\u2013neurofibromin interaction regulating CRMP2\u2019s phosphorylation status. xref This resulted in the identification of 3 neurofibromin peptides that highly bound CRMP2 or phosphorylated CRMP2 ( xref and xref , available online at); these were designated as neurofibromin\u2013CRMP2 regulating peptides (NCRPs 1\u20133) ( xref ).", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "4346fcdd-3e18-4972-bd02-103807b7986d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -6683830430183669619 }, { "source_api": "sparser", "pmid": "29655575", "text": "These observations suggested that the loss of protein-protein interactions (PPIs) between CRMP2 and neurofibromin might explain NF1-related pain.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "f0d95a91-9394-44a5-8d7a-ec103abbf610" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -1573197246651856610 }, { "source_api": "sparser", "pmid": "28767512", "text": "Here, we investigated the function of neurofibromin\u2013CRMP2 interaction on Cav2.2.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "4ee0f9ce-3ead-4ba1-a9d4-d07eb8b0cd08" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "28767512", "PMCID": "PMC6359908", "DOI": "10.1097/J.PAIN.0000000000001026", "MANUSCRIPT_ID": "NIHMS1008507", "TRID": 5370115 }, "source_hash": -2604822415775104239 }, { "source_api": "reach", "pmid": "22449146", "text": "Through its C-terminal domain, neurofibromin interacts with collapsing response mediator proteins, CRMP-2 and CRMP-4 [XREF_BIBR, XREF_BIBR].", "annotations": { "found_by": "binding13", "agents": { "coords": [ [ 31, 44 ], [ 99, 105 ] ], "raw_text": [ "CRMP-2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP-2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "3cf32839-d773-474b-8de3-3bf193756aec" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0043197" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0000540" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "22449146", "PMCID": "PMC3326706", "DOI": "10.1186/1423-0127-19-33", "TRID": 4340591 }, "source_hash": -1513484932373039171 }, { "source_api": "sparser", "pmid": "29655575", "text": "Also, CRMP2\u2019s interaction with syntaxin 1A, which is augmented when CRMP2\u2019s interaction with neurofibromin is lost ( xref ), could aid in docking of synaptic vesicles directly to these channels.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "7a21685f-0c48-4566-bc47-cead78e50f2a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 5972989463975780739 }, { "source_api": "sparser", "pmid": "29655575", "text": "The CRMP2-neurofibromin interaction likely regulates CRMP2 functions by ( i ) modifying CRMP2\u2019s post-translational state (Moutal, et al., 2017f;Patrakitkomjorn, et al., 2008) and ( ii ) controlling CRMP2\u2019s interactome [33].", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "eec12378-fee7-4166-9c9a-a560cc26e57d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 7476500357016320513 }, { "source_api": "sparser", "pmid": "29655575", "text": "The functional association of neurofibromin and CRMP2 was reported to be essential for neuronal cell differentiation; lack of expression or abnormal regulation of neurofibromin resulted in impaired function of neuronal cells ( xref ; xref ).", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "3ff6b165-b913-46bf-9eaa-597ce7d6b57a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": -8909045307923217482 }, { "source_api": "sparser", "pmid": "18218617", "text": "CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation.", "annotations": { "found_by": "BINDING", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP-2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP-2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "90a5402b-42bf-4a13-b97d-3dd90bd4d792" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "18218617", "DOI": "10.1074/JBC.M708206200", "TRID": 18126414 }, "source_hash": -2316801975422009371 }, { "source_api": "reach", "pmid": "29655575", "text": "These observations suggested that the loss of protein protein interactions (PPIs) between CRMP2 and neurofibromin might explain NF1 related pain.", "annotations": { "found_by": "binding11", "agents": { "coords": [ [ 90, 95 ], [ 100, 113 ] ], "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "UP": "Q16555", "HGNC": "3014", "TEXT": "CRMP2", "EGID": "1808" }, { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" } ] }, "prior_hash": 325259531219378, "prior_uuids": [ "076cd975-fe23-4ec3-8300-ad0f12992ec1" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "cell_type": { "name": null, "db_refs": { "CL": "CL:0000540" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10116" } }, "type": "bio" }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": "S0306-4522(18)30253-7", "MANUSCRIPT_ID": "NIHMS966004", "TRID": 28497380 }, "source_hash": 8091529904646359585 }, { "source_api": "sparser", "pmid": "29655575", "text": "Also, CRMP2\u2019s interaction with syntaxin 1A, which is augmented when CRMP2\u2019s interaction with neurofibromin is lost (Moutal, et al., 2017e), could aid in docking of synaptic vesicles directly to these channels.", "annotations": { "found_by": "INTERACT", "prior_hash": 325259531219378, "agents": { "raw_text": [ "CRMP2", "neurofibromin" ], "raw_grounding": [ { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" }, { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "d7f086f5-ea3c-41bb-9571-6f48547eae2e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 42, "stmt_hash": 325259531219378, "belief": 1, "source_counts": { "sparser": 28, "reach": 13, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "29655575", "PMCID": "PMC5963520", "DOI": "10.1016/J.NEUROSCIENCE.2018.04.002", "PII": 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"text_refs": { "PMID": "29847659", "PMCID": "PMC5963003", "DOI": "10.1167/IOVS.17-22588", "TRID": 28886422 }, "source_hash": -1377301384471867030 }, { "source_api": "sparser", "pmid": "32697994", "text": "In the ternary complex structure of SPRED1-NF1-KRAS, GMPPNP-bound KRAS is bound to the GAPc domain of NF1(GRD) and provides the ground-state conformation of the NF1-KRAS complex.", "annotations": { "found_by": "BINDING", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "f9633bfc-3f3b-45e6-b3f0-15eccd05b367" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { "sparser": 24, "reach": 2, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 3943892351670505190 }, { "source_api": "sparser", "pmid": "32697994", "text": "This allows a comparison between the transition-state structure of HRAS-RASA1(GAP334) and the ground-state structure of KRAS-NF1(GAP328).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "16c365e9-519f-438e-929c-d833824e3eab" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { "sparser": 24, "reach": 2, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": 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"S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 7751285310786740116 }, { "source_api": "sparser", "pmid": "32697994", "text": "The structural comparison between NF1-KRAS(GMPPNP) and RASA1-HRAS(GDP-AlF 3 ) complexes showed the presence of five strong salt-bridge interactions in the NF1-KRAS complex spanning the protein-protein interface, whereas the RASA1-HRAS complex has only two such interactions at its interface ( xref and xref ).", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "7994d557-a959-4914-8680-54705d5ed59c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { "sparser": 24, "reach": 2, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 8125962935820614659 }, { "source_api": "sparser", "pmid": "32697994", "text": "Mapping the insertion site on the SPRED1-NF1-KRAS complex suggest that the inserted region does not directly affect either the NF1-SPRED1 interface or the NF1-KRAS interface.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "31fc8f69-2fbb-40c6-94b8-a6e226c29cc9" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { 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"text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 7618696899594542886 }, { "source_api": "sparser", "pmid": "32697994", "text": "Unlike the substitution of residues located on the edge of the interface, point mutants of NF1 residues present in the center of the protein-protein interface had a significant effect on NF1-KRAS interaction.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "e1f7e180-8678-40af-b66e-ffbe0a6d7a6e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { "sparser": 24, "reach": 2, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 3389783118229327356 }, { "source_api": "sparser", "pmid": "32697994", "text": "The structural superposition of NF1(GRD) in the ternary complex and apo-NF1(GRD) (PDB: 1NF1) shows no structural rearrangement at the NF1-KRAS interface, suggesting that KRAS binding does not cause any major allosteric effects on NF1.", "annotations": { "found_by": "BIO-COMPLEX", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "5c5b065a-4c2c-472b-b8b8-4f4ec36e1380" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, 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xref ).", "annotations": { "found_by": "BINDING", "prior_hash": 1712547623720672, "agents": { "raw_text": [ "KRAS", "NF1" ], "raw_grounding": [ { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "KRAS" }, { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "18abacb2-f9d4-4afb-b87e-cc813ff845ae" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 27, "stmt_hash": 1712547623720672, "belief": 1, "source_counts": { "sparser": 24, "reach": 2, "isi": 1 }, "internal": true } }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": 3499535120722050325 }, { "source_api": "sparser", "pmid": "32697994", "text": "Point-mutation studies suggest that the residues located in the central part of the NF1-KRAS interface play a more significant role in the complex formation 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{ "UP": "Q16584", "HGNC": "6850", "TEXT": "MLK3", "EGID": "4296" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": -17533316209106298, "prior_uuids": [ "396407c9-bc21-4b11-9460-57ca0a18e29c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "cell_line": { "name": null, "db_refs": { "CELLOSAURUS": "CVCL_0045" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", "MANUSCRIPT_ID": "NIHMS231829", "TRID": 25682461 }, "source_hash": -3169267130793029556 }, { "source_api": "sparser", "pmid": "16537381", "text": "Finally, we demonstrate that merlin and MLK3 can interact in situ and that merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1.", "annotations": { "found_by": "INTERACT", "prior_hash": -17533316209106298, "agents": { "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "TEXT": "MLK3", "HGNC": "6850", "EGID": "4296", "UP": "Q16584" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "a42c1df6-22ad-457a-a3f7-eb52eb62e8ac" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "16537381", "PMCID": "PMC1450194", "DOI": "10.1073/PNAS.0510651103", "TRID": 18676107 }, "source_hash": 545867861544567803 }, { "source_api": "sparser", "pmid": "20890305", "text": "To identify the region of merlin required for the MLK3-merlin interaction, and to determine whether merlin interacts directly with MLK3, in vitro binding assays were performed with GST-merlin deletion mutants ( xref ) and His-MLK3 proteins purified from bacteria.", "annotations": { "found_by": "INTERACT", "prior_hash": -17533316209106298, "agents": { "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "TEXT": "MLK3", "HGNC": "6850", "EGID": "4296", "UP": "Q16584" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "f78113a8-e327-40f5-8bb0-3dc6be056c5d" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", "MANUSCRIPT_ID": "NIHMS231829", "TRID": 25682461 }, "source_hash": 4762331102901181664 }, { "source_api": "sparser", "pmid": "20890305", "text": "These results indicate that phosphorylation of merlin on Ser518 impairs the interaction between merlin and MLK3 and the inhibition of MLK3 activity by merlin.", "annotations": { "found_by": "INTERACT", "prior_hash": -17533316209106298, "agents": { "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "TEXT": "MLK3", "HGNC": "6850", "EGID": "4296", "UP": "Q16584" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "40cadcf4-e1fd-4b50-82dd-8cc1612f147c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", "MANUSCRIPT_ID": "NIHMS231829", "TRID": 25682461 }, "source_hash": 8712937716493515017 }, { "source_api": "sparser", "pmid": "20890305", "text": "Here, we demonstrate that endogenous MLK3 and merlin are also associated in situ and co-immunoprecipitate from human TOV21G ovarian tumor cells ( xref ).", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": -17533316209106298, "agents": { "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "TEXT": "MLK3", "HGNC": "6850", "EGID": "4296", "UP": "Q16584" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "d833ea0d-6a79-4094-9e49-1e33da50f203" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", "MANUSCRIPT_ID": "NIHMS231829", "TRID": 25682461 }, "source_hash": -5230211898355550595 }, { "source_api": "reach", "pmid": "20890305", "text": "To determine whether the C-terminal region of merlin that bound to MLK3 was sufficient for the inhibition of MLK3 activity, increasing quantities of purified GST-merlin (residues 340-590) were incubated with FLAG-MLK3-wild-type (WT) or a FLAG-MLK3-kinase dead (KD) K144R mutant, and a MLK3 kinase assay was performed.", "annotations": { "found_by": "binding1b", "agents": { "coords": [ [ 46, 52 ], [ 67, 71 ] ], "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "UP": "Q16584", "HGNC": "6850", "TEXT": "MLK3", "EGID": "4296" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": -17533316209106298, "prior_uuids": [ "19d8a9e8-9255-4631-97b4-876a399b342f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", 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7281080834925536070 }, { "source_api": "sparser", "pmid": "20890305", "text": "The C-terminus of merlin interacts with MLK3 and inhibits MLK3 kinase activity.", "annotations": { "found_by": "INTERACT", "prior_hash": -17533316209106298, "agents": { "raw_text": [ "MLK3", "merlin" ], "raw_grounding": [ { "TEXT": "MLK3", "HGNC": "6850", "EGID": "4296", "UP": "Q16584" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "8a7758b2-91b5-4b8f-9f94-b215afff5f53" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 12, "stmt_hash": -17533316209106298, "belief": 1, "source_counts": { "sparser": 10, "reach": 2 }, "internal": true } }, "text_refs": { "PMID": "20890305", "PMCID": "PMC3017676", "DOI": "10.1038/ONC.2010.453", "MANUSCRIPT_ID": "NIHMS231829", "TRID": 25682461 }, "source_hash": 301464493157546515 }, { "source_api": "sparser", "pmid": "20890305", "text": "Our results demonstrate that merlin and MLK3 are 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"section_type": null }, "text_refs": { "PMID": "30158278", "DOI": "10.1183/16000617.0053-2018", "PII": "180053", "TRID": 29292264 }, "source_hash": -2448972928252643586 } ], "id": "77484600-5d7b-4648-9b91-4fca0ca2c798", "matches_hash": "17454657599614565" }, { "type": "Complex", "members": [ { "name": "NF1", "db_refs": { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } }, { "name": "PTCH1", "db_refs": { "TEXT": "PTCH", "HGNC": "9585", "UP": "Q13635", "EGID": "5727" } } ], "belief": 0.17982065390150026, "evidence": [ { "source_api": "sparser", "pmid": "19083227", "text": "Epidemiologic studies of children with inherited cancer predisposition syndromes, such as retinoblastoma (Rb) caused by mutations in the RB1 tumor suppressor gene, Li-Fraumeni (LFS) caused by mutations in the p53 gene, neurofibromatosis type 1 associated with mutations in the NF1 gene, and nevoid basal cell carcinoma syndrome characterized by mutations in the PTCH gene provide examples of pediatric 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assay with the baculoviral purified FAK ( xref , left panel).", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "NF1", "FAK" ], "raw_grounding": [ { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "2423e009-3c20-4ebd-8814-1d284bfde2f1" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -8517246601628641673 }, { "source_api": "reach", "pmid": "19479903", "text": "Then we show that neurofibromin interacts directly with FAK and mapped this interaction to the N-terminal domain of FAK by immunoprecipitation and pull-down assays.", "annotations": { "found_by": "binding13", "agents": { "coords": [ [ 18, 31 ], [ 56, 59 ] ], "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "3e631360-3297-48d2-bc9a-ec7b6b8c5625" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005925" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0000066" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10090" } }, "type": "bio" }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -151534743844415364 }, { "source_api": "sparser", "pmid": "19479903", "text": "Thus, C-terminal domain of NF1 specifically interacts with endogenous FAK.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "NF1", "FAK" ], "raw_grounding": [ { "TEXT": "NF1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "0c234cf3-e009-4818-a370-39c230ca89db" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -7933668260180606153 }, { "source_api": "sparser", "pmid": "19479903", "text": "Then we show that neurofibromin interacts directly with FAK and mapped this interaction to the N-terminal domain of FAK by immunoprecipitation and pull-down assays.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "2d9981cb-fe0f-4d5f-8f31-d1c93c4a243f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -7248420713681524002 }, { "source_api": "sparser", "pmid": "19479903", "text": "These results demonstrate that neurofibromin interacts with the N-terminal domain of FAK.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "39423a36-f554-4dd4-b8a0-96cab5bb664b" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 8718014191831764298 }, { "source_api": "sparser", "pmid": "19479903", "text": "To determine that C-terminal domain of neurofibromin directly interacts with FAK, we generated the GST-NF1, containing the C-terminal part of neurofibromin, called GST-NF1-CD.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "b40ac3a5-20f9-44db-b5df-811e1c5d923f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 6713429732166448299 }, { "source_api": "sparser", "pmid": "19479903", "text": "We have shown a novel interaction of neurofibromin and FAK in vitro and in vivo , their co-localization and distribution inside the cells, and demonstrate that inhibition of FAK has differential effect on adhesion inNf1 \u2212 / \u2212 andNf1 + / + cells, suggesting that FAK and NF1 interaction can play significant role in the intracellular signaling and carcinogenesis.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "e98b4ab3-fbbb-40f4-9674-28a2fe728cd2" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 2110787201899101666 }, { "source_api": "sparser", "pmid": "19479903", "text": "We also detected binding of neurofibromin and FAK in normal and tumor Schwann cells.", "annotations": { "found_by": "BINDING", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "d8c96aed-284d-4ecf-9cc9-62fa3a7709e4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -7641294504728470917 }, { "source_api": "sparser", "pmid": "23082153", "text": "A direct interaction between Nf1 and FAK has also been described xref , suggesting a role of Nf1 in cell adhesion.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "Nf1", "FAK" ], "raw_grounding": [ { "TEXT": "Nf1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "8967ec50-1a99-4ff7-a34a-9a141876bb82" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 2900935831174539194 }, { "source_api": "reach", "pmid": "19479903", "text": "Thus, this is the first report demonstrating direct interaction between FAK and neurofibromin that can play an important role in cellular signaling.", "annotations": { "found_by": "binding11", "agents": { "coords": [ [ 72, 75 ], [ 80, 93 ] ], "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "89a461c2-3fa6-4357-b0f9-b4c068bff217" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "cell_line": { "name": null, "db_refs": { "CELLOSAURUS": "CVCL_K164" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0002573" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10090" } }, "type": "bio" }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -4311741702118819504 }, { "source_api": "reach", "pmid": "19479903", "text": "To check specificity of GST-NF1 binding with FAK, we used purified recombinant baculoviral GFP protein in the same pull-down assay with GST, GST-NF1-CD and GST-paxillin (XREF_FIG, right panel).", "annotations": { "found_by": "binding_token_1", "agents": { "coords": [ [ 24, 31 ], [ 45, 48 ] ], "raw_text": [ "GST-NF1", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "GST-NF1", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "49100c7d-c40b-492e-a87b-cd73c4adba31" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 5555559432650289429 }, { "source_api": "sparser", "pmid": "19479903", "text": "To determine whether FAK and neurofibromin (NF1) interact in vivo , we performed co-immunoprecipitation of FAK and NF1 in mouse embryonic fibroblasts (MEF) cells ( xref ).", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "7bc6681a-6329-4af4-9833-aaa0439727d7" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -6620482419768059812 }, { "source_api": "reach", "pmid": "19479903", "text": "By binding with FAK in the peri-nuclear region, neurofibromin may inhibit FAK transportation into the nucleus or recruitment to the focal adhesions or it may enhance FAK degradation via the ubiquitin-proteosome pathway that was recently reported to regulate neurofibromin levels in the cell [XREF_BIBR].", "annotations": { "found_by": "binding1b", "agents": { "coords": [ [ 48, 61 ], [ 16, 19 ] ], "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "38022acd-391a-44fa-aa84-cf2d13426cd6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": 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"raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "c4140e1c-c12c-47f7-bafc-9bd219f42eb6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "cell_line": { "name": null, "db_refs": { "CELLOSAURUS": "CVCL_K164" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0002573" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10090" } }, "type": "bio" }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 7403996890471563235 }, { "source_api": "sparser", "pmid": "19479903", "text": "To demonstrate interaction of FAK and neurofibromin in human cell lines, we performed co-immunoprecipitation of FAK and neurofibromin in human BT474 breast cancer cells ( xref , left panels) and in human normal Schwann cells (pn97.4) and Schwann-derived MPNST cells (SNF02.2, SNF94.3) ( xref , right panels).", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "ef14176d-4f5c-4bec-b0f6-88be01790993" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 1591018724983781422 }, { "source_api": "sparser", "pmid": "19479903", "text": "Thus, endogenous FAK and neurofibromin interact in vivo .", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "defb8160-370c-45c0-a231-153e071a70c2" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -6348945591637802969 }, { "source_api": "sparser", "pmid": "19479903", "text": "We show that neurofibromin associates with the N-terminal domain of FAK, and that the C-terminal domain of neurofibromin directly interacts with FAK.", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "21bec098-cc5e-41ee-8b10-2a33ef6d320e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 3264253488289232613 }, { "source_api": "sparser", "pmid": "19479903", "text": "FAK and neurofibromin binding was not detected in control immunoprecipitations without antibody ( xref ).", "annotations": { "found_by": "BINDING", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "090be137-0832-49d2-af8c-d6f44338c730" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -8039965606248524222 }, { "source_api": "sparser", "pmid": "19479903", "text": "Neurofibromin interacts with the N-terminal domain of FAK in Vitro .", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "Neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "Neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "60311962-51aa-4b1b-949d-d4cbfc06bdb8" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 3901629553560820534 }, { "source_api": "reach", "pmid": "21855613", "text": "Neurofibromin also interacts with focal adhesion kinase (FAK) through a C-terminal region surrounding the NLS and can regulate FAK mediated substrate adherence in serum deprived cells via an unknown mechanism [XREF_BIBR].", "annotations": { "found_by": "binding6", "agents": { "coords": [ [ 0, 13 ], [ 127, 130 ] ], "raw_text": [ "Neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "Neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "669581b1-5d3b-4c74-9567-fcd9408b090a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005925" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0000127" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10090" } }, "type": "bio" }, "text_refs": { "PMID": "21855613", "PMCID": "PMC3263419", "DOI": "10.1016/J.BRAINRESBULL.2011.08.005", "MANUSCRIPT_ID": "NIHMS322799", "TRID": 17149807 }, "source_hash": -3273499015392874984 }, { "source_api": "reach", "pmid": "19479903", "text": "We also detected binding of neurofibromin and FAK in normal and tumor Schwann cells.", "annotations": { "found_by": "binding_of_and", "agents": { "coords": [ [ 28, 41 ], [ 46, 49 ] ], "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "UP": "P21359", "HGNC": "7765", "TEXT": "neurofibromin", "EGID": "4763" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_hash": 22863444323723422, "prior_uuids": [ "7b9d3944-743d-4486-a84b-a1f374a917f6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005925" } }, "cell_line": { "name": null, "db_refs": { "CELLOSAURUS": "CVCL_0179" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0002573" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -7158930819360091031 }, { "source_api": "sparser", "pmid": "19479903", "text": "Thus, the results demonstrate the novel interaction of neurofibromin and FAK and suggest their involvement in cell adhesion, cell growth, and other cellular events and pathways.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "424fc014-a3b6-4a83-9c3e-0539f9a619b7" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -9031100581811730684 }, { "source_api": "sparser", "pmid": "19479903", "text": "Since we demonstrated interaction between the N-terminal domain of FAK (FAK-NT) and neurofibromin, we performed phage display assay with the purified FAK-NT protein using a degenerate 7 amino acid phage library consisting of >2 \u00d7 10 9 peptide sequences (New England Biolabs).", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "e8f81dcb-e694-4773-855b-09101bbced5c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -6191193838005900789 }, { "source_api": "sparser", "pmid": "19479903", "text": "Using immunoprecipitation, we demonstrated association of FAK with neurofibromin inNf1 + / + MEF cells and BT474 cancer cells.", "annotations": { "found_by": "BIO-ASSOCIATE", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "8041737a-0b45-40a4-99e2-0a6fe1ab5477" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -4677053471119363664 }, { "source_api": "sparser", "pmid": "19479903", "text": "Thus, this is the first report demonstrating direct interaction between FAK and neurofibromin that can play an important role in cellular signaling.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "6ba18de0-f8f5-4c6d-aceb-65a7e9027348" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 9190199646671154114 }, { "source_api": "sparser", "pmid": "19479903", "text": "We did not detect binding of control GFP protein ( xref , right panel) with the GST-NF1-CD protein compared with the FAK protein ( xref , left panel), indicating the specificity of FAK and neurofibromin binding.", "annotations": { "found_by": "BINDING", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "56acf929-d2d4-48b7-bd64-ad360923226f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": -1101922904083348231 }, { "source_api": "sparser", "pmid": "19479903", "text": "Thus, the C-terminal domain of neurofibromin directly interacts with FAK in vitro .", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "90eecf4f-da0a-496e-b1d9-70f27e2f5aff" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 600679376504549770 }, { "source_api": "sparser", "pmid": "19479903", "text": "C-terminal domain of neurofibromin directly interacts with FAK in Vitro .", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "c86e89b3-ef11-4535-971c-41d822d7062f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, "source_counts": { "sparser": 23, "reach": 9 }, "internal": true } }, "text_refs": { "PMID": "19479903", "PMCID": "PMC2783617", "DOI": "10.1002/MC.20552", "MANUSCRIPT_ID": "NIHMS146169", "TRID": 23661211 }, "source_hash": 837051100732658551 }, { "source_api": "sparser", "pmid": "19479903", "text": "Because neurofibromin has been suggested to be important in many FAK signaling pathways such as focal adhesion formation, cell motility, and cytoskeletal reorganization [ xref ], and several other reports suggesting indirect link of FAK and NF1 [ xref ],[ xref ], we analyzed whether FAK and neurofibromin can interact directly.", "annotations": { "found_by": "INTERACT", "prior_hash": 26580761885233849, "agents": { "raw_text": [ "neurofibromin", "FAK" ], "raw_grounding": [ { "TEXT": "neurofibromin", "HGNC": "7765", "EGID": "4763", "UP": "P21359" }, { "UP": "Q05397", "HGNC": "9611", "EGID": "5747", "TEXT": "FAK" } ] }, "prior_uuids": [ "500b780c-8229-4f0f-8ba1-b8c038410181" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 32, "stmt_hash": 22863444323723422, "belief": 1, 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"internal": true } }, "text_refs": { "PMID": "18486129", "DOI": "10.1016/J.YEXCR.2008.03.019", "TRID": 18882139 }, "source_hash": 4255430533307750205 }, { "source_api": "sparser", "pmid": "12118253", "text": "Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2.", "annotations": { "found_by": "BINDING", "prior_hash": -5557644621293980, "agents": { "raw_text": [ "schwannomin", "paxillin" ], "raw_grounding": [ { "TEXT": "schwannomin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "UP": "P49023", "HGNC": "9718", "EGID": "5829", "TEXT": "paxillin" } ] }, "prior_uuids": [ "d163b37a-6f86-427f-b62b-73ffae387686" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 22, "stmt_hash": -5557644621293980, "belief": 1, "source_counts": { "reach": 6, "sparser": 16 }, "internal": true } }, "text_refs": { "PMID": "12118253", "DOI": "10.1038/NG930", "TRID": 27382316 }, "source_hash": -8969767420608382153 }, { "source_api": "sparser", "pmid": "18486129", "text": "Although it remains unknown whether RGB functionally associates with paxillin, it reminds us of the possible relationship between many small GTPase networks and the paxillin\u2013merlin interaction in neurite outgrowth.", "annotations": { "found_by": "INTERACT", "prior_hash": -5557644621293980, "agents": { "raw_text": [ "merlin", "paxillin" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "UP": "P49023", "HGNC": "9718", "EGID": "5829", "TEXT": "paxillin" } ] }, "prior_uuids": [ "12e2bdf3-541f-4411-8400-3c9c18e7f41f" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 22, "stmt_hash": -5557644621293980, "belief": 1, "source_counts": { "reach": 6, "sparser": 16 }, "internal": true } }, "text_refs": { "PMID": "18486129", "DOI": "10.1016/J.YEXCR.2008.03.019", "TRID": 18882139 }, "source_hash": -772830913383307216 }, { "source_api": "sparser", "pmid": "22247700", "text": "Paxillin binds schwannomin and regulates its\ndensity-dependent localization and effect on cell morphology.", "annotations": { "found_by": "BINDING", "prior_hash": -5557644621293980, "agents": { "raw_text": [ "schwannomin", "Paxillin" ], "raw_grounding": [ { "TEXT": "schwannomin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "TEXT": "Paxillin", "HGNC": "9718", "UP": "P49023", "EGID": "5829" } ] }, "prior_uuids": [ "3ba07202-fe90-4f30-9801-1a9314ebf7b7" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 22, "stmt_hash": -5557644621293980, "belief": 1, "source_counts": { "reach": 6, "sparser": 16 }, "internal": true } }, "text_refs": { "PMID": "22247700", "PMCID": "PMC3257450", "DOI": "10.1593/NEO.111060", "TRID": 8573546 }, "source_hash": 7102896783733417416 }, { "source_api": "reach", "pmid": "12118253", "text": "Paxillin binds schwannomin and regulates its density dependent localization and effect on cell morphology.", "annotations": { "found_by": "binding1b", "agents": { "coords": [ [ 0, 8 ], [ 15, 26 ] ], "raw_text": [ "schwannomin", "Paxillin" ], "raw_grounding": [ { "UP": "P35240", "HGNC": "7773", "TEXT": "schwannomin", "EGID": "4771" }, { "UP": "P49023", "HGNC": "9718", "TEXT": "Paxillin", "EGID": "5829" } ] }, "prior_hash": -5557644621293980, "prior_uuids": [ "a63eccf9-cb01-49cd-84fe-6081c7db8ad1" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 22, "stmt_hash": -5557644621293980, "belief": 1, "source_counts": { "reach": 6, "sparser": 16 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "12118253", "DOI": "10.1038/NG930", "TRID": 27382316 }, "source_hash": 5474444188770304511 }, { "source_api": "sparser", "pmid": "24393766", "text": "Interestingly, binding of merlin to ErbB2 is initiated by paxillin binding to merlin on exon 2 at residues 50-70, causing merlin to move to the plasma membrane where it binds ErbB2[ xref ].", "annotations": { "found_by": "BINDING", "prior_hash": -5557644621293980, "agents": { "raw_text": [ "merlin", "paxillin" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "UP": "P49023", "HGNC": "9718", "EGID": "5829", "TEXT": "paxillin" } ] }, "prior_uuids": [ "482e125b-6b54-463a-b13c-a2f98ca86a1a" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Complex", "evidence_count": 22, "stmt_hash": -5557644621293980, "belief": 1, "source_counts": { "reach": 6, "sparser": 16 }, "internal": true } }, "text_refs": { "PMID": "24393766", "PMCID": "PMC3960189", "DOI": "10.18632/ONCOTARGET.1557", "TRID": 12856661 }, "source_hash": -1796155787722746045 }, { "source_api": "sparser", "pmid": "12118253", "text": "Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology.", "annotations": { 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33, "ctd": 4, "drugbank": 4 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "17242161", "TRID": 25225260, "PMID_NUM": 17242161, "PMCID": "PMC2118736", "PMCID_NUM": 2118736, "DOI": "10.1084/JEM.20061617", "DOI_NS": 1084, "DOI_ID": "JEM.20061617", "TCID": 18989268, "SOURCE": "pmc_oa", "RID": 10100018989268, "READER": "REACH" }, "source_hash": -1808774938243252260 }, { "source_api": "sparser", "pmid": "24852729", "text": "Aspirin irreversibly inhibits cyclooxygenase-1 (COX-1) and thereby prevents the conversion of arachidonic acid (AA) to thromboxane A 2 (TxA 2 ), while clopidogrel irreversibly blocks adenosine diphosphate (ADP) receptor P2RY12 [ xref ].", "annotations": { "agents": { "raw_text": [ "Aspirin", "cyclooxygenase-1" ], "raw_grounding": [ { "TEXT": "Aspirin", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "MESH": "D001241", "HMDB": "HMDB0001879", "PUBCHEM": "2244", "CAS": "50-78-2", "CHEMBL": "CHEMBL25" }, { "TEXT": 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high, aspirin inhibits COX-1 and both COX-1/2, respectively, thereby blocking the formation of prostanoids.", "annotations": { "agents": { "raw_text": [ "aspirin", "COX-1 and both COX-1/2" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P23219", "HGNC": "9604", "MESH": "D051545", "TEXT": "COX-1 and both COX-1/2", "EGID": "5742" } ] }, "prior_uuids": [ "538d6427-1646-49e2-9164-c859c27ed0d4", "be2e8665-0ce8-401a-a4f7-7ca4245cf387" ], "content_source": "pmc_oa", "prior_hash": 11129124160206722, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 103, "stmt_hash": 11129124160206722, "belief": 1, "source_counts": { "reach": 62, "sparser": 33, "ctd": 4, "drugbank": 4 }, "internal": true } }, "text_refs": { "PMID": "26056460", "TRID": 2918807, "PMID_NUM": 26056460, "PMCID": "PMC4445694", 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"source_api": "reach", "pmid": "19960045", "text": "Finally in all conditions associated with a high platelet turnover (coronary artery bypass grafting, acute coronary syndrome (ACS), acute or chronic infection, or inflammation), low-dose aspirin is associated with a short half-life (15 to 20 minutes) and might not be able to suppress COX-1 in fresh platelets that are continuously and quickly released into the circulation in such stressful circumstances, leading to higher platelet reactivity (XREF_FIG) [XREF_BIBR - XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "aspirin", "COX-1" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P23219", "HGNC": "9604", "MESH": "D051545", "TEXT": "COX-1", "EGID": "5742" } ] }, "prior_uuids": [ "d72a7de2-1841-43ca-968b-c03e371b2e56", 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cysteinyl leukotrienes (Cys-LTs) [ xref - xref ].", "annotations": { "agents": { "raw_text": [ "aspirin", "COX-1" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "TEXT": "COX-1", "HGNC": "9604", "EGID": "5742", "UP": "P23219" } ] }, "prior_uuids": [ "383ca56b-2108-4a34-b431-fa3329ba4f8b", "be2e8665-0ce8-401a-a4f7-7ca4245cf387" ], "content_source": "pmc_oa", "prior_hash": 11129124160206722, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 103, "stmt_hash": 11129124160206722, "belief": 1, "source_counts": { "reach": 62, "sparser": 33, "ctd": 4, "drugbank": 4 }, "internal": true } }, "text_refs": { "PMID": "20525128", "TRID": 13781542, "PMID_NUM": 20525128, "PMCID": "PMC2868885", "PMCID_NUM": 2868885, "DOI": "10.1186/1710-1492-4-2-75", "DOI_NS": 1186, "DOI_ID": "1710-1492-4-2-75", "TCID": 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vitro experimental study and platelet aggregation rate may be fluctuant if the elapsed time after aspirin addition was not constant; therefore, preparation of washed platelets started 6min after aspirin addition.", "annotations": { "found_by": "Negative_activation_syntax_2_verb", "agents": { "raw_text": [ "aspirin", "COX-1" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P23219", "HGNC": "9604", "MESH": "D051545", "TEXT": "COX-1", "EGID": "5742" } ] }, "prior_uuids": [ "c0291084-d6ed-4f34-bdb3-81fe9b0db969", "be2e8665-0ce8-401a-a4f7-7ca4245cf387" ], "content_source": "pmc_oa", "prior_hash": 11129124160206722, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 103, "stmt_hash": 11129124160206722, "belief": 1, "source_counts": { "reach": 62, "sparser": 33, "ctd": 4, "drugbank": 4 }, 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"text": "Aspirin inhibits the cyclooxygenase (COX) enzymes COX-1 and COX-2, which synthesize inflammatory mediators like prostaglandins and thromboxanes .", "annotations": { "agents": { "raw_text": [ "Aspirin", "COX-1 and COX-2" ], "raw_grounding": [ { "TEXT": "Aspirin", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "MESH": "D001241", "HMDB": "HMDB0001879", "PUBCHEM": "2244", "CAS": "50-78-2", "CHEMBL": "CHEMBL25" }, { "UP": "P35354", "HGNC": "9605", "MESH": "D051546", "TEXT": "COX-1 and COX-2", "EGID": "5743" } ] }, "prior_uuids": [ "1eb41f87-bd7f-42ff-bae6-5b4bf613ef54", "4c0fd9a1-3397-4ea7-93cc-52c8655216eb" ], "content_source": "elsevier", "prior_hash": -15052582355557878, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 98, "stmt_hash": -15052582355557878, "belief": 1, "source_counts": { "reach": 62, "sparser": 30, "signor": 1, "ctd": 3, "drugbank": 2 }, "internal": true } }, "text_refs": { "PMID": "24613833", "TRID": 25733797, 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"READER": "REACH" }, "source_hash": 3667555107754398408 }, { "source_api": "reach", "pmid": "22292117", "text": "Aspirin also inhibits COX 2 but at higher doses than required for COX 1 inhibition [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Aspirin", "COX 2" ], "raw_grounding": [ { "PUBCHEM": "2244", "MESH": "D001241", "HMDB": "HMDB0001879", "CHEBI": "CHEBI:15365", "CHEMBL": "CHEMBL25", "CAS": "50-78-2", "DRUGBANK": "DB00945", "TEXT": "Aspirin" }, { "UP": "P35354", "HGNC": "9605", "MESH": "D051546", "TEXT": "COX 2", "EGID": "5743" } ] }, "prior_uuids": [ "cbe8969a-3fc4-419e-9ec2-02c982b5aa24", "4c0fd9a1-3397-4ea7-93cc-52c8655216eb" ], "content_source": "pmc_oa", "prior_hash": -15052582355557878, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 98, "stmt_hash": -15052582355557878, "belief": 1, "source_counts": { "reach": 62, "sparser": 30, "signor": 1, "ctd": 3, "drugbank": 2 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "22292117", "TRID": 2013615, "PMID_NUM": 22292117, "PMCID": "PMC3265119", "PMCID_NUM": 3265119, "DOI": "10.1155/2012/676237", "DOI_NS": 1155, "DOI_ID": "2012/676237", "TCID": 19523891, "SOURCE": "pmc_oa", "RID": 10100019523891, "READER": "REACH" }, "source_hash": 5003871858377109406 }, { "source_api": "reach", "pmid": "28418881", "text": "Aspirin may block the COX-2 enzyme to inhibit this process [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Aspirin", "COX-2" ], "raw_grounding": [ { "PUBCHEM": "2244", "MESH": "D001241", "HMDB": "HMDB0001879", "CHEBI": "CHEBI:15365", "CHEMBL": "CHEMBL25", "CAS": "50-78-2", "DRUGBANK": "DB00945", "TEXT": "Aspirin" }, { "UP": "P35354", "EGID": "5743", "HGNC": "9605", "TEXT": "COX-2" } ] }, "prior_uuids": [ "41f83bc4-e388-490a-838f-29dada21a9ee", "4c0fd9a1-3397-4ea7-93cc-52c8655216eb" ], 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that both NS398 and aspirin decreased the levels of COX-2 protein.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "aspirin", "COX-2" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P35354", "EGID": "5743", "HGNC": "9605", "TEXT": "COX-2" } ] }, "prior_uuids": [ "f47780c0-649d-4c8f-b295-c587ebd524df", "4c0fd9a1-3397-4ea7-93cc-52c8655216eb" ], "content_source": "pmc_oa", "prior_hash": -15052582355557878, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 98, "stmt_hash": -15052582355557878, "belief": 1, "source_counts": { "reach": 62, "sparser": 30, "signor": 1, "ctd": 3, "drugbank": 2 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "24395886", "TRID": 12852554, "PMID_NUM": 24395886, "PMCID": "PMC3892971", "PMCID_NUM": 3892971, "DOI": "10.1084/JEM.20131080", "DOI_NS": 1084, "DOI_ID": "JEM.20131080", "TCID": 18991389, "SOURCE": "pmc_oa", "RID": 10100018991389, "READER": "REACH" }, "source_hash": 657287580227901622 }, { "source_api": "reach", "pmid": "21304164", "text": "Around 17 million items for non steroidal anti-inflammatory drugs (NSAIDs) are prescribed annually in England alone.1 These drugs are associated with upper gastrointestinal complications.2 For example, each year, NSAIDs cause about 3,500 hospitalisations for, and 400 deaths from, ulcer bleeding in people aged 60 years or above.3 Aspirin, even in low doses, is also associated with gastrointestinal complications.4 5 Here we assess strategies for reducing gastrointestinal complications induced by NSAIDs, including aspirin and selective inhibitors of cyclo-oxygenase-2 (coxibs).", "annotations": { "found_by": "Negative_activation_syntax_3_noun", "agents": { "raw_text": [ "aspirin", "cyclo-oxygenase-2" ], 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"REACH" }, "source_hash": 3242489364596505854 }, { "source_api": "reach", "pmid": "22988348", "text": "[XREF_BIBR] But COX-2 mRNA and protein expression upregulation are reversible and can be inhibited by indomethacin and aspirin.", "annotations": { "found_by": "Negative_activation_syntax_2_verb", "agents": { "raw_text": [ "aspirin", "COX-2" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P35354", "EGID": "5743", "HGNC": "9605", "TEXT": "COX-2" } ] }, "prior_uuids": [ "52f0412c-7b80-4662-96d7-08b8f51cabcc", "4c0fd9a1-3397-4ea7-93cc-52c8655216eb" ], "content_source": "pmc_oa", "prior_hash": -15052582355557878, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 98, "stmt_hash": -15052582355557878, "belief": 1, "source_counts": { "reach": 62, "sparser": 30, "signor": 1, "ctd": 3, "drugbank": 2 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "22988348", "TRID": 10202806, "PMID_NUM": 22988348, "PMCID": "PMC3439794", "PMCID_NUM": 3439794, "DOI": "10.4103/0971-5851.99726", "DOI_NS": 4103, "DOI_ID": "0971-5851.99726", "TCID": 17965261, "SOURCE": "pmc_oa", "RID": 10100017965261, "READER": "REACH" }, "source_hash": 4969873637222588779 }, { "source_api": "sparser", "pmid": "25290692", "text": "As known, aspirin inhibits both COX-1 and COX-2; but it preferentially inhibits COX-1.", "annotations": { "agents": { "raw_text": [ "aspirin", "COX-1 and COX-2" ], "raw_grounding": [ { "PUBCHEM": "2244", "CHEBI": "CHEBI:15365", "DRUGBANK": "DB00945", "HMDB": "HMDB0001879", "MESH": "D001241", "CAS": "50-78-2", "CHEMBL": "CHEMBL25", "TEXT": "aspirin" }, { "UP": "P35354", "HGNC": "9605", "MESH": "D051546", "TEXT": "COX-1 and COX-2", "EGID": "5743" } ] }, "prior_uuids": [ "867a1b49-b344-4d28-95c3-9447e3b22fc2", 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{ "source_api": "sparser", "pmid": "30248132", "text": "Another study also reported that quercetin inhibits the Src- and Syk-mediated PI3K phosphorylation and subsequent TLR4/MyD88/PI3K complex formation, resulting in the reduced activation of downstream signaling [ xref ].", "annotations": { "agents": { "raw_text": [ "quercetin", "Src" ], "raw_grounding": [ { "CHEBI": "CHEBI:16243", "PUBCHEM": "5280343", "MESH": "D011794", "HMDB": "HMDB0005794", "CHEMBL": "CHEMBL50", "CAS": "117-39-5", "DRUGBANK": "DB04216", "TEXT": "quercetin" }, { "UP": "P12931", "HGNC": "11283", "EGID": "6714", "TEXT": "Src" } ] }, "prior_uuids": [ "69cf0d64-baf4-419c-aefc-cf296785e24a", "1703d573-e48e-4a31-8093-9c88750032d1" ], "content_source": "pmc_oa", "prior_hash": -4151302185560616, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 6, "stmt_hash": -4151302185560616, "belief": 0.566935658220623, "source_counts": { "reach": 4, "ctd": 1, "sparser": 1 }, 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could inhibit IL-6-induced activation of STAT3 in PATU-8988 cells.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "quercetin", "STAT3" ], "raw_grounding": [ { "CHEBI": "CHEBI:16243", "PUBCHEM": "5280343", "MESH": "D011794", "HMDB": "HMDB0005794", "CHEMBL": "CHEMBL50", "CAS": "117-39-5", "DRUGBANK": "DB04216", "TEXT": "quercetin" }, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "bae37a94-9d83-40bf-943b-c6a10f006d62", "e2ceea2c-222c-49a3-b965-a81ef87e3acf" ], "content_source": "pmc_oa", "prior_hash": 22150006738749236, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 22, "stmt_hash": 22150006738749236, "belief": 0.6129845980269941, "source_counts": { "reach": 21, "ctd": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "29026320", "TRID": 15731145, "PMID_NUM": 29026320, "PMCID": "PMC5626388", 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"annotations": { "agents": { "raw_text": [ "quercetin", "GSTP1" ], "raw_grounding": [ { "CHEBI": "CHEBI:16243", "PUBCHEM": "5280343", "MESH": "D011794", "HMDB": "HMDB0005794", "CHEMBL": "CHEMBL50", "CAS": "117-39-5", "DRUGBANK": "DB04216", "TEXT": "quercetin" }, { "TEXT": "GSTP1", "HGNC": "4638", "UP": "P09211", "EGID": "2950" } ] }, "prior_uuids": [ "1658579b-0732-4b9e-b000-b3ffb34d6552", "016b7a4e-f356-4389-95da-fc9f35fada23" ], "content_source": "pmc_oa", "prior_hash": -1166066650974058, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 17, "stmt_hash": -1166066650974058, "belief": 0.58974417056193, "source_counts": { "reach": 9, "sparser": 7, "ctd": 1 }, "internal": true } }, "text_refs": { "PMID": "26927197", "TRID": 12276778, "PMID_NUM": 26927197, "PMCID": "PMC4810398", "PMCID_NUM": 4810398, "DOI": "10.3390/BIOS6010006", "DOI_NS": 3390, "DOI_ID": "BIOS6010006", "PII": "E6", "TCID": 18809031, "SOURCE": "pmc_oa", "RID": 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Incubation of GSTP1-1 with 25 \u03bcM of quercetin results in a time-dependent inhibition, which is complete after 2 h.", "annotations": { "agents": { "raw_text": [ "quercetin", "GSTP1-1" ], "raw_grounding": [ { "CHEBI": "CHEBI:16243", "PUBCHEM": "5280343", "MESH": "D011794", "HMDB": "HMDB0005794", "CHEMBL": "CHEMBL50", "CAS": "117-39-5", "DRUGBANK": "DB04216", "TEXT": "quercetin" }, { "TEXT": "GSTP1-1", "HGNC": "4638", "UP": "P09211", "EGID": "2950" } ] }, "prior_uuids": [ "f41a6c59-0de3-43f7-a30a-6fa480e63944", "016b7a4e-f356-4389-95da-fc9f35fada23" ], "content_source": "elsevier", "prior_hash": -1166066650974058, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 17, "stmt_hash": -1166066650974058, "belief": 0.58974417056193, "source_counts": { "reach": 9, "sparser": 7, "ctd": 1 }, "internal": true } }, "text_refs": { "PMID": "12686490", "TRID": 3571424, "PMID_NUM": 12686490, "DOI": "10.1016/S0009-2797(02)00250-8", "DOI_NS": 1016, 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"type": "bio" }, "text_refs": { "PMID": "15041478" }, "source_hash": 7742307393048680193 }, { "source_api": "reach", "pmid": "12686490", "text": "The results of the present study reveal that quercetin is a potent inhibitor of human GSTP1-1 in vitro.Incubation of the wild-type enzyme with 25 muM of quercetin, resulted in complete inhibition of the enzyme activity which could be significantly prevented by the addition of ascorbic acid or GSH.", "annotations": { "found_by": "Negative_activation_copula_1", "agents": { "raw_text": [ "quercetin", "GSTP1-1" ], "raw_grounding": [ { "CHEBI": "CHEBI:16243", "PUBCHEM": "5280343", "MESH": "D011794", "HMDB": "HMDB0005794", "CHEMBL": "CHEMBL50", "CAS": "117-39-5", "DRUGBANK": "DB04216", "TEXT": "quercetin" }, { "UP": "P09211", "HGNC": "4638", "TEXT": "GSTP1-1", "EGID": "2950" } ] }, "prior_uuids": [ "6480a0da-560d-4c62-8b8e-8b213f576355", "016b7a4e-f356-4389-95da-fc9f35fada23" ], "content_source": "elsevier", "prior_hash": -1166066650974058, 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"7792388", "TRID": 1719073, "PMID_NUM": 7792388, "DOI": "10.1016/0090-6980(94)00009-L", "DOI_NS": 1016, "DOI_ID": "0090-6980(94)00009-L", "TCID": 21786953, "SOURCE": "elsevier", "RID": 10100021786953, "READER": "REACH" }, "source_hash": -5202923096167405541 }, { "source_api": "reach", "pmid": "9167213", "text": "Prostaglandins 53:91-106, 1997 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 0090-6980/97/$ 17.00 PII S0090-6980/97100002-6 Progesterone Suppresses Prostaglandin Synthesis : Hedin and Eriksson Keywords : Prostaglandin endoperoxide synthase-2; Prostaglandin endoperoxide synthase-1; PGEz; preovulatory follicles; progesterone; rat ovary Introduction The cyclic events leading to follicular development, ovulation and luteolysis in mammals demand an intricate interplay between endocrine, paracrine and autocrine factors (1).", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Progesterone", "Prostaglandin 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"RID": 10100020704767, "READER": "REACH" }, "source_hash": 5693364524615014911 }, { "source_api": "reach", "pmid": "29946321", "text": "Progesterone acts via GR to repress IL-1beta-driven COX-2 activation.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Progesterone", "COX-2" ], "raw_grounding": [ { "PUBCHEM": "5994", "HMDB": "HMDB0001830", "CHEMBL": "CHEMBL103", "CHEBI": "CHEBI:17026", "DRUGBANK": "DB00396", "MESH": "D011374", "CAS": "57-83-0", "TEXT": "Progesterone" }, { "UP": "P35354", "EGID": "5743", "HGNC": "9605", "TEXT": "COX-2" } ] }, "prior_uuids": [ "794bac1e-23a1-4975-8e69-96ce6d9b747a", "e2598e63-afb0-4f34-a6cb-4d3abe02f2f3" ], "content_source": "pmc_oa", "prior_hash": 30981535686732161, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 17, "stmt_hash": 30981535686732161, "belief": 0.6050047897284639, "source_counts": { "reach": 16, "ctd": 1 }, "internal": true } }, "epistemics": 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be responsible for progesterone repression of IL-1beta-induced COX-2 expression.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "progesterone", "COX-2" ], "raw_grounding": [ { "CHEBI": "CHEBI:17026", "PUBCHEM": "5994", "DRUGBANK": "DB00396", "MESH": "D011374", "HMDB": "HMDB0001830", "CAS": "57-83-0", "CHEMBL": "CHEMBL103", "TEXT": "progesterone" }, { "UP": "P35354", "EGID": "5743", "HGNC": "9605", "TEXT": "COX-2" } ] }, "prior_uuids": [ "c612a7e1-8a13-49c5-85e3-fa3827d84478", "e2598e63-afb0-4f34-a6cb-4d3abe02f2f3" ], "content_source": "pmc_oa", "prior_hash": 30981535686732161, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 17, "stmt_hash": 30981535686732161, "belief": 0.6050047897284639, "source_counts": { "reach": 16, "ctd": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "23209664", "TRID": 10674145, "PMID_NUM": 23209664, 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acute myeloid leukemia (AML) containing p53-system defects XREF_BIBR, XREF_BIBR, and multiple clinical trials are ongoing to evaluate DNMT1-depletion more broadly in cancer therapy (although decitabine and 5-azacytidine used to deplete DNMT1 have pharmacologic limitations which can undermine their ability to deplete-DNMT1 from solid tumors).", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "5-azacytidine", "DNMT1" ], "raw_grounding": [ { "PUBCHEM": "9444", "HMDB": "HMDB0015063", "MESH": "D001374", "LINCS": "LSM-5218", "CHEMBL": "CHEMBL1489", "CAS": "320-67-2", "HMS-LINCS": "10300", "CHEBI": "CHEBI:2038", "DRUGBANK": "DB00928", "TEXT": "5-azacytidine" }, { "UP": "P26358", "HGNC": "2976", "MESH": "D000076123", "TEXT": "DNMT1", "EGID": "1786" } ] }, "prior_uuids": [ "b7da6a0f-a5db-4fbd-9b74-a2be4b0d8710", "ebd9d3cc-b4e1-4fd5-ae49-af7de12f6fde" ], "content_source": "pmc_oa", "prior_hash": -22974513064316407, "indranet_edge": { "residue": null, 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{ "source_api": "sparser", "pmid": "29908298", "text": "Furthermore, to acquire evidence explaining the role of DNA methylation during HHcy in the expression of RANKL and OPG, we administered DNA methylation inhibitor 5-azacytidine (5\u2032-Aza) which specifically inhibits DNMTs in HHcy mice.", "annotations": { "agents": { "raw_text": [ "5-azacytidine", "DNMTs" ], "raw_grounding": [ { "TEXT": "5-azacytidine", "CHEBI": "CHEBI:2038", "PUBCHEM": "9444", "HMS-LINCS": "10300", "CHEMBL": "CHEMBL1489", "LINCS": "LSM-5218", "MESH": "D001374", "HMDB": "HMDB0015063", "CAS": "320-67-2", "DRUGBANK": "DB00928" }, { "TEXT": "DNMTs", "HGNC": "2976", "EGID": "1786", "UP": "P26358" } ] }, "prior_uuids": [ "b69f4833-cb84-41a3-a2b0-981dabab8302", "ebd9d3cc-b4e1-4fd5-ae49-af7de12f6fde" ], "content_source": "manuscripts", "prior_hash": -22974513064316407, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 48, "stmt_hash": -22974513064316407, "belief": 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[XREF_BIBR] have reported cilostazol reduces intracellular Abeta and phosphorylated tau levels in N2a cells stably expressing human APP Swedish mutation (N2aSwe cells), and in-line with these results, cilostazol significantly improved brain function such as spatial learning and memory in an experimental model of Alzheimer 's disease.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "cilostazol", "Abeta" ], "raw_grounding": [ { "PUBCHEM": "2754", "HMDB": "HMDB0015297", "MESH": "D000077407", "CHEBI": "CHEBI:31401", "CHEMBL": "CHEMBL799", "CAS": "73963-72-1", "DRUGBANK": "DB01166", "TEXT": "cilostazol" }, { "UP": "P05067", "CHEBI": "CHEBI:64645", "HGNC": "620", "EGID": "351", "TEXT": "Abeta" } ] }, "prior_uuids": [ "559890b6-378d-46bc-a939-90650955cdcb", "f877cd00-e962-4c49-9ba6-1aa7c871b3d6" ], "content_source": "pmc_oa", "prior_hash": 146033827603675, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", 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"text": "The aldosterone induced decrease in ouabain sensitive (86) Rb/K uptake was prevented by the new mineralocorticoid receptor antagonist eplerenone.", "annotations": { "found_by": "Negative_activation_token_1_noun", "agents": { "raw_text": [ "eplerenone", "mineralocorticoid receptor" ], "raw_grounding": [ { "PUBCHEM": "443872", "CAS": "107724-20-9", "HMDB": "HMDB0014838", "DRUGBANK": "DB00700", "MESH": "C058465", "CHEBI": "CHEBI:31547", "CHEMBL": "CHEMBL1095097", "TEXT": "eplerenone" }, { "UP": "P08235", "HGNC": "7979", "MESH": "D018161", "TEXT": "mineralocorticoid receptor", "EGID": "4306" } ] }, "prior_uuids": [ "8f06b874-5da2-4446-b2a2-04b7787218ef", "e315ff54-33bc-4bab-810e-b70330bd14e2" ], "content_source": "pubmed", "prior_hash": 7609453955589344, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 104, "stmt_hash": 7609453955589344, "belief": 1, "source_counts": { "reach": 95, "ctd": 5, "drugbank": 4 }, "internal": true } }, 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activation in different modes by a variety of TRPV1 antagonists.5, 16, 47 In this set-up, both A-1165901 and AMG7905 potently blocked activation of TRPV1 by capsaicin in a concentration dependent manner, with IC 50 values of 3.7 +/-1.4 and 29.3 +/-12.4 nmol L -1 respectively.", "annotations": { "found_by": "Positive_activation_token_2_noun", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "39f53d74-44bd-4342-a2de-afc8664100da", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pmc_oa", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, 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[transient receptor potential vanilloid type 1 (TRPV1) antagonist] but not FR172357 [3-bromo-8-[2,6-dichloro-3-[N [(E)-4-(N,N-dimethylcarbamoyl) cinnamidoacetyl]-N-methylamino] benzyloxy]-2-metylimidazo [1,2-a] pyridine; bradykinin B2 antagonist] or the EP1 antagonist.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "f043fbd6-30eb-4aed-9918-5aa05a82a5cc", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pubmed", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, 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current enhancement was blocked by PI3K inhibition.", "annotations": { "found_by": "Positive_early_activation", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "0f9fa636-64d5-4531-bb22-6a660ec1c18a", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pmc_oa", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, "source_counts": { "reach": 85, "tas": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "21152313", "TRID": 17752538, "PMID_NUM": 21152313, "PMCID": "PMC2996792", "PMCID_NUM": 2996792, "DOI": "10.3390/IJMS11103965", "DOI_NS": 3390, "DOI_ID": "IJMS11103965", "TCID": 18256453, "SOURCE": "pmc_oa", "RID": 10100018256453, "READER": "REACH" }, "source_hash": -350611811446863177 }, { "source_api": "reach", "pmid": "29393417", "text": "The results of the present study demonstrated that the amount of CGRP in the cell culture supernatant and the mRNA expression of CGRP-alpha and CGRP-beta in DRG maybe upregulated by rutaecarpine in a concentration dependent manner, and the effects of rutaecarpine were abolished by the TRPV1 antagonist capsaicin, indicating that the stimulatory effect of rutaecarpine on the synthesis and release of CGRP may be mediated by TRPV1.", "annotations": { "found_by": "Negative_activation_token_1_noun", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "26d7a0fe-cd79-4c54-a139-8c4e618c8797", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pmc_oa", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, "source_counts": { "reach": 85, "tas": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "29393417", "TRID": 28395402, "PMID_NUM": 29393417, "PMCID": "PMC5865982", "PMCID_NUM": 5865982, "DOI": "10.3892/MMR.2018.8494", "DOI_NS": 3892, "DOI_ID": "MMR.2018.8494", "TCID": 19514082, "SOURCE": "pmc_oa", "RID": 10100019514082, "READER": "REACH" }, "source_hash": -3065898215199134520 }, { "source_api": "reach", "pmid": "17540346", "text": "Resiniferatoxin (RTX; 2 microg/ml, 100 microl), an ultra potent analog of capsaicin, was injected locally into the left hindpaw to functionally inactivate TRPV-1 containing sensory terminals.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "capsaicin", "TRPV-1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV-1", "EGID": "7442" } ] }, "prior_uuids": [ "1b3596fe-8a74-4f00-b028-097514c8dd7d", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pubmed", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, "source_counts": { "reach": 85, "tas": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "17540346", "TRID": 15385222, "PMID_NUM": 17540346, "PMCID": "PMC1995562", "PMCID_NUM": 1995562, "DOI": "10.1016/J.BRAINRES.2007.04.065", "DOI_NS": 1016, "DOI_ID": "J.BRAINRES.2007.04.065", "TCID": 9725768, "SOURCE": "pubmed", "RID": 10100009725768, "READER": "REACH" }, "source_hash": -2041222259723692273 }, { "source_api": "reach", "pmid": "27227029", "text": "XREF_BIBR It is particularly interesting that induction of PKCbetaII in capsaicin sensitive DRG neurons reduced the activation threshold of TRPV1 to 36.8 degreesC XREF_BIBR providing evidence that TRPV1 could operate not only as a nociceptive transducer for signaling pain sensation but in other neurons or nerve terminals as a plasma membrane transducer molecule for signaling innocuous warm stimuli for thermoregulation.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "c54eccc0-ece1-40ef-a873-0bed4276f913", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pmc_oa", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, "source_counts": { "reach": 85, "tas": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "27227029", "TRID": 22952577, "PMID_NUM": 27227029, "PMCID": "PMC4843897", "PMCID_NUM": 4843897, "DOI": "10.1080/23328940.2015.1048928", "DOI_NS": 1080, "DOI_ID": "23328940.2015.1048928", "TCID": 19496910, "SOURCE": "pmc_oa", "RID": 10100019496910, "READER": "REACH" }, "source_hash": -6988216282377738488 }, { "source_api": "reach", "pmid": "24075930", "text": "Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1 independent mechanisms.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "CAS": "404-86-4", "CHEMBL": "CHEMBL294199", "DRUGBANK": "DB06774", "MESH": "D002211", "TEXT": "Capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ "bf7bcfd7-4944-47a9-bc88-629042f52e1e", "8cd64c38-84e6-46ba-9608-f52fa349d6e7" ], "content_source": "pubmed", "prior_hash": -33072706786674696, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 86, "stmt_hash": -33072706786674696, "belief": 0.6137113184389943, "source_counts": { "reach": 85, "tas": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, 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sensitivity to pain with LY379268 treatment has been noted following the injection of the inflammatory agent carrageenan into the footpad of mice or with the TRPV1 activator capsaicin.37 A similar analgesic effect is also observed with (2R, 4R)-4-aminopyrrolidin-2, 4-dicarboxylate, another Group II mGluR3 agonist.35 It was supposed that these mGluR2/3 agonists modulate the sensory receptors in the peripheral tissue and produce the analgesic effect.35 The results presented here suggest that activation of the group II mGlu2/3 receptor also occurs at the level of DRG.", "annotations": { "found_by": "Positive_activation_token_1_noun", "agents": { "raw_text": [ "capsaicin", "TRPV1" ], "raw_grounding": [ { "PUBCHEM": "1548943", "CHEBI": "CHEBI:3374", "HMDB": "HMDB0002227", "MESH": "D002211", "CAS": "404-86-4", "DRUGBANK": "DB06774", "CHEMBL": "CHEMBL294199", "TEXT": "capsaicin" }, { "UP": "Q8NER1", "HGNC": "12716", "TEXT": "TRPV1", "EGID": "7442" } ] }, "prior_uuids": [ 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"text": "Furthermore, P2Y12 receptor antagonists such as clopidogrel, ticagrelor, prasugrel and cangrelor have been shown to chemically block the adenosine diphosphate (ADP) receptors (P2Y12) [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_noun_Hearst", "agents": { "raw_text": [ "clopidogrel", "P2Y12" ], "raw_grounding": [ { "PUBCHEM": "60606", "HMDB": "HMDB0005011", "CHEBI": "CHEBI:37941", "CAS": "113665-84-2", "CHEMBL": "CHEMBL1771", "MESH": "D000077144", "DRUGBANK": "DB00758", "TEXT": "clopidogrel" }, { "UP": "Q9H244", "HGNC": "18124", "MESH": "D058925", "TEXT": "P2Y12", "EGID": "64805" } ] }, "prior_uuids": [ "76f8977d-da23-49ef-ac86-f74845adb06d", "412468e5-e8be-4cc2-8512-441c55b94fa8" ], "content_source": "pmc_oa", "prior_hash": -33896127956060615, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 101, "stmt_hash": -33896127956060615, "belief": 1, "source_counts": { "reach": 90, "eidos": 1, "drugbank": 9, 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"DOI_NS": 1093, "DOI_ID": "CVR/CVW089", "TCID": 17771881, "SOURCE": "pmc_oa", "RID": 10100017771881, "READER": "REACH" }, "source_hash": 7364662333002509732 }, { "source_api": "reach", "pmid": "28352337", "text": "Compared with other P2Y12 receptor antagonists such as clopidogrel or prasugrel, ticagrelor could, without metabolic activation, exert its effect immediately after oral administration with a median peak reaching time of 1.5 h, and combine with the P2Y12 receptor reversibly, resulting in a rapid recovery of platelets after drug withdrawal.", "annotations": { "found_by": "Negative_activation_syntax_noun_Hearst", "agents": { "raw_text": [ "clopidogrel", "P2Y12" ], "raw_grounding": [ { "PUBCHEM": "60606", "HMDB": "HMDB0005011", "CHEBI": "CHEBI:37941", "CAS": "113665-84-2", "CHEMBL": "CHEMBL1771", "MESH": "D000077144", "DRUGBANK": "DB00758", "TEXT": "clopidogrel" }, { "UP": "Q9H244", "HGNC": "18124", "MESH": "D058925", "TEXT": "P2Y12", "EGID": "64805" } ] }, "prior_uuids": [ "df92f1af-ded7-4d81-b70b-b78bf3c4b40e", "412468e5-e8be-4cc2-8512-441c55b94fa8" ], "content_source": "pmc_oa", "prior_hash": -33896127956060615, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 101, "stmt_hash": -33896127956060615, "belief": 1, "source_counts": { "reach": 90, "eidos": 1, "drugbank": 9, "ctd": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "28352337", "TRID": 20009206, "PMID_NUM": 28352337, "PMCID": "PMC5348695", "PMCID_NUM": 5348695, "DOI": "10.3892/ETM.2016.3987", "DOI_NS": 3892, "DOI_ID": "ETM.2016.3987", "TCID": 18635251, "SOURCE": "pmc_oa", "RID": 10100018635251, "READER": "REACH" }, "source_hash": -4681843151631070714 }, { "source_api": "reach", "pmid": "21479342", "text": "Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA).", "annotations": { "found_by": 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"text": "This suggests genes with premature clusters are more likely to be targets of active pausing at the +1 stable nucleosome.We next closely compared differential sensitivity of Pol II pausing at genes with or without premature clusters to experimental modulation of Pol II pause regulators : treatment with flavopiridol (an inhibitor of Cdk9 and Cdk12) or knockdown of DSIF and NELF, using previously published datasets (Rahl et al., 2010).", "annotations": { "found_by": "Negative_activation_syntax_7_noun", "agents": { "raw_text": [ "flavopiridol", "Cdk9" ], "raw_grounding": [ { "PUBCHEM": "5287969", "CHEMBL": "CHEMBL428690", "CHEBI": "CHEBI:47344", "HMS-LINCS": "10011", "CAS": "146426-40-6", "DRUGBANK": "DB03496", "LINCS": "LSM-1011", "TEXT": "flavopiridol", "MESH": "C077990" }, { "UP": "P50750", "HGNC": "1780", "MESH": "D042863", "TEXT": "Cdk9", "EGID": "1025" } ] }, "prior_uuids": [ "ea83842a-363e-41b6-aa56-60b9c790f543", "792a91a8-cc5c-4c60-a69f-91df94801c47" ], "content_source": 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but not in MMP-9 knockout mice. xref Our laboratory showed that minocycline potently inhibits MMP 9 in vitro and in brain at doses of 3 mg/kg. xref In a prospective, randomized placebo-controlled pilot study of submicrobial doses of doxycycline in patients with acute coronary syndrome, pro MMP-9 activity was reduced by 50% in doxycycline-treated patients. xref ", "annotations": { "agents": { "raw_text": [ "minocycline", "MMP 9" ], "raw_grounding": [ { "TEXT": "minocycline", "CHEBI": "CHEBI:50694", "PUBCHEM": "51537604", "CAS": "10118-90-8", "DRUGBANK": "DB01017", "HMS-LINCS": "10647", "HMDB": "HMDB0015152", "CHEMBL": "CHEMBL1434" }, { "UP": "P14780", "HGNC": "7176", "MESH": "D020780", "TEXT": "MMP 9", "EGID": "4318" } ] }, "prior_uuids": [ "599975a7-12ab-4be3-8651-e310b7c6c5f7", "5cd1683e-891a-45f8-96d9-6f5c04abb22d" ], "content_source": "manuscripts", "prior_hash": 18871278555963820, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 93, 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"sparser": 14, "ctd": 1, "drugbank": 5 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "27352957", "TRID": 27953127, "PMID_NUM": 27352957, "PMCID": "PMC4926223", "PMCID_NUM": 4926223, "DOI": "10.1038/SREP28548", "DOI_NS": 1038, "DOI_ID": "SREP28548", "TCID": 19324306, "SOURCE": "pmc_oa", "RID": 10100019324306, "READER": "REACH" }, "source_hash": -1988723331010864891 }, { "source_api": "reach", "pmid": "19628804", "text": "Minocycline treatment has been shown to decrease the disruption and leakage of the blood brain barrier [XREF_BIBR] and attenuate the enzymatic activity of the proteolytic enzyme MMP-9 following stimulation with vascular endothelial growth factor [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Minocycline", "MMP-9" ], "raw_grounding": [ { "PUBCHEM": "51537604", "CHEMBL": "CHEMBL1434", "CHEBI": "CHEBI:50694", "CAS": "10118-90-8", "DRUGBANK": "DB01017", 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triggers an ischemia resistant phenotype while minocycline inhibits PARP 1, microglial activation, peroxynitrite and MMP-9 (Hoda et al., 2014a).", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "minocycline", "MMP-9" ], "raw_grounding": [ { "PUBCHEM": "51537604", "CHEMBL": "CHEMBL1434", "CHEBI": "CHEBI:50694", "CAS": "10118-90-8", "DRUGBANK": "DB01017", "HMS-LINCS": "10647", "HMDB": "HMDB0015152", "MESH": "D008911", "TEXT": "minocycline" }, { "UP": "P14780", "EGID": "4318", "HGNC": "7176", "TEXT": "MMP-9" } ] }, "prior_uuids": [ "a5149787-5e39-4e24-8828-b15823e52521", "5cd1683e-891a-45f8-96d9-6f5c04abb22d" ], "content_source": "pmc_oa", "prior_hash": 18871278555963820, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 93, "stmt_hash": 18871278555963820, "belief": 0.9979762746954514, "source_counts": { "reach": 73, "sparser": 14, "ctd": 1, "drugbank": 5 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "26170804", "TRID": 11256675, "PMID_NUM": 26170804, "PMCID": "PMC4424736", "PMCID_NUM": 4424736, "DOI": "10.4103/1673-5374.155413", "DOI_NS": 4103, "DOI_ID": "1673-5374.155413", "TCID": 19631750, "SOURCE": "pmc_oa", "RID": 10100019631750, "READER": "REACH" }, "source_hash": -2845654457993354409 }, { "source_api": "sparser", "pmid": "28369077", "text": "As expected from previous research [ xref ], minocycline inhibited MMP-9 when present at high concentrations (>50 \u03bcM).", "annotations": { "agents": { "raw_text": [ "minocycline", "MMP-9" ], "raw_grounding": [ { "TEXT": "minocycline", "CHEBI": "CHEBI:50694", "PUBCHEM": "51537604", "CAS": "10118-90-8", "DRUGBANK": "DB01017", "HMS-LINCS": "10647", "HMDB": "HMDB0015152", "CHEMBL": "CHEMBL1434" }, { "UP": "P14780", "EGID": "4318", "HGNC": "7176", "TEXT": "MMP-9" } ] }, "prior_uuids": [ "8d3aaa64-fa8e-4e3a-a5b3-a9b7fd89b5c1", "5cd1683e-891a-45f8-96d9-6f5c04abb22d" ], 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"TRID": 13241879, "PMID_NUM": 20371721, "PMCID": "PMC2852467", "PMCID_NUM": 2852467, "DOI": "10.1158/1535-7163.MCT-09-0947", "DOI_NS": 1158, "DOI_ID": "1535-7163.MCT-09-0947", "MANUSCRIPT_ID": "NIHMS183899", "TCID": 19906829, "SOURCE": "manuscripts", "RID": 10100019906829, "READER": "REACH" }, "source_hash": 703274094092079989 }, { "source_api": "reach", "pmid": "25013907", "text": "Because p38 MAPK is activated by oxidative stress, sorafenib and sunitinib may inhibit STAT3 activity via negative regulation by p38 MAPK, and p38 MAPK inhibitor can ameliorate the cytotoxicity of sorafenib and sunitinib.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "sorafenib", "STAT3" ], "raw_grounding": [ { "PUBCHEM": "216239", "CHEBI": "CHEBI:50924", "MESH": "D000077157", "HMS-LINCS": "10008", "CHEMBL": "CHEMBL1336", "CAS": "284461-73-0", "HMDB": "HMDB0014542", "LINCS": "LSM-1008", "DRUGBANK": "DB00398", "TEXT": "sorafenib" }, { "UP": "P40763", "HGNC": 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protein kinase pathway in HaCaT cells, while sunitinib induced inhibition was not.", "annotations": { "found_by": "Positive_early_activation", "agents": { "raw_text": [ "sorafenib", "STAT3" ], "raw_grounding": [ { "PUBCHEM": "216239", "CHEBI": "CHEBI:50924", "MESH": "D000077157", "HMS-LINCS": "10008", "CHEMBL": "CHEMBL1336", "CAS": "284461-73-0", "HMDB": "HMDB0014542", "LINCS": "LSM-1008", "DRUGBANK": "DB00398", "TEXT": "sorafenib" }, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "546ac0a6-f19f-4580-aad1-5bd0921e6636", "58e32406-d1c0-4cac-b6b1-0b99407eeac8" ], "content_source": "elsevier", "prior_hash": -24970126905449120, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 76, "stmt_hash": -24970126905449120, "belief": 0.7680658834859738, "source_counts": { "reach": 74, "ctd": 1, "trips": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "25976912", "TRID": 21147976, "PMID_NUM": 25976912, "DOI": "10.1016/J.PHARMTHERA.2015.05.009", "DOI_NS": 1016, "DOI_ID": "J.PHARMTHERA.2015.05.009", "PII": "S0163-7258(15)00100-X", "TCID": 22569683, "SOURCE": "elsevier", "RID": 10100022569683, "READER": "REACH" }, "source_hash": -2617572680515592455 }, { "source_api": "reach", "pmid": "24418169", "text": "Sorafenib suppresses the activity of STAT3 through enhancing SHP-1 activity [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Sorafenib", "STAT3" ], "raw_grounding": [ { "PUBCHEM": "216239", "CHEBI": "CHEBI:50924", "MESH": "D000077157", "HMS-LINCS": "10008", "CHEMBL": "CHEMBL1336", "CAS": "284461-73-0", "HMDB": "HMDB0014542", "LINCS": "LSM-1008", "DRUGBANK": "DB00398", "TEXT": "Sorafenib" }, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "bb46ee35-0f45-4f45-a602-305a6773a66a", "58e32406-d1c0-4cac-b6b1-0b99407eeac8" ], "content_source": "pmc_oa", "prior_hash": -24970126905449120, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 76, "stmt_hash": -24970126905449120, "belief": 0.7680658834859738, "source_counts": { "reach": 74, "ctd": 1, "trips": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "24418169", "TRID": 26794366, "PMID_NUM": 24418169, "PMCID": "PMC3895679", "PMCID_NUM": 3895679, "DOI": "10.1186/1476-4598-13-7", "DOI_NS": 1186, "DOI_ID": "1476-4598-13-7", "TCID": 19507191, "SOURCE": "pmc_oa", "RID": 10100019507191, "READER": "REACH" }, "source_hash": -4131452980401006136 }, { "source_api": "reach", "pmid": "25013907", "text": "Sorafenib induced STAT3 inhibition was mediated by regulation via MAPK pathways in HaCaT cells, while sunitinib induced STAT3 inhibition was not.", "annotations": { "found_by": "Positive_early_activation", "agents": { "raw_text": [ "Sorafenib", "STAT3" ], "raw_grounding": [ { "PUBCHEM": "216239", "CHEBI": "CHEBI:50924", "MESH": "D000077157", "HMS-LINCS": "10008", "CHEMBL": "CHEMBL1336", "CAS": "284461-73-0", "HMDB": "HMDB0014542", "LINCS": "LSM-1008", "DRUGBANK": "DB00398", "TEXT": "Sorafenib" }, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "f64dfcb3-14f4-419b-81ed-3a80ecd1e8af", "58e32406-d1c0-4cac-b6b1-0b99407eeac8" ], "content_source": "pmc_oa", "prior_hash": -24970126905449120, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 76, "stmt_hash": -24970126905449120, "belief": 0.7680658834859738, "source_counts": { "reach": 74, "ctd": 1, "trips": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "25013907", "TRID": 23731172, "PMID_NUM": 25013907, "PMCID": "PMC4094497", "PMCID_NUM": 4094497, "DOI": "10.1371/JOURNAL.PONE.0102110", "DOI_NS": 1371, "DOI_ID": "JOURNAL.PONE.0102110", "TCID": 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"READER": "REACH" }, "source_hash": -1058719922121003586 }, { "source_api": "reach", "pmid": "23474115", "text": "Sorafenib enhances radiation induced apoptosis in hepatocellular carcinoma by inhibiting STAT3.", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "raw_text": [ "Sorafenib", "STAT3" ], "raw_grounding": [ { "PUBCHEM": "216239", "CHEBI": "CHEBI:50924", "MESH": "D000077157", "HMS-LINCS": "10008", "CHEMBL": "CHEMBL1336", "CAS": "284461-73-0", "HMDB": "HMDB0014542", "LINCS": "LSM-1008", "DRUGBANK": "DB00398", "TEXT": "Sorafenib" }, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "b3545dd8-446a-4c12-a0d6-7ef50241aba4", "58e32406-d1c0-4cac-b6b1-0b99407eeac8" ], "content_source": "pubmed", "prior_hash": -24970126905449120, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 76, "stmt_hash": -24970126905449120, "belief": 0.7680658834859738, "source_counts": { 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lipid and protein kinases (for example, LY294002 also inhibits mTOR, casein kinase 2 (CK2), DNA dependent protein kinase (DNA-PK) and others) [XREF_BIBR], and their unfavorable pharmaceutical properties, both wortmannin and LY294002 have served as important research tools for more than a decade in elucidating the role of PI3K in the biology of human cancer [XREF_BIBR - XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "LY294002", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "3973", "CHEMBL": "CHEMBL98350", "CAS": "154447-36-6", "DRUGBANK": "DB02656", "CHEBI": "CHEBI:65329", "HMS-LINCS": "10510", "TEXT": "LY294002", "MESH": "C085911" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "cdc3a639-68d9-4b9a-b89c-f686abc42cff", "464aa964-362a-4c55-a96b-ef542b559a78" ], "content_source": "pmc_oa", "prior_hash": 2664338488258222, "indranet_edge": { "residue": null, "position": null, "stmt_type": 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Furthermore, we found that the Akt inhibitor LY294002 restored SPC mediated downregulation of LC3 II and inhibited the activation of mTOR by SPC. Conclusions.", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "raw_text": [ "LY294002", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "3973", "CHEMBL": "CHEMBL98350", "CAS": "154447-36-6", "DRUGBANK": "DB02656", "CHEBI": "CHEBI:65329", "HMS-LINCS": "10510", "TEXT": "LY294002", "MESH": "C085911" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "b1e5f82f-f37a-4241-9c81-ac74756eb5c1", "464aa964-362a-4c55-a96b-ef542b559a78" ], "content_source": "pmc_oa", "prior_hash": 2664338488258222, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 68, "stmt_hash": 2664338488258222, "belief": 0.6946343798956595, "source_counts": { "reach": 66, "ctd": 1, "sparser": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "21838918", "TRID": 5110785, "PMID_NUM": 21838918, "PMCID": "PMC3166904", "PMCID_NUM": 3166904, "DOI": "10.1186/1423-0127-18-55", "DOI_NS": 1186, "DOI_ID": "1423-0127-18-55", "TCID": 18581501, "SOURCE": "pmc_oa", "RID": 10100018581501, "READER": "REACH" }, "source_hash": 9008193389747145423 }, { "source_api": "reach", "pmid": "28108737", "text": "LY294002 can inhibit both PI3K and mTOR but is generally considered a PI3K inhibitor.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "LY294002", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "3973", "CHEMBL": "CHEMBL98350", "CAS": "154447-36-6", "DRUGBANK": "DB02656", "CHEBI": "CHEBI:65329", "HMS-LINCS": "10510", "TEXT": "LY294002", "MESH": "C085911" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "a8f226bb-9769-4c4d-a567-490e0c877a8b", "464aa964-362a-4c55-a96b-ef542b559a78" ], "content_source": "pmc_oa", "prior_hash": 2664338488258222, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 68, "stmt_hash": 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"source_hash": 4938362032681332786 }, { "source_api": "reach", "pmid": "20513425", "text": "Although LY294002 can catalytically inhibit mTOR, this was not a concern as rapamycin was used in the same experiment.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "LY294002", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "3973", "CHEMBL": "CHEMBL98350", "CAS": "154447-36-6", "DRUGBANK": "DB02656", "CHEBI": "CHEBI:65329", "HMS-LINCS": "10510", "TEXT": "LY294002", "MESH": "C085911" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "456c4c1d-3cd1-4df7-b2d0-a6340ca634c9", "464aa964-362a-4c55-a96b-ef542b559a78" ], "content_source": "manuscripts", "prior_hash": 2664338488258222, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 68, "stmt_hash": 2664338488258222, "belief": 0.6946343798956595, "source_counts": { "reach": 66, "ctd": 1, "sparser": 1 }, "internal": true } 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found that another inhibitor PD98059 which only inhibits MEK1 modestly reduced mitochondrial mass and partially suppressed the expression of these genes ( supplemental data Fig. S6 ).", "annotations": { "agents": { "raw_text": [ "PD98059", "MEK1" ], "raw_grounding": [ { "PUBCHEM": "4713", "CAS": "167869-21-8", "HMS-LINCS": "10271", "LINCS": "LSM-3394", "CHEBI": "CHEBI:77954", "CHEMBL": "CHEMBL35482", "TEXT": "PD98059", "MESH": "C093973" }, { "UP": "Q02750", "EGID": "5604", "HGNC": "6840", "TEXT": "MEK1" } ] }, "prior_uuids": [ "9499ac74-3822-4eeb-847d-8f1c29cfc85b", "a5fc52d1-5e97-4557-ba93-9bb05ee6b782" ], "content_source": "elsevier", "prior_hash": -6692080735932599, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 45, "stmt_hash": -6692080735932599, "belief": 0.756430444585315, "source_counts": { "reach": 9, "sparser": 35, "signor": 1 }, "internal": true } }, "text_refs": { "PMID": "21458501", "TRID": 2570614, "PMID_NUM": 21458501, 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heart after myocardial infarction in mice than currently used beta-blocker therapy.", "annotations": { "found_by": "Negative_activation_syntax_5_verb", "agents": { "raw_text": [ "paroxetine", "GRK2" ], "raw_grounding": [ { "PUBCHEM": "43815", "CAS": "61869-08-7", "HMDB": "HMDB0014853", "CHEMBL": "CHEMBL490", "DRUGBANK": "DB00715", "MESH": "D017374", "CHEBI": "CHEBI:7936", "TEXT": "paroxetine" }, { "UP": "P25098", "HGNC": "289", "MESH": "D054769", "TEXT": "GRK2", "EGID": "156" } ] }, "prior_uuids": [ "213dcbd9-d9f3-4cd8-8bee-7625218fc6cf", "324fe54d-958e-41a7-87c6-abcad0a6831a" ], "content_source": "manuscripts", "prior_hash": 33002641564357844, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": 33002641564357844, "belief": 0.6618367054728057, "source_counts": { "reach": 22, "ctd": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "25995314", "TRID": 21167498, 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"READER": "REACH" }, "source_hash": -6998630892681302437 }, { "source_api": "reach", "pmid": "30206219", "text": "These results show that GRK2 inhibition by paroxetine from d-1 up to d2 results in a significant reduction of virus titers upon challenge with a lethal dose of pandemic H1N1, but is not potent enough to protect from weight loss, death or lung pathology.", "annotations": { "found_by": "Negative_activation_syntax_2_noun", "agents": { "raw_text": [ "paroxetine", "GRK2" ], "raw_grounding": [ { "PUBCHEM": "43815", "CAS": "61869-08-7", "HMDB": "HMDB0014853", "CHEMBL": "CHEMBL490", "DRUGBANK": "DB00715", "MESH": "D017374", "CHEBI": "CHEBI:7936", "TEXT": "paroxetine" }, { "UP": "P25098", "HGNC": "289", "MESH": "D054769", "TEXT": "GRK2", "EGID": "156" } ] }, "prior_uuids": [ "b21a9471-23ef-4923-ad49-b31d21a59e27", "324fe54d-958e-41a7-87c6-abcad0a6831a" ], "content_source": "cord19_pdf", "prior_hash": 33002641564357844, "indranet_edge": { "residue": null, "position": null, 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three translational states: 1) dividing cells, which have very active translation [polysome to monosome ratio (P:M) = 11.6], 2) contact-inhibited cells (P:M = 1.4), and 3) contact-inhibited cells under Torin1-induced mTOR inhibition (P:M = 0.4) ( xref ).", "annotations": { "agents": { "raw_text": [ "Torin1", "mTOR" ], "raw_grounding": [ { "TEXT": "Torin1", "CHEBI": "CHEBI:84327", "PUBCHEM": "49836027", "HMS-LINCS": "10079", "LINCS": "LSM-1079", "CHEMBL": "CHEMBL1256459", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "d0893ecd-a203-48ab-8eef-cd4160b6fadf", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "manuscripts", "prior_hash": -11337472130631534, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 88, "stmt_hash": -11337472130631534, "belief": 0.7945646209694207, "source_counts": { "sparser": 36, "reach": 47, "trips": 1, "tas": 1, "eidos": 3 }, "internal": true 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"RID": 20300054676008, "READER": "SPARSER" }, "source_hash": -7884798740890457118 }, { "source_api": "reach", "pmid": "25945839", "text": "Whole-exome sequencing of pretreatment and drug resistant tumors revealed a mutation in mTOR that conferred resistance to allosteric mTOR inhibition (everolimus), but the mutation remained sensitive to a direct ATP-competitive mTOR kinase inhibitor such as Torin1 [XREF_BIBR].", "annotations": { "found_by": "Negative_activation_syntax_noun_Hearst", "agents": { "raw_text": [ "Torin1", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "49836027", "HMS-LINCS": "10079", "CHEMBL": "CHEMBL1256459", "CHEBI": "CHEBI:84327", "LINCS": "LSM-1079", "TEXT": "Torin1", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "e5dab3f2-a75b-42d5-a0f5-0ead3e8f091e", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "pmc_oa", "prior_hash": -11337472130631534, "indranet_edge": { "residue": null, "position": null, 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8588459339096445591 }, { "source_api": "sparser", "pmid": "28102733", "text": "To test whether enhanced RPS6KB (p70) phospho-(T389) in PLK1-inhibited cells is consistent with MTORC1 activation, we combined PLK1 inhibition by BI2536 with MTOR inhibition by Torin1. xref Torin1 reduced RPS6KB (p70) T389 phosphorylation both in control and BI2536-treated cells ( xref ), consistent with the notion that increased RPS6KB (p70) phosphorylation at T389 in PLK1-inhibited cells is mediated by MTOR.", "annotations": { "agents": { "raw_text": [ "Torin1", "MTOR" ], "raw_grounding": [ { "TEXT": "Torin1", "CHEBI": "CHEBI:84327", "PUBCHEM": "49836027", "HMS-LINCS": "10079", "LINCS": "LSM-1079", "CHEMBL": "CHEMBL1256459", "MESH": "C553294" }, { "TEXT": "MTOR", "HGNC": "3942", "EGID": "2475", "UP": "P42345" } ] }, "prior_uuids": [ "7b4223da-8100-42f5-a006-e5ba7bce6d7f", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "pmc_oa", "prior_hash": -11337472130631534, "indranet_edge": { "residue": 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"mTOR" ], "raw_grounding": [ { "TEXT": "torin1", "CHEBI": "CHEBI:84327", "PUBCHEM": "49836027", "HMS-LINCS": "10079", "LINCS": "LSM-1079", "CHEMBL": "CHEMBL1256459", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "c0d43672-e149-41da-ad1f-c5118962643a", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "elsevier", "prior_hash": -11337472130631534, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 88, "stmt_hash": -11337472130631534, "belief": 0.7945646209694207, "source_counts": { "sparser": 36, "reach": 47, "trips": 1, "tas": 1, "eidos": 3 }, "internal": true } }, "text_refs": { "PMID": "29555211", "TRID": 28528543, "PMID_NUM": 29555211, "DOI": "10.1016/J.BBADIS.2018.03.013", "DOI_NS": 1016, "DOI_ID": "J.BBADIS.2018.03.013", "PII": "S0925-4439(18)30093-0", "TCID": 22585086, "SOURCE": "elsevier", "RID": 20300022585086, "READER": "SPARSER" }, "source_hash": -2342917972535963589 }, { "source_api": "reach", "pmid": "25813352", "text": "We used two mTOR inhibitors, Torin1 and Rapamycin, which target mTOR complex 1 and both mTOR complexes 1 and 2, respectively, and quantified the rate of BrdU incorporation.", "annotations": { "found_by": "Positive_activation_syntax_5_verb", "agents": { "raw_text": [ "Torin1", "mTOR" ], "raw_grounding": [ { "PUBCHEM": "49836027", "HMS-LINCS": "10079", "CHEMBL": "CHEMBL1256459", "CHEBI": "CHEBI:84327", "LINCS": "LSM-1079", "TEXT": "Torin1", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "5753261c-ca4b-45b6-bf31-712c7059459a", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "manuscripts", "prior_hash": -11337472130631534, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 88, "stmt_hash": -11337472130631534, "belief": 0.7945646209694207, "source_counts": { "sparser": 36, "reach": 47, "trips": 1, "tas": 1, "eidos": 3 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "25813352", "TRID": 8048254, "PMID_NUM": 25813352, "PMCID": "PMC4456277", "PMCID_NUM": 4456277, "DOI": "10.1158/2159-8290.CD-14-0921", "DOI_NS": 1158, "DOI_ID": "2159-8290.CD-14-0921", "MANUSCRIPT_ID": "NIHMS676551", "TCID": 19717698, "SOURCE": "manuscripts", "RID": 10100019717698, "READER": "REACH" }, "source_hash": 8946399194699651637 }, { "source_api": "sparser", "pmid": "28697336", "text": "Torin1 inhibits mTOR present in both mTORC1 and mTORC2.", "annotations": { "agents": { "raw_text": [ "Torin1", "mTOR" ], "raw_grounding": [ { "TEXT": "Torin1", "CHEBI": "CHEBI:84327", "PUBCHEM": "49836027", "HMS-LINCS": "10079", "LINCS": "LSM-1079", "CHEMBL": "CHEMBL1256459", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "aac39b6f-f73f-47e5-9969-300bf08680d9", 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significantly restored FLIP levels in p95HER2/611CTF cells.", "annotations": { "agents": { "raw_text": [ "torin1", "mTOR" ], "raw_grounding": [ { "TEXT": "torin1", "CHEBI": "CHEBI:84327", "PUBCHEM": "49836027", "HMS-LINCS": "10079", "LINCS": "LSM-1079", "CHEMBL": "CHEMBL1256459", "MESH": "C553294" }, { "UP": "P42345", "HGNC": "3942", "EGID": "2475", "TEXT": "mTOR" } ] }, "prior_uuids": [ "474425cc-c97e-441c-92f1-6acd1c6d6ef6", "13373fdc-0c7e-4489-871c-7615540289d7" ], "content_source": "pmc_oa", "prior_hash": -11337472130631534, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 88, "stmt_hash": -11337472130631534, "belief": 0.7945646209694207, "source_counts": { "sparser": 36, "reach": 47, "trips": 1, "tas": 1, "eidos": 3 }, "internal": true } }, "text_refs": { "PMID": "29212182", "TRID": 28194143, "PMID_NUM": 29212182, "PMCID": "PMC5706828", "PMCID_NUM": 5706828, "DOI": "10.18632/ONCOTARGET.21458", "DOI_NS": 18632, "DOI_ID": 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kinase activity of EGFR).", "annotations": { "found_by": "Negative_activation_syntax_7_noun", "agents": { "raw_text": [ "PD153035", "EGFR" ], "raw_grounding": [ { "PUBCHEM": "4705", "CHEBI": "CHEBI:91076", "CHEMBL": "CHEMBL29197", "CAS": "153436-54-5", "TEXT": "PD153035" }, { "UP": "P00533", "EGID": "1956", "HGNC": "3236", "TEXT": "EGFR" } ] }, "prior_uuids": [ "45567ed3-7cef-47d5-8138-40d8843840ec", "8a17f75c-4972-4a15-9fb2-498acc23a33f" ], "content_source": "pmc_oa", "prior_hash": -32837411713344460, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 42, "stmt_hash": -32837411713344460, "belief": 0.39198048877606706, "source_counts": { "reach": 26, "tas": 16 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "16899133", "TRID": 1354157, "PMID_NUM": 16899133, "PMCID": "PMC1559648", "PMCID_NUM": 1559648, "DOI": "10.1186/1475-2867-6-20", "DOI_NS": 1186, "DOI_ID": "1475-2867-6-20", 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genistein and the EGFR antagonist PD153035, indicating that contraction was, at least in part, attributable to PTKs phosphorylation that activates VR1, resulting in increased intracellular calcium content in the smooth muscle cells.", "annotations": { "found_by": "Negative_activation_token_1_noun", "agents": { "raw_text": [ "PD153035", "EGFR" ], "raw_grounding": [ { "PUBCHEM": "4705", "CHEBI": "CHEBI:91076", "CHEMBL": "CHEMBL29197", "CAS": "153436-54-5", "TEXT": "PD153035" }, { "UP": "P00533", "EGID": "1956", "HGNC": "3236", "TEXT": "EGFR" } ] }, "prior_uuids": [ "4e479fde-fe9b-4fee-ba04-a7af7dec1570", "8a17f75c-4972-4a15-9fb2-498acc23a33f" ], "content_source": "pubmed", "prior_hash": -32837411713344460, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 42, "stmt_hash": -32837411713344460, "belief": 0.39198048877606706, "source_counts": { "reach": 26, "tas": 16 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "16039679", "TRID": 16054668, "PMID_NUM": 16039679, "DOI": "10.1016/J.TAAP.2005.06.015", "DOI_NS": 1016, "DOI_ID": "J.TAAP.2005.06.015", "TCID": 10119269, "SOURCE": "pubmed", "RID": 10100010119269, "READER": "REACH" }, "source_hash": 7663420102427352935 }, { "source_api": "reach", "pmid": "25744849", "text": "We show here that treatment with EGFR antagonist PD153035 markedly inhibits AR induced hHSC proliferation (XREF_FIG), pointing for the first time to a role for EGFR in AR induced hHSC proliferation.", "annotations": { "found_by": "Negative_activation_token_1_noun", "agents": { "raw_text": [ "PD153035", "EGFR" ], "raw_grounding": [ { "PUBCHEM": "4705", "CHEBI": "CHEBI:91076", "CHEMBL": "CHEMBL29197", "CAS": "153436-54-5", "TEXT": "PD153035" }, { "UP": "P00533", "EGID": "1956", "HGNC": "3236", "TEXT": "EGFR" } ] }, "prior_uuids": [ "9a154e3c-c377-48ea-a15f-a96a1d40a8c0", "8a17f75c-4972-4a15-9fb2-498acc23a33f" ], "content_source": "pmc_oa", 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"annotations": { "found_by": "Negative_activation_token_1_noun", "agents": { "raw_text": [ "PD153035", "EGFR" ], "raw_grounding": [ { "PUBCHEM": "4705", "CHEBI": "CHEBI:91076", "CHEMBL": "CHEMBL29197", "CAS": "153436-54-5", "TEXT": "PD153035" }, { "UP": "P00533", "EGID": "1956", "HGNC": "3236", "TEXT": "EGFR" } ] }, "prior_uuids": [ "e7287043-6f47-4174-a541-7f141ec4d69c", "8a17f75c-4972-4a15-9fb2-498acc23a33f" ], "content_source": "elsevier", "prior_hash": -32837411713344460, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 42, "stmt_hash": -32837411713344460, "belief": 0.39198048877606706, "source_counts": { "reach": 26, "tas": 16 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "15191553", "TRID": 6827073, "PMID_NUM": 15191553, "DOI": "10.1111/J.0022-202X.2004.22731.X", "DOI_NS": 1111, "DOI_ID": "J.0022-202X.2004.22731.X", "TCID": 22498488, "SOURCE": "elsevier", "RID": 10100022498488, "READER": "REACH" }, "source_hash": -4876374818285783516 }, { "source_api": "reach", "pmid": "9815602", "text": "PD153035 caused a dose dependent growth inhibition of EGF receptor overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested.", "annotations": { "found_by": "Positive_activation_syntax_1_verb", "agents": { "raw_text": [ "PD153035", "EGF receptor" ], "raw_grounding": [ { "PUBCHEM": "4705", "CHEBI": "CHEBI:91076", "CHEMBL": "CHEMBL29197", "CAS": "153436-54-5", "TEXT": "PD153035" }, { "UP": "P00533", "EGID": "1956", "HGNC": "3236", "TEXT": "EGF receptor" } ] }, "prior_uuids": [ "f1cef573-76f2-48c2-ad2e-af11ed9bbb94", "8a17f75c-4972-4a15-9fb2-498acc23a33f" ], "content_source": "pubmed", "prior_hash": -32837411713344460, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 42, "stmt_hash": -32837411713344460, "belief": 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explore whether p53-R175H-induced PI3K and AKT signaling is mediated by EGFR activation, we pretreated KLE cells with specific EGFR tyrosine kinase inhibitor PD153035 (20 muM) for 2 h. 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true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "28250973", "TRID": 16401422, "PMID_NUM": 28250973, "PMCID": "PMC5327502", "PMCID_NUM": 5327502, "DOI": "10.1038/CDDISCOVERY.2017.13", "DOI_NS": 1038, "DOI_ID": "CDDISCOVERY.2017.13", "TCID": 17863379, "SOURCE": "pmc_oa", "RID": 10100017863379, "READER": "REACH" }, "source_hash": -6643621807382148428 }, { "source_api": "reach", "pmid": "24808358", "text": "Since necrostatin-1 has been shown to block not only RIPK1 but also indoleamine 2,3-dioxygenase (IDO), the IDO2 specific inhibitor 1-methyl-D-tryptophan (1-MT) was added to BMDC cultures as a control.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "necrostatin-1", "RIPK1" ], "raw_grounding": [ { "PUBCHEM": "2828334", "HMS-LINCS": "10403", "CHEBI": "CHEBI:91658", "CHEMBL": "CHEMBL195008", "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "HGNC": "10019", "TEXT": "RIPK1", "EGID": "8737" 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protected the same subset of sensitive tumor cell lines that we had used for analysis in Figure XREF_FIG d (resistant KNS-62 cells were again included as control) from both TRAIL/zVAD/CHX- and TNF/zVAD/CHX induced programmed necrosis.", "annotations": { "found_by": "Negative_activation_token_2_noun", "agents": { "raw_text": [ "necrostatin-1", "RIPK1" ], "raw_grounding": [ { "PUBCHEM": "2828334", "HMS-LINCS": "10403", "CHEBI": "CHEBI:91658", "CHEMBL": "CHEMBL195008", "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "HGNC": "10019", "TEXT": "RIPK1", "EGID": "8737" } ] }, "prior_uuids": [ "aa708725-287f-4c31-aa26-38dbfa1936ec", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 68, "stmt_hash": -11973237187754732, "belief": 0.9674704585548729, "source_counts": { "reach": 65, "signor": 1, "tas": 2 }, "internal": true } }, 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"DOI_NS": 1016, "DOI_ID": "J.BMCL.2016.12.056", "PII": "S0960-894X(16)31335-X", "MANUSCRIPT_ID": "NIHMS840221", "TCID": 19720853, "SOURCE": "manuscripts", "RID": 10100019720853, "READER": "REACH" }, "source_hash": -2126204359146659319 }, { "source_api": "reach", "pmid": "29760377", "text": "As dinaciclib might also inhibit CDK1 and cyclin B1, it was added to the cell culture at 3h following release from the M phase.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "4fe494e8-606a-450f-88ce-7a60a194c78a", "dddce5a7-39f6-40ce-885c-c620de450bf2" ], "content_source": "pmc_oa", "prior_hash": -22397166002887280, "indranet_edge": { 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"section_type": null }, "text_refs": { "PMID": "28077789", "TRID": 8457515, "PMID_NUM": 28077789, "PMCID": "PMC5370047", "PMCID_NUM": 5370047, "DOI": "10.18632/ONCOTARGET.14538", "DOI_NS": 18632, "DOI_ID": "ONCOTARGET.14538", "TCID": 17906612, "SOURCE": "pmc_oa", "RID": 10100017906612, "READER": "REACH" }, "source_hash": 5284467762603402898 }, { "source_api": "tas", "pmid": "28280261", "annotations": { "class_min": "Kd < 100nM", "agents": { "raw_text": [ null, null ], "raw_grounding": [ { "LSPCI": "97820", "HMS-LINCS": "10287", "PUBCHEM": "46926350", "LINCS": "LSM-6306", "DRUGBANK": "DB12021", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "MESH": "C553669" }, { "EGID": "983", "HGNC": "1722", "MESH": "D016203", "UP": "P06493" } ] }, "prior_uuids": [ "ef636691-0a5c-4101-9aeb-4067dd811067", "dddce5a7-39f6-40ce-885c-c620de450bf2" ], "prior_hash": -22397166002887280, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": 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"position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": -22397166002887280, "belief": 0.96908696272776, "source_counts": { "eidos": 1, "reach": 19, "tas": 2, "signor": 1 }, "internal": true } }, "epistemics": { "direct": true }, "context": { "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "source_hash": -125178270049944755 }, { "source_api": "reach", "pmid": "22430491", "text": "Dinaciclib inhibits CDK1, 2, 5, and 9 at concentrations of 1-5 nM, which can be readily achieved in vivo, and exhibits improved pharmacokinetic (PK) and pharmacodynamic (PD) properties, compared with other CDK inhibitors previously evaluated in clinical trials.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "Dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "6a4aba28-d78e-4e5c-b815-463577939f5d", "dddce5a7-39f6-40ce-885c-c620de450bf2" ], "content_source": "pmc_oa", "prior_hash": -22397166002887280, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": -22397166002887280, "belief": 0.96908696272776, "source_counts": { "eidos": 1, "reach": 19, "tas": 2, "signor": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "22430491", "TRID": 4342249, "PMID_NUM": 22430491, "PMCID": "PMC3328367", "PMCID_NUM": 3328367, "DOI": "10.1084/JEM.20111512", "DOI_NS": 1084, "DOI_ID": "JEM.20111512", "TCID": 18989654, "SOURCE": "pmc_oa", "RID": 10100018989654, "READER": "REACH" }, "source_hash": -8531721840206863016 }, { "source_api": "reach", "pmid": "32726663", "text": "Accordingly, FDA approved CDK inhibitors such as Dinaciclib that blocks CDK1, 2, 5, and 9, and exhibits significant anticancer activity.", "annotations": { "found_by": "Negative_activation_syntax_5_verb", "agents": { "raw_text": [ "Dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "Dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "9f36c6d5-4421-4566-b979-8dea857bbe37", "dddce5a7-39f6-40ce-885c-c620de450bf2" ], "content_source": "pubmed", "prior_hash": -22397166002887280, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": -22397166002887280, "belief": 0.96908696272776, "source_counts": { "eidos": 1, "reach": 19, "tas": 2, "signor": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "32726663", "TRID": 31897037, "PMID_NUM": 32726663, "DOI": "10.1016/J.LFS.2020.118150", "DOI_NS": 1016, "DOI_ID": "J.LFS.2020.118150", "PII": "S0024-3205(20)30902-4", "TCID": 57034375, "SOURCE": "pubmed", "RID": 10100057034375, "READER": "REACH" }, "source_hash": 5179503193782413271 }, { "source_api": "reach", "pmid": "27550941", "text": "Since dinaciclib potently inhibits CDK1, CDK5 and CDK9, in addition to CDK2, in vitro, the consequences of ablation of the individual CDKs on anaphase catastrophe induction were assessed in lung cancer cells.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "26df46a5-bce2-4223-be51-2b980e4bebae", 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which inhibits MEK1 and MEK2 35, dinaciclib, which inhibits CDK1 and CDK5 36, and rigosertib, which inhibits polo like kinase 1 37.", "annotations": { "found_by": "Negative_activation_syntax_5_verb", "agents": { "raw_text": [ "dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "4388ef8b-6482-4224-b8da-b450c019f662", "dddce5a7-39f6-40ce-885c-c620de450bf2" ], "content_source": "pmc_oa", "prior_hash": -22397166002887280, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 23, "stmt_hash": -22397166002887280, "belief": 0.96908696272776, "source_counts": { "eidos": 1, "reach": 19, "tas": 2, "signor": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "29968772", "TRID": 29021527, "PMID_NUM": 29968772, "PMCID": "PMC6030070", "PMCID_NUM": 6030070, "DOI": "10.1038/S41598-018-28335-8", "DOI_NS": 1038, "DOI_ID": "S41598-018-28335-8", "TCID": 22136004, "SOURCE": "pmc_oa", "RID": 10100022136004, "READER": "REACH" }, "source_hash": -8741335565171897321 }, { "source_api": "reach", "pmid": "25882699", "text": "Dinaciclib inhibits CDK1, 2, 5, and 9 with greater potency and specificity than flavopiridol or roscovitine and has a far superior therapeutic index in vivo.", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "Dinaciclib", "CDK1" ], "raw_grounding": [ { "PUBCHEM": "46926350", "CHEMBL": "CHEMBL2103840", "CHEBI": "CHEBI:95060", "HMS-LINCS": "10287", "DRUGBANK": "DB12021", "LINCS": "LSM-6306", "MESH": "C553669", "TEXT": "Dinaciclib" }, { "UP": "P06493", "EGID": "983", "HGNC": "1722", "TEXT": "CDK1" } ] }, "prior_uuids": [ "7fcaf5b7-a4b5-4ba4-9958-3823eecb3c4d", 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Recently, we (12) andjiang et al (13) found troglitazone suppressed TNFa production in U937 cell, a human macrophage derived cell line, and freshly prepared human monocytes, respectively, probably through activating PPAR y in these cells (13).", "annotations": { "found_by": "Negative_activation_syntax_1_verb", "agents": { "raw_text": [ "troglitazone", "TNFa" ], "raw_grounding": [ { "PUBCHEM": "5591", "CHEBI": "CHEBI:9753", "CHEMBL": "CHEMBL408", "MESH": "D000077288", "DRUGBANK": "DB00197", "CAS": "97322-87-7", "TEXT": "troglitazone" }, { "UP": "P01375", "HGNC": "11892", "MESH": "D014409", "TEXT": "TNFa", "EGID": "7124" } ] }, "prior_uuids": [ "aaaa3d61-af1b-4c5a-9152-fb7e595e950b", "8a0a7f44-9929-482d-8bf5-f7f1b15b1745" ], "content_source": "elsevier", "prior_hash": 28274926162236214, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 38, "stmt_hash": 28274926162236214, "belief": 0.5443532685514391, "source_counts": { "reach": 36, "ctd": 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0.2657023202317943, "source_counts": { "sparser": 11 }, "internal": true } }, "text_refs": { "PMID": "12429346", "TRID": 17497302, "PMID_NUM": 12429346, "DOI": "10.1016/S0006-2952(02)01355-2", "DOI_NS": 1016, "DOI_ID": "S0006-2952(02)01355-2", "TCID": 21036494, "SOURCE": "elsevier", "RID": 20300021036494, "READER": "SPARSER" }, "source_hash": 3756020227388770409 }, { "source_api": "sparser", "pmid": "28752600", "text": "Inhibition of P-glycoprotein by verapamil has been used with drugs that are known to be efflux substrates of P-glycoprotein (including phenobarbital, topiramate, levetiracetam, phenytoin, and lamotrigine).", "annotations": { "agents": { "raw_text": [ "verapamil", "P-glycoprotein" ], "raw_grounding": [ { "TEXT": "verapamil", "CHEBI": "CHEBI:9948", "CHEMBL": "CHEMBL6966", "DRUGBANK": "DB00661", "HMDB": "HMDB0001850", "CAS": "52-53-9", "PUBCHEM": "2520", "HMS-LINCS": "10616" }, { "TEXT": "P-glycoprotein", "HGNC": "40", "UP": "P08183", "EGID": "5243" } ] }, "prior_uuids": [ "cbc47e70-b61e-4280-a05b-5137854b8cae", "b3f8aba4-5858-420a-938c-9b9b5aa7f14a" ], "content_source": "manuscripts", "prior_hash": 11139863124063533, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 11, "stmt_hash": -29843924244133949, "belief": 0.2657023202317943, "source_counts": { "sparser": 11 }, "internal": true } }, "text_refs": { "PMID": "28752600", "TRID": 5376540, "PMID_NUM": 28752600, "PMCID": "PMC5683089", "PMCID_NUM": 5683089, "DOI": "10.1002/ADMA.201606596", "DOI_NS": 1002, "DOI_ID": "ADMA.201606596", "MANUSCRIPT_ID": "NIHMS915232", "TCID": 53480671, "SOURCE": "manuscripts", "RID": 20300053480671, "READER": "SPARSER" }, "source_hash": 368755792797313110 }, { "source_api": "sparser", "pmid": "17923155", "text": "As well, verapamil, a calcium channel blocker, competitively inhibits the PGP protein in vivo at concentrations of 6\u201310 \u03bcM. In our functional studies, a concentration of 200 \u03bcM was employed and may have resulted in alteration in the Ca 2+ (ATP)-mediated functions of the placental vesicle [2,11\u201315] as well as potentially altering non-selective cation channels of the placental membrane necessary in maintaining vesicular (osmotic) volume [15] .", "annotations": { "agents": { "raw_text": [ "verapamil", "PGP" ], "adeft": { "adeft": [ null, null ], "1": { "MESH:C428643": 0.0, "MESH:D059388": 0.0, "ungrounded": 0.0, "HGNC:40": 1.0, "CHEBI:CHEBI:17089": 0.0, "HGNC:8909": 0.0 } }, "raw_grounding": [ { "TEXT": "verapamil", "CHEBI": "CHEBI:9948", "CHEMBL": "CHEMBL6966", "DRUGBANK": "DB00661", "HMDB": "HMDB0001850", "CAS": "52-53-9", "PUBCHEM": "2520", "HMS-LINCS": "10616" }, { "TEXT": "PGP", "HGNC": "40", "UP": "P08183", "EGID": "5243" } ] }, "prior_uuids": [ "2bfae365-2695-42f3-bb55-eed84c337bb3", "b3f8aba4-5858-420a-938c-9b9b5aa7f14a" ], "content_source": "elsevier", "prior_hash": 11139863124063533, 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"annotations": { "agents": { "raw_text": [ "verapamil", "PGP" ], "adeft": { "adeft": [ null, null ], "1": { "MESH:C428643": 0.0, "MESH:D059388": 0.0, "ungrounded": 0.0, "HGNC:40": 1.0, "CHEBI:CHEBI:17089": 0.0, "HGNC:8909": 0.0 } }, "raw_grounding": [ { "TEXT": "verapamil", "CHEBI": "CHEBI:9948", "CHEMBL": "CHEMBL6966", "DRUGBANK": "DB00661", "HMDB": "HMDB0001850", "CAS": "52-53-9", "PUBCHEM": "2520", "HMS-LINCS": "10616" }, { "TEXT": "PGP", "HGNC": "40", "UP": "P08183", "EGID": "5243" } ] }, "prior_uuids": [ "6e25697d-e79b-4d19-91a0-9146fb0a9c78", "b3f8aba4-5858-420a-938c-9b9b5aa7f14a" ], "content_source": "pubmed", "prior_hash": 11139863124063533, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 11, "stmt_hash": -29843924244133949, "belief": 0.2657023202317943, "source_counts": { "sparser": 11 }, "internal": true } }, "text_refs": { "PMID": "12113905", "TRID": 27359125, "PMID_NUM": 12113905, "DOI": "10.1016/S0304-3940(02)00423-8", 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"name": "ABCC2", "db_refs": { "UP": "Q92887", "HGNC": "53", "TEXT": "the multidrug transporter and reverses multidrug-resistance", "EGID": "1244" } }, "obj_activity": "activity", "belief": 0.23898471907602303, "evidence": [ { "source_api": "sparser", "pmid": "2570070", "text": "Vinblastine transport was also inhibited by 20 microM verapamil, which inhibits the multidrug transporter and reverses multidrug-resistance in non-polarized cells.", "annotations": { "agents": { "raw_text": [ "verapamil", "the multidrug transporter and reverses multidrug-resistance" ], "raw_grounding": [ { "TEXT": "verapamil", "CHEBI": "CHEBI:9948", "CHEMBL": "CHEMBL6966", "DRUGBANK": "DB00661", "HMDB": "HMDB0001850", "CAS": "52-53-9", "PUBCHEM": "2520", "HMS-LINCS": "10616" }, { "UP": "Q92887", "HGNC": "53", "TEXT": "the multidrug transporter and reverses multidrug-resistance", "EGID": "1244" } ] }, "prior_uuids": [ "0b73f3fa-09f1-4649-aef8-259afdd29e88", "e61d04ed-3a5c-4e3e-a999-37db0a7c72d5" ], 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complexes with verapamil were published. xref Verapamil is a currently marketed pharmaceutical, an ion-channel blocker as well as a broad-spectrum inhibitor of multidrug transporters. xref Verapamil can inhibit multidrug transporters from the ABC, MATE and MFS families, and given the structural differences among those multidrug transporters, it seems remarkable that verapamil can exert inhibitory effects on so many structurally and mechanistically different membrane transporters.", "annotations": { "agents": { "raw_text": [ "Verapamil", "multidrug" ], "raw_grounding": [ { "TEXT": "Verapamil", "CHEBI": "CHEBI:9948", "CHEMBL": "CHEMBL6966", "DRUGBANK": "DB00661", "HMDB": "HMDB0001850", "CAS": "52-53-9", "PUBCHEM": "2520", "HMS-LINCS": "10616" }, { "UP": "Q92887", "HGNC": "53", "TEXT": "multidrug", "EGID": "1244" } ] }, "prior_uuids": [ "b45ac002-3e84-4bae-8a23-ad1318ca1f27", "e61d04ed-3a5c-4e3e-a999-37db0a7c72d5" ], "content_source": "pmc_oa", "prior_hash": -16350860393565159, 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2869737181323466345 }, { "source_api": "reach", "pmid": "20554030", "text": "Importantly, our previous studies demonstrated that changes in GRK2 activity correlated with differences in CXCL12 induced cAMP suppression.", "annotations": { "found_by": "Positive_early_activation", "agents": { "coords": [ [ 108, 114 ], [ 123, 127 ] ], "raw_text": [ "CXCL12", "cAMP" ], "raw_grounding": [ { "UP": "P48061", "HGNC": "10672", "EGID": "6387", "TEXT": "CXCL12" }, { "PUBCHEM": "6076", "CHEBI": "CHEBI:17489", "HMDB": "HMDB0000058", "CAS": "60-92-4", "DRUGBANK": "DB02527", "CHEMBL": "CHEMBL316966", "TEXT": "cAMP" } ] }, "prior_hash": 6349375502633761, "prior_uuids": [ "1fbe2723-dc26-461f-be11-fe4588587777" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 8, "stmt_hash": -25632645143763438, "belief": 1, "source_counts": { "reach": 8 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "20554030", 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"10.18632/ONCOTARGET.1557", "TRID": 12856661 }, "source_hash": -5545268662418922996 }, { "source_api": "sparser", "pmid": "22595235", "text": "At the membrane, merlin inhibits signalling by integrins and tyrosine receptor kinases (RTKs) and the activation of downstream pathways, including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/\u03b2-catenin pathways.", "annotations": { "prior_hash": 15146391469355191, "agents": { "raw_text": [ "merlin", "signalling" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "TEXT": "signalling", "GO": "GO:0023052" } ] }, "prior_uuids": [ "025d7b26-811e-4a24-9232-165d8d3d33bf" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 10, "stmt_hash": 32608808284739844, "belief": 1, "source_counts": { "sparser": 10 }, "internal": true } }, "text_refs": { "PMID": "22595235", "DOI": "10.1016/J.FEBSLET.2012.03.016", "TRID": 4462119 }, "source_hash": 6559680728949796906 }, { "source_api": "sparser", "pmid": "22247700", "text": "If nuclear \u00df-catenin is a main stimulator of\ntranscriptional activity and proliferation in merlin-deficient tumors,\none could hypothesize that Ser518 hypophosphorylated merlin would\ninhibit Wnt/\u00df-catenin signaling through physical interaction and\nstabi\u00adlization of \u00df-catenin/N-cadherin complex at the AJs.", "annotations": { "prior_hash": 17584731191150960, "agents": { "raw_text": [ "merlin", "signaling" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "TEXT": "signaling", "GO": "GO:0023052" } ] }, "prior_uuids": [ "a7e4378f-022f-4c59-afda-5d1195bae0d7" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 10, "stmt_hash": 32608808284739844, "belief": 1, "source_counts": { "sparser": 10 }, "internal": true } }, "text_refs": { "PMID": "22247700", "PMCID": "PMC3257450", "DOI": 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suggested that TNF-\u03b1 induced an increase in NF-\u03baB responsive reporter gene activity and merlin successfully inhibited the TNF-\u03b1-induced transactivation of NF-\u03baB ().", "annotations": { "prior_hash": 22611794883186790, "agents": { "raw_text": [ "merlin", "transactivation" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "TEXT": "transactivation", "GO": "GO:2000144" } ] }, "prior_uuids": [ "7c107401-9ea8-4324-b8e6-6b332c4010c2" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 3, "stmt_hash": -1574576164843263, "belief": 0.2659947518051682, "source_counts": { "sparser": 3 }, "internal": true } }, "text_refs": { "PMID": "12207915", "DOI": "10.1016/S0006-291X(02)02077-6", "TRID": 21340987 }, "source_hash": 4629149005602363932 }, { "source_api": "sparser", "pmid": "12604337", "text": "Consistent with the above data, wild type merlin successfully inhibited serum-induced and Elk-mediated SRE transactivation ( Figs.", "annotations": { "prior_hash": 22611794883186790, "agents": { "raw_text": [ "merlin", "transactivation" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" }, { "TEXT": "transactivation", "GO": "GO:2000144" } ] }, "prior_uuids": [ "744fdef2-e793-4c18-91fd-fc931fe49cd9" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 3, "stmt_hash": -1574576164843263, "belief": 0.2659947518051682, "source_counts": { "sparser": 3 }, "internal": true } }, "text_refs": { "PMID": "12604337", "DOI": "10.1016/S0006-291X(03)00124-4", "TRID": 7226896 }, "source_hash": 2294595470888035005 }, { "source_api": "sparser", "pmid": "12604337", "text": "These results suggest that merlin inhibits SRE dependent transactivation by repressing serum-induced ERK phosphorylation and its downstream effector, Elk phosphorylation.", "annotations": { "prior_hash": 22611794883186790, "agents": { 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430 in PAX3-FOXO1 (corresponds to Ser 249 in FOXO1), we tested whether inhibition of Cdk4 by fascaplysin alters the subcellular localization of PAX3-FOXO1.", "annotations": { "agents": { "raw_text": [ "fascaplysin", "Cdk4" ], "raw_grounding": [ { "TEXT": "fascaplysin", "MESH": "C069346", "CAS": "114719-57-2" }, { "UP": "P11802", "EGID": "1019", "HGNC": "1773", "TEXT": "Cdk4" } ] }, "prior_uuids": [ "7f9c5989-51c0-4799-bd54-be0506832f60", "f9ac32ca-e629-40c4-8121-7c6f660090d4" ], "content_source": "pmc_oa", "prior_hash": -21805092503379476, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 9, "stmt_hash": -32582956263919172, "belief": 0.28556147954264366, "source_counts": { "sparser": 9 }, "internal": true } }, "text_refs": { "PMID": "23469153", "TRID": 24359282, "PMID_NUM": 23469153, "PMCID": "PMC3585270", "PMCID_NUM": 3585270, "DOI": "10.1371/JOURNAL.PONE.0058193", "DOI_NS": 1371, "DOI_ID": "JOURNAL.PONE.0058193", "TCID": 18390862, 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"text_refs": { "PMID": "29786660", "TRID": 28991582, "PMID_NUM": 29786660, "PMCID": "PMC5983306", "PMCID_NUM": 5983306, "DOI": "10.3390/MD16050175", "DOI_NS": 3390, "DOI_ID": "MD16050175", "PII": "E175", "TCID": 22129068, "SOURCE": "pmc_oa", "RID": 20300022129068, "READER": "SPARSER" }, "source_hash": -337257871584573387 }, { "source_api": "sparser", "pmid": "23469153", "text": "Here we report that inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin (a small molecule selective inhibitor of Cdk4/cyclin D1 that we identified in a screen for compounds that inhibit PAX3-FOXO1) led to inhibition of the transcriptional activity of PAX3-FOXO1 in ARMS cell line Rh30.", "annotations": { "agents": { "raw_text": [ "fascaplysin", "cyclin-dependent kinase 4" ], "raw_grounding": [ { "TEXT": "fascaplysin", "MESH": "C069346", "CAS": "114719-57-2" }, { "TEXT": "cyclin-dependent kinase 4", "HGNC": "1773", "EGID": "1019", "UP": "P11802" } ] }, "prior_uuids": [ 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necrostatin-1 did not have an effect on the cytotoxic activity of NaD1, the ability of NaD1 to effect the necroptotic pathway downstream of RIP1 kinase activity, such as via direct modulation of MLKL-mediated membrane disruption, xref not addressed in our current study should be determined to eliminate definitively necroptosis as having a role.", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "5b08dd84-f382-478f-b5a3-a9d3eacfd857", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "28179997", "TRID": 2654070, "PMID_NUM": 28179997, "PMCID": "PMC5253418", "PMCID_NUM": 5253418, "DOI": "10.1038/CDDISCOVERY.2016.102", "DOI_NS": 1038, "DOI_ID": "CDDISCOVERY.2016.102", "TCID": 17854946, "SOURCE": "pmc_oa", "RID": 20300017854946, "READER": "SPARSER" }, "source_hash": 703382543478344196 }, { "source_api": "sparser", "pmid": "29212215", "text": "Necrostatin-1 inhibits RIPK1 by blocking its association with RIP3.", "annotations": { "agents": { "raw_text": [ "Necrostatin-1", "RIPK1" ], "raw_grounding": [ { "TEXT": "Necrostatin-1", "MESH": "C507699" }, { "TEXT": "RIPK1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "1e000ebd-e683-428c-a2dd-1490aa0cd9f9", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, 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null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "23319235", "TRID": 7554310, "PMID_NUM": 23319235, "PMCID": "PMC3628968", "PMCID_NUM": 3628968, "DOI": "10.1002/HEP.26200", "DOI_NS": 1002, "DOI_ID": "HEP.26200", "MANUSCRIPT_ID": "NIHMS428737", "TCID": 20052011, "SOURCE": "manuscripts", "RID": 20300020052011, "READER": "SPARSER" }, "source_hash": 1725477409976084073 }, { "source_api": "sparser", "pmid": "23145018", "text": "Necrostatin-1 specifically inhibits RIP1 kinase and disrupts regulated necrosis in tissue culture xref \u2013 xref .", "annotations": { "agents": { "raw_text": [ "Necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "Necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "fbd37f65-50cf-4171-90d3-d7ed95d5c8dd", 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A1-IRS, and mitochondria appeared normal when observed under electronic microscopy (data not shown).", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "528a02f8-a076-4ff0-aa1e-42e06ba955a2", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "25356869", "TRID": 8917450, "PMID_NUM": 25356869, "PMCID": "PMC4237268", "PMCID_NUM": 4237268, "DOI": "10.1038/CDDIS.2014.457", "DOI_NS": 1038, "DOI_ID": "CDDIS.2014.457", "TCID": 17855560, "SOURCE": "pmc_oa", "RID": 20300017855560, "READER": "SPARSER" }, "source_hash": -762752891745029934 }, { "source_api": "sparser", "pmid": "28615451", "text": "Indeed, inhibition of RIP1 by necrostatin-1 abolishes both apoptosis and necrosis in RPE cells.", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "65f4f52f-4f30-4650-803a-0e9a00e57277", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "28615451", "TRID": 26227288, "PMID_NUM": 28615451, "PMCID": "PMC5535015", "PMCID_NUM": 5535015, "DOI": "10.1074/JBC.R117.783076", "DOI_NS": 1074, "DOI_ID": "JBC.R117.783076", "TCID": 18577224, "SOURCE": "pmc_oa", "RID": 20300018577224, "READER": "SPARSER" }, "source_hash": -8830616386010601659 }, { "source_api": "sparser", "pmid": "30042663", "text": "Here, we investigated whether inhibiting RIPK1 by necrostatin-1 (Nec-1) could limit neuroinflammation and attenuate POCD in D-Galactose (D-Gal)-induced aged mice.", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIPK1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "TEXT": "RIPK1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "88858119-96cb-4056-8c1a-9c7a1a0f2642", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "30042663", "TRID": 29170592, "PMID_NUM": 30042663, "PMCID": "PMC6048190", "PMCID_NUM": 6048190, "DOI": "10.3389/FNBEH.2018.00138", "DOI_NS": 3389, "DOI_ID": "FNBEH.2018.00138", "TCID": 22246534, "SOURCE": "pmc_oa", "RID": 20300022246534, "READER": "SPARSER" }, "source_hash": -4718522104963175608 }, { "source_api": "sparser", "pmid": "24198446", "text": "Necrostatin-1 (Nec-1) inhibits receptor-interacting protein 1 (RIP1) kinase and programmed necrosis.", "annotations": { "agents": { "raw_text": [ "Necrostatin-1", "receptor-interacting protein 1" ], "raw_grounding": [ { "TEXT": "Necrostatin-1", "MESH": "C507699" }, { "TEXT": "receptor-interacting protein 1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "62072141-c936-4068-8c22-504de791daa3", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "24198446", "TRID": 13294225, "PMID_NUM": 24198446, "PMCID": "PMC3806455", "PMCID_NUM": 3806455, "DOI": "10.1155/2013/706156", "DOI_NS": 1155, "DOI_ID": "2013/706156", "TCID": 19430251, "SOURCE": "pmc_oa", "RID": 20300019430251, "READER": "SPARSER" }, "source_hash": 4505466454619392026 }, { "source_api": "sparser", "pmid": "29199874", "text": "We found that RIP-1 expression was upregulated in the lung of ALI mice and inhibition of RIP-1 by necrostatin-1 significantly prolonged the survival time of mice, which was accompanied by less serve lung injury.", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP-1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "TEXT": "RIP-1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "55925087-289c-4aaa-b85b-66abc7f16a50", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pubmed", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "29199874", "TRID": 28606578, "PMID_NUM": 29199874, "DOI": "10.1080/01902148.2017.1384083", "DOI_NS": 1080, "DOI_ID": "01902148.2017.1384083", "TCID": 20410214, "SOURCE": "pubmed", "RID": 20300020410214, "READER": "SPARSER" }, "source_hash": 7078065943833214900 }, { "source_api": "sparser", "pmid": "27177159", "text": "Generally, necroptosis is defined as cell death mediated through a pathway that depends on the RIPK1-RIPK3 complex that may be inhibited by necrostatin-1 (Nec-1) ( xref ).", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIPK1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "TEXT": "RIPK1", "HGNC": "10019", "EGID": 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"TEXT": "Necrostatin-1", "MESH": "C507699" }, { "TEXT": "RIP-1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "011725e0-66b9-450c-83f8-cd76bd363dec", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "23928697", "TRID": 16141225, "PMID_NUM": 23928697, "PMCID": "PMC3763428", "PMCID_NUM": 3763428, "DOI": "10.1038/CDDIS.2013.251", "DOI_NS": 1038, "DOI_ID": "CDDIS.2013.251", "TCID": 17854546, "SOURCE": "pmc_oa", "RID": 20300017854546, "READER": "SPARSER" }, "source_hash": 9151990575488036657 }, { "source_api": "sparser", "pmid": "31534131", "text": "Inhibition of RIPK1 by Necrostatin-1s (Nec1s) resulted in reduced, but not totally inhibited, caspase activation and cell death, demonstrating simultaneous occurrence of RIPK1 kinase-dependent and -independent apoptosis (Fig. xref ).", "annotations": { "agents": { "raw_text": [ "Necrostatin-1s", "RIPK1" ], "raw_grounding": [ { "TEXT": "Necrostatin-1s", "MESH": "C507699" }, { "TEXT": "RIPK1", "HGNC": "10019", "EGID": "8737", "UP": "Q13546" } ] }, "prior_uuids": [ "a5056aff-ed3c-40f3-8091-f9af286bcf97", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "31534131", "TRID": 31427232, "PMID_NUM": 31534131, "PMCID": "PMC6751190", "PMCID_NUM": 6751190, "DOI": "10.1038/S41419-019-1937-Y", "DOI_NS": 1038, "DOI_ID": "S41419-019-1937-Y", "TCID": 53961520, "SOURCE": "pmc_oa", "RID": 20300053961520, "READER": "SPARSER" }, "source_hash": 5288682291946390919 }, { "source_api": "sparser", "pmid": "22372834", "text": "Necroptosis was significantly reduced when RIP1 kinase was inhibited by necrostatin-1, whereas inhibition of caspases with z-vad-fmk, an irreversible pan-caspase inhibitor, did not prevent necroptosis.", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "6873ae6a-04f7-4d00-b13c-f1a4aa5b4328", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pubmed", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 17856232349999442, "belief": 0.6279699142122275, "source_counts": { "sparser": 24, "reach": 1 }, "internal": true } }, "text_refs": { "PMID": "22372834", "TRID": 19141971, "PMID_NUM": 22372834, "DOI": "10.3109/01480545.2011.633087", "DOI_NS": 3109, "DOI_ID": "01480545.2011.633087", "TCID": 12201759, "SOURCE": "pubmed", "RID": 20300012201759, "READER": "SPARSER" }, "source_hash": -1793852359024878055 }, { "source_api": "sparser", "pmid": "23760205", "text": "Inhibition of RIP1 by necrostatin-1 clearly protected from TNF-induced necroptosis in all three L929 sublines, but had no effect on the course of MNNG-induced necrosis over 16\u00a0h (Fig.\u00a0 xref b).", "annotations": { "agents": { "raw_text": [ "necrostatin-1", "RIP1" ], "raw_grounding": [ { "TEXT": "necrostatin-1", "MESH": "C507699" }, { "UP": "Q13546", "EGID": "8737", "HGNC": "10019", "TEXT": "RIP1" } ] }, "prior_uuids": [ "289522fa-a158-4ea5-970b-3404244bfd9e", "9b6a60bb-1fae-4cb5-b5c3-8fe5c231817d" ], "content_source": "pmc_oa", "prior_hash": -11973237187754732, "indranet_edge": { "residue": null, "position": null, "stmt_type": "Inhibition", "evidence_count": 25, "stmt_hash": 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were found to be methylated in sperm DNA (Rodenhiser et al. 1993 ; Andrews et al. 1996 ).", "annotations": { "prior_hash": -33463163637727699, "agents": { "raw_text": [ null, "CpGs" ], "raw_grounding": [ null, { "TEXT": "CpGs", "CHEBI": "CHEBI:167896", "PUBCHEM": "145459096", "MESH": "C015772", "CAS": "2382-65-2" } ] }, "prior_uuids": [ "3b6e8c27-fb37-4d81-aef9-c66807718127" ] }, "text_refs": { "PMID": "10712197", "PMCID": "PMC1288164", "DOI": "10.1086/302809", "TRID": 1466487 }, "source_hash": -368181119396888836 } ], "id": "044c0a6b-34b4-4ab2-9685-f6ff54211fe6", "matches_hash": "6270125487968437" }, { "type": "Methylation", "sub": { "name": "deoxyribonucleic acid", "db_refs": { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } }, "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "32150022", "text": "Epigenetic events, such as DNA methylation and histone modifications, also contribute to the development and progression of hearing loss in NF2 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"D004247" } ] }, "prior_uuids": [ "50fb5e53-b221-410e-a16d-9e1e659e68ce" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 145026158226857862 }, { "source_api": "sparser", "pmid": "35945463", "text": "Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "af0288a2-d86c-4a75-bd0c-ae51cae0a7e9" ] }, "text_refs": { "PMID": "35945463", "TRID": 35315178, "DOI": "10.1007/S00401-022-02478-5" }, "source_hash": 2438070701271473483 }, { "source_api": "sparser", "pmid": "32252413", "text": "A smaller number of high quality samples derived from snap frozen DNA will undergo whole genome bisulfite sequencing to achieve a genome-wide view of DNA methylation with a higher resolution compared to the EPIC array.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "62c99ee6-bd09-4594-a1b4-66127f1a38f9" ] }, "text_refs": { "PMID": "32252413", "PMCID": "PMC7231181", "DOI": "10.3390/GENES11040387", "PII": "E387", "TRID": 31369726 }, "source_hash": -4892470716712831827 }, { "source_api": "sparser", "pmid": "32150022", "text": "Aside from DNA methylation, there are other epigenetic mechanisms that have been linked to the development of VS: ( xref ) post-transcriptional modifications of NF2 transcripts, ( xref ) changes in lysine acetylation, and ( xref ) dysregulation of miRNA expression.( xref \u2013 xref ) While only a few studies to date have examined the epigenetic changes in VS, the much larger body of literature addressing epigenetic changes in meningiomas provides an example of what could be done for VS and NF2.( xref , xref ) Meningioma classification using DNA methylation is more relevant clinically but it captures more clinically homogenous groups that are better at predicting tumor prognosis and recurrence than the traditional WHO classification.( xref )", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "956660f6-d7c5-4e29-9373-89fc19cafa17" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 7097143752510343193 }, { "source_api": "sparser", "pmid": "32150022", "text": "Stankovic and colleagues demonstrated that VS in patients with hearing loss express higher levels of inflammatory factors such as tumor necrosis factor alpha and components of the NRLP3 inflammasome, an example of a potential mechanistic bridge between genotype and phenotype.( xref , xref ) In addition, Fernandez-Valle and colleagues showed that differences in aberrant DNA methylation across a variety of genes was correlated with varying levels of resistance to MEK1/2 inhibitors for NF2-associated VS, suggesting that epigenetics can contribute to the genotype-phenotype relationship as well.( xref ) More work is necessary to further identify and characterize these mechanisms, as they may represent targets for the development of novel treatment modalities.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "e72f7c32-f0aa-4823-9460-d40f2352255f" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": -6878743168425923673 }, { "source_api": "sparser", "pmid": "32666581", "text": "We show that DNA methylation profiling distinguish MPNST from its histological mimics, was unrelated to anatomical site and formed two main clusters, MeGroup 4 and 5.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "642dca05-abd8-4885-878d-ed1ad16448ba" ] }, "text_refs": { "PMID": "32666581", "DOI": "10.1002/PATH.5507", "TRID": 31831599 }, "source_hash": 7289967302589631706 }, { "source_api": "sparser", "pmid": "33574795", "text": "It is therefore important to obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, such as gene mutations, DNA methylation, microRNA (miRNA) regulation, and regulation at other levels, to allow the targeted treatment of individuals, thus achieving better prognoses.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "476d0b7b-044c-42fa-a4c2-5f236aae4e1c" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": 2798186393560666029 }, { "source_api": "sparser", "pmid": "33588439", "text": "Finally, in addition to genetic data, epigenetic alterations, specifically deoxyribonucleic acid methylation, are being increasingly recognized for their prognostic value, potentially adding objectivity to a currently subjective grading scheme.", "annotations": { "prior_hash": -12626787267772351, "agents": { "raw_text": [ null, "deoxyribonucleic acid" ], "raw_grounding": [ null, { "TEXT": "deoxyribonucleic acid", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "7ff536ae-0c6e-4dd6-afcc-1d6b91895d3f" ] }, "text_refs": { "PMID": "33588439", "TRID": 32810024, "DOI": "10.1093/NEUROS/NYAB001" }, "source_hash": -2123142183801915143 }, { "source_api": "sparser", "pmid": "32366326", "text": "The regulation of HOX genes during development and disease is complex, but epigenetic changes such as DNA methylation appear to be important mediators [ xref ].", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "d164a18f-f7a6-4e18-8f74-ec5e72edeb7d" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": -4822651815322604543 }, { "source_api": "sparser", "pmid": "32366326", "text": "DNA methylation profiles vary according to tumor subtypes.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "cd36533b-b491-4b83-9f3a-edaadc11efdd" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": 9025645894571158791 }, { "source_api": "sparser", "pmid": "32366326", "text": "In our study, we found decreased DNA methylation in several HOX family genes in orbitofacial NFs.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "fef88f0f-44c7-4e41-b055-12d2899d92ea" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": -8526235795797915523 }, { "source_api": "sparser", "pmid": "38411836", "text": "Demonstration of MYCN amplification by DNA methylation or fluorescence-in situ hybridization (FISH) is required for diagnosis.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "18b57d88-874a-4dd7-9c42-2adb04c10d69" ] }, "text_refs": { "PMID": "38411836", "TRID": 37848250, "DOI": "10.1007/S13577-024-01037-2" }, "source_hash": -785576856036952891 }, { "source_api": "sparser", "pmid": "32252413", "text": "This highlights the potential emerging role of DNA methylation profiles for diagnosis and categorization of nerve sheath tumors.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "16566c09-f46f-4392-a685-bff1f31059d0" ] }, "text_refs": { "PMID": "32252413", "PMCID": "PMC7231181", "DOI": "10.3390/GENES11040387", "PII": "E387", "TRID": 31369726 }, "source_hash": -4517513379498208528 }, { "source_api": "sparser", "pmid": "33574795", "text": "Methylation sequencing of NF-PAs revealed the presence of ING2 DNA methylation in NF-PAs, and the methylation and expression levels were correlated with tumor recurrence.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "a075a92d-166d-4ebb-8e5c-cd40a5a32283" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": -2406022213763758610 }, { "source_api": "sparser", "pmid": "38565263", "text": "The DNA-methylation profile, using a t-distributed stochastic neighbor embedding analysis, evidenced that MAM (pure or associated with meningiomas) clustered in a separate group from pediatric meningiomas.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "e54f0859-fd21-4ddf-b4d0-50eabd8cd64f" ] }, "text_refs": { "PMID": "38565263", "TRID": 38005758, "DOI": "10.1111/BPA.13259" }, "source_hash": -5357581231899995191 }, { "source_api": "sparser", "pmid": "38565263", "text": "In the present study, we characterized a series of pure MAM (n\u2009=\u20097) and MAM associated with meningiomas (n\u2009=\u20094) using histopathology, immunohistochemistry, genetic (fluorescent in situ and DNA sequencing analyses), and epigenetic (DNA-methylation profiling) data.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "5c6811d3-42c2-4b47-979f-43fb03a679de" ] }, "text_refs": { "PMID": "38565263", "TRID": 38005758, "DOI": "10.1111/BPA.13259" }, "source_hash": 2434262503124837878 }, { "source_api": "sparser", "pmid": "33574795", "text": "DNA methylation, a complementary mechanism for gene mutations, also plays an important role in PAs.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "dc45d76a-1730-4fd7-a56f-167576b27b63" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": 186804852437767777 }, { "source_api": "sparser", "pmid": "33574795", "text": "Approximately 80% of CpG dinucleotides are methylated in the human genome throughout the lifespan, and nearly 70% of CpG islands are methylated at any time, suggesting a widespread regulatory scope of DNA methylation ( xref ).", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "4aeaeca8-6e41-47fe-9a8c-4ec0b5b874b6" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": 1025528133809098710 }, { "source_api": "sparser", "pmid": "33574795", "text": "DNA methylation is the most frequently studied epigenetic phenomenon, in which alterations of CpG dinucleotides block the transcriptional mechanism and silence gene expression ( xref ).", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "973cb970-2bb1-4404-983f-e5cb6450c95f" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": 3664221215044150334 }, { "source_api": "sparser", "pmid": "33574795", "text": "DNA Methylation.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "5037d179-2b3a-49ef-ae85-f703712f4eda" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": 6675461449837563098 }, { "source_api": "sparser", "pmid": "32150022", "text": "In mammals, almost all DNA methylation occurs at CpG dinucleotide sites.( xref )", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "8c8aca4b-426c-4eed-ba5c-62eac68953b4" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": -3535026601379839501 }, { "source_api": "sparser", "pmid": "33574795", "text": "To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "d9f37efb-c447-4f8d-80b6-9644358aac60" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": "10.3389/FENDO.2020.596554" }, "source_hash": -4918725221346210761 }, { "source_api": "sparser", "pmid": "32252413", "text": "We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "4db13d65-90f9-4fdb-8940-b761dd830daf" ] }, "text_refs": { "PMID": "32252413", "PMCID": "PMC7231181", "DOI": "10.3390/GENES11040387", "PII": "E387", "TRID": 31369726 }, "source_hash": -1676794190595393698 }, { "source_api": "sparser", "pmid": "33436083", "text": "As p38 is the primary effector of MKK3 signaling in response to cellular stress and cytokine stimulation [ xref ], as well as chromatin conformational changes such as those observed in Fig.\u00a0 xref , we hypothesized that DNA methylation also regulates p38 expression in CNFs and PNFs.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "934a4a10-76c9-4264-94cc-d961501ae7b6" ] }, "text_refs": { "PMID": "33436083", "TRID": 32651803, "PMCID": "PMC7805211", "DOI": "10.1186/S13072-020-00380-6" }, "source_hash": -2487581783809144505 }, { "source_api": "sparser", "pmid": "33436083", "text": "Across DMR1, PNFs displayed higher DNA methylation, while CNFs were more highly methylated in DMR2 (Fig.\u00a0 xref c).", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "f0573dcc-62c1-4fa5-a40d-2c8d15b3d9ea" ] }, "text_refs": { "PMID": "33436083", "TRID": 32651803, "PMCID": "PMC7805211", "DOI": "10.1186/S13072-020-00380-6" }, "source_hash": 5694911240548659182 }, { "source_api": "sparser", "pmid": "33436083", "text": "In this study, we performed genome-wide DNA methylation profiling using the Illumina Infinium MethylationEPIC BeadChip platform on a large discovery cohort of CNFs and PNFs.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "3729b5e4-3c3f-4f02-8a0c-d6af781ba176" ] }, "text_refs": { "PMID": "33436083", "TRID": 32651803, "PMCID": "PMC7805211", "DOI": "10.1186/S13072-020-00380-6" }, "source_hash": 3779812984583827563 }, { "source_api": "sparser", "pmid": "34701028", "text": "Unsupervised hierarchical clustering of DNA methylation profiles identified two groups with significant differences in chromosome instability and tumor purity but not clinical outcome.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "37640921-5f5c-4a11-aa27-16aba8f4f326" ] }, "text_refs": { "PMID": "34701028", "TRID": 34007006, "DOI": "10.1016/J.IJROBP.2021.07.849" }, "source_hash": 4773206320453035655 }, { "source_api": "sparser", "pmid": "34701028", "text": "We identified a total of 54 consecutive patients treated at one institution between 1990 and 2019 with tumors meeting diagnostic criteria for MPNST and had sufficient tissue available for comprehensive histopathological evaluation (n\u202f=\u202f54), DNA methylation profiling (n\u202f=\u202f45) and whole exome sequencing (n\u202f=\u202f35, n\u202f=\u202f15 with paired normal).", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "ad3e25b6-8df6-40dc-b9e9-4090ceee95a8" ] }, "text_refs": { "PMID": "34701028", "TRID": 34007006, "DOI": "10.1016/J.IJROBP.2021.07.849" }, "source_hash": -4753217612645969092 }, { "source_api": "sparser", "pmid": "34701028", "text": "To elucidate markers of prognosis and treatment response, we retrospectively identified MPNST tumor resection specimens at a single institution and performed histopathologic evaluation, immunohistochemistry (IHC), DNA methylation profiling, and whole exome sequencing (WES).", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "395e7a6c-749f-493a-acb0-901e0336aec6" ] }, "text_refs": { "PMID": "34701028", "TRID": 34007006, "DOI": "10.1016/J.IJROBP.2021.07.849" }, "source_hash": -1900200063690937388 }, { "source_api": "sparser", "pmid": "36418240", "text": "Most MAPK pathway-activated tumors corresponded to high-grade astrocytomas with piloid features based on DNA methylation profiling.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "0afea844-c328-4208-a5ad-3aa792745bd1" ] }, "text_refs": { "PMID": "36418240", "TRID": 35863574, "DOI": "10.1097/PAS.0000000000001996" }, "source_hash": 2046937490886557914 }, { "source_api": "sparser", "pmid": "32150022", "text": "Epigenetics is a field of study that focuses on alterations in the expression of genes rather than changes to the gene sequence itself, and how that affects phenotype.( xref ) Examples of epigenetic modifications are DNA methylation, histone modifications, and non-coding RNAs.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "2b721df5-6646-4c69-9b61-c2761f949914" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 3466986368808335138 }, { "source_api": "sparser", "pmid": "38178234", "text": "DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "d51328cd-9c17-48c8-97a4-84725ab0a3e0" ] }, "text_refs": { "PMID": "38178234", "TRID": 37619086, "DOI": "10.1186/S13148-023-01621-7" }, "source_hash": -5661065351009212685 }, { "source_api": "sparser", "pmid": "32150022", "text": "Although not related to hearing, DNA methylation of CASP8 was found to be associated with patient age and tumor size.", "annotations": { "prior_hash": 15623462082528595, "agents": { "raw_text": [ null, "DNA" ], "raw_grounding": [ null, { "TEXT": "DNA", "CHEBI": "CHEBI:16991", "CAS": "9007-49-2", "MESH": "D004247" } ] }, "prior_uuids": [ "d55604db-cfd4-4ccc-aa7b-964ecea72a93" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 4697485088076820091 } ], "id": "60d74f9c-949e-4a0c-bb14-33e791543c29", "matches_hash": "15529987391657306" }, { "type": "Methylation", "sub": { "name": "oxalate(1-)", "db_refs": { "TEXT": "HOX", "CHEBI": "CHEBI:46904", "PUBCHEM": "3716971" } }, "belief": 0.3214662266393091, "evidence": [ { "source_api": "sparser", "pmid": "32366326", "text": "Variable HOX gene methylation has also been described in oral squamous cell carcinoma cell lines [ xref ].", "annotations": { "prior_hash": 2906867042987658, "agents": { "raw_text": [ null, "HOX" ], "raw_grounding": [ null, { "TEXT": "HOX", "CHEBI": "CHEBI:46904", "PUBCHEM": "3716971" } ] }, "prior_uuids": [ "13a83930-5929-4679-82a4-34c0df7695bb" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": -7792924711122888145 }, { "source_api": "sparser", "pmid": "32366326", "text": "Differential gene methylation and expression of HOX transcription factor family in orbitofacial neurofibroma.", "annotations": { "prior_hash": 2906867042987658, "agents": { "raw_text": [ null, "HOX" ], "raw_grounding": [ null, { "TEXT": "HOX", "CHEBI": "CHEBI:46904", "PUBCHEM": "3716971" } ] }, "prior_uuids": [ "f3c74002-7ebb-41f8-bbb0-77b2689e6a88" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": -5232125319222636784 }, { "source_api": "sparser", "pmid": "32366326", "text": "In our study, we found decreased DNA methylation in several HOX family genes in orbitofacial NFs.", "annotations": { "prior_hash": 2906867042987658, "agents": { "raw_text": [ null, "HOX" ], "raw_grounding": [ null, { "TEXT": "HOX", "CHEBI": "CHEBI:46904", "PUBCHEM": "3716971" } ] }, "prior_uuids": [ "824172e2-4230-438f-9459-7166429e8768" ] }, "text_refs": { "PMID": "32366326", "PMCID": "PMC7197183", "DOI": "10.1186/S40478-020-00940-7", "TRID": 31502570 }, "source_hash": -8526235795797915523 }, { "source_api": "sparser", "pmid": "32366326", "text": "In summary, we report that there is differential methylation and expression of HOX genes in orbitofacial NFs when compared to NFs developing at other sites.", "annotations": 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of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -13996879583825110, "agents": { "raw_text": [ null, "DAPK" ], "raw_grounding": [ null, { "FPLX": "DAPK", "HGNC_GROUP": "1021", "TEXT": "DAPK" } ] }, "prior_uuids": [ "f50ce445-72f0-4455-8363-f078a2f5ed29" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "f50ce445-72f0-4455-8363-f078a2f5ed29", "matches_hash": "35728814125675936" }, { "type": "Methylation", "sub": { "name": "Histone_H3", "db_refs": { "FPLX": "Histone_H3", "IP": "IPR000164", "NCIT": "C16685", "TEXT": "histone H3" } }, "residue": "K", "position": "27", "belief": 0.24854957729005966, 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multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.", "annotations": { "prior_hash": 32612885277492699, "agents": { "raw_text": [ null, "BRCA1" ], "raw_grounding": [ null, { "UP": "P38398", "EGID": "672", "HGNC": "1100", "TEXT": "BRCA1" } ] }, "prior_uuids": [ "e6f8ff0a-50ce-4f3f-af77-ee7fb92caf66" ] }, "text_refs": { "PMID": "26017449", "DOI": "10.1038/NATURE14410", "TRID": 13988910 }, "source_hash": 5080506413084930201 } ], "id": "e6f8ff0a-50ce-4f3f-af77-ee7fb92caf66", "matches_hash": "32612885277492699" }, { "type": "Methylation", "sub": { "name": "SMARCB1", "db_refs": { "TEXT": "SMARCB1", "HGNC": "11103", "UP": "Q12824", "EGID": "6598" } }, "belief": 0.3453007326979145, "evidence": [ { "source_api": "sparser", "pmid": "24443315", "text": "Arkadiusz Piotrowski (University of Alabama) reported that his laboratory has found no convincing evidence of germline methylation of SMARCB1 as a cause of schwannomatosis.", "annotations": { "prior_hash": -9537129902601897, "agents": { "raw_text": [ null, "SMARCB1" ], "raw_grounding": [ null, { "TEXT": "SMARCB1", "HGNC": "11103", "UP": "Q12824", "EGID": "6598" } ] }, "prior_uuids": [ "40be30a4-fa1a-431b-a7cb-07962bb3c6bd" ] }, "text_refs": { "PMID": "24443315", "PMCID": "PMC4150212", "DOI": "10.1002/AJMG.A.36312", "MANUSCRIPT_ID": "NIHMS590886", "TRID": 25678522 }, "source_hash": 2022142639274811322 } ], "id": "40be30a4-fa1a-431b-a7cb-07962bb3c6bd", "matches_hash": "-9537129902601897" }, { "type": "Methylation", "sub": { "name": "SYK", "db_refs": { "TEXT": "SYK", "HGNC": "11491", "EGID": "6850", "UP": "P43405" } }, "belief": 0.2896944789148237, "evidence": [ { "source_api": "sparser", "pmid": "15467753", "text": "Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal.", "annotations": { "prior_hash": -19322226958850673, "agents": { "raw_text": [ null, "SYK" ], "raw_grounding": [ null, { "TEXT": "SYK", "HGNC": "11491", "EGID": "6850", "UP": "P43405" } ] }, "prior_uuids": [ "ce10f4bc-562a-46bd-a19c-1b2f0929df8a" ] }, "text_refs": { "PMID": "15467753", "DOI": "10.1038/SJ.ONC.1207962", "TRID": 17347593 }, "source_hash": 8239617018010956757 } ], "id": "ce10f4bc-562a-46bd-a19c-1b2f0929df8a", "matches_hash": "-19322226958850673" }, { "type": "Methylation", "sub": { "name": "TAGLN", "db_refs": { "TEXT": "TAGLN", "HGNC": "11553", "UP": "Q01995", "EGID": "6876" } }, "belief": 0.32327461216972575, "evidence": [ { "source_api": "sparser", "pmid": "25109740", "text": "Notably, we found that this upregulation was caused by an alteration of the DNA methylation in the TAGLN genes in MPNSTs.", "annotations": { "prior_hash": 26262405036919554, "agents": { "raw_text": [ null, "TAGLN" ], "raw_grounding": [ null, { "TEXT": "TAGLN", 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"PMID": "23328233", "TRID": 7551158 }, "source_hash": 4576902408202771789 }, { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -16485722057565302, "agents": { "raw_text": [ null, "THBS1" ], "raw_grounding": [ null, { "TEXT": "THBS1", "HGNC": "11785", "UP": "P07996", "EGID": "7057" } ] }, "prior_uuids": [ "a120ce10-3ab4-4c95-ad43-0330306e479e" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 }, { "source_api": "sparser", "pmid": "23328233", "text": "The results of methylation in different types of meningiomas demonstrated that the rates of NF2, TIMP-3 and THBS1 methylation were 26.7% (8/30), 16.7% (5/30) and 36.7% (11/30) in 30 SMs tissues and 30.6% (11/36), 22.2% (8/36) and 22.2% (8/36) in 36 MMs tissues respectively.", "annotations": { "prior_hash": -16485722057565302, "agents": { "raw_text": [ null, "NF2, TIMP-3 and THBS1" ], "raw_grounding": [ null, { "UP": "P07996", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11785", "EGID": "7057" } ] }, "prior_uuids": [ "be7da82b-3edf-481c-95e6-6ed8ea90a056" ] }, "text_refs": { "PMID": "23328233", "TRID": 7551158 }, "source_hash": -1829820813697392446 }, { "source_api": "sparser", "pmid": "23328233", "text": "The methylation of NF2, TIMP-3 and THBS1 is correlated with the tumorigenesis of meningiomas (grade II and III).", "annotations": { "prior_hash": -16485722057565302, "agents": { "raw_text": [ null, "NF2, TIMP-3 and THBS1" ], "raw_grounding": [ null, { "UP": "P07996", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11785", "EGID": "7057" } ] }, "prior_uuids": [ "0fc5515a-e348-4d03-b2b8-9233eb6e165a" ] }, "text_refs": { "PMID": "23328233", "TRID": 7551158 }, "source_hash": -8806699741886106068 } ], "id": "bfbd94ed-917a-48d0-847c-03c193cab10f", "matches_hash": "-16485722057565302" }, { "type": "Methylation", "sub": { "name": "TIMP3", "db_refs": { "UP": "P35625", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11822", "EGID": "7078" } }, "belief": 0.3129356955199183, "evidence": [ { "source_api": "sparser", "pmid": "23328233", "text": "The results of methylation in different types of meningiomas demonstrated that the rates of NF2, TIMP-3 and THBS1 methylation were 26.7% (8/30), 16.7% (5/30) and 36.7% (11/30) in 30 SMs tissues and 30.6% (11/36), 22.2% (8/36) and 22.2% (8/36) in 36 MMs tissues respectively.", "annotations": { "prior_hash": 27159974613708069, "agents": { "raw_text": [ null, "NF2, TIMP-3 and THBS1" ], "raw_grounding": [ null, { "UP": "P35625", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11822", "EGID": "7078" } ] }, "prior_uuids": [ "bf2ebb97-52d0-4d8a-9fc4-43255dfb9fb7" ] }, "text_refs": { "PMID": "23328233", "TRID": 7551158 }, "source_hash": -1829820813697392446 }, { "source_api": "sparser", "pmid": "23328233", "text": "The methylation of NF2, TIMP-3 and THBS1 is correlated with the tumorigenesis of meningiomas (grade II and III).", "annotations": { "prior_hash": 27159974613708069, "agents": { "raw_text": [ null, "NF2, TIMP-3 and THBS1" ], "raw_grounding": [ null, { "UP": "P35625", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11822", "EGID": "7078" } ] }, "prior_uuids": [ "91317ff4-49c9-48f3-85c4-75da7ac17586" ] }, "text_refs": { "PMID": "23328233", "TRID": 7551158 }, "source_hash": -8806699741886106068 }, { "source_api": "sparser", "pmid": "23328233", "text": "But no aberrant methylation of NF2, TIMP-3 and THBS1 genes was found in normal brain tissue.", "annotations": { "prior_hash": 27159974613708069, "agents": { "raw_text": [ null, "NF2, TIMP-3 and THBS1" ], "raw_grounding": [ null, { "UP": "P35625", "TEXT": "NF2, TIMP-3 and THBS1", "HGNC": "11822", "EGID": "7078" } ] }, "prior_uuids": [ "b185db48-d170-4855-8c73-bc01500a213d" ] }, "text_refs": { "PMID": "23328233", "TRID": 7551158 }, "source_hash": 4576902408202771789 }, { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": 27159974613708069, "agents": { "raw_text": [ null, "TIMP3" ], "raw_grounding": [ null, { "TEXT": "TIMP3", "HGNC": "11822", "EGID": "7078", "UP": "P35625" } ] }, "prior_uuids": [ "1912782f-bc26-46b7-9fec-42dac0643564" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "5217c99c-b544-473d-b0fb-47e825248546", "matches_hash": "27159974613708069" }, { "type": "Methylation", "sub": { "name": "TMPO", "db_refs": { "TEXT": "TP", "HGNC": "11875", "UP": "P42166", "EGID": "7112" } }, "belief": 0.2002827827025908, "evidence": [ { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": 23024481043405780, "agents": { "raw_text": [ null, "TP" ], "raw_grounding": [ null, { "TEXT": "TP", "HGNC": "11875", "UP": "P42166", "EGID": "7112" } ] }, "prior_uuids": [ "47a240a8-8494-4ab9-9931-fb32a345436f" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": 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chromosomes 11 (module 2), 7 (modules 11 and 29), NF1 mutations (module 41), methylations of CD40 (module 42) and GSTM1 (module 43) are negatively associated with survival times, as their Cox regression coefficients have positive deviations from the background distributions.", "annotations": { "prior_hash": 16542609096136624, "agents": { "raw_text": [ null, "CD40 (module 42) and GSTM1 (module 43)" ], "raw_grounding": [ null, { "UP": "P25942", "TEXT": "CD40 (module 42) and GSTM1 (module 43)", "HGNC": "11919", "EGID": "958" } ] }, "prior_uuids": [ "b1fc2338-c17b-4085-96da-7baf47c19516" ] }, "text_refs": { "PMID": "23907387", "PMCID": "PMC3799430", "DOI": "10.1093/NAR/GKT656", "TRID": 19276270 }, "source_hash": 8521797621160651619 }, { "source_api": "sparser", "pmid": "23907387", "text": "G-CIMP positive tumors typically lack chromosome 7 amplification, chromosome 10 deletion and NF1 mutation, but harbor methylations of RBP1, CD40 and GSTM1.", "annotations": { "prior_hash": 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and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -30785753871949625, "agents": { "raw_text": [ null, "TP73" ], "raw_grounding": [ null, { "TEXT": "TP73", "HGNC": "12003", "EGID": "7161", "UP": "O15350" } ] }, "prior_uuids": [ "ad5c4e1b-542a-4b74-9944-e8cca6152e5a" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "500d75ee-0a89-4dbf-9140-0761d4db8e01", "matches_hash": "-30785753871949625" }, { "type": "Methylation", "sub": { "name": "VHL", "db_refs": { "TEXT": "VHL", "HGNC": "12687", "EGID": "7428", "UP": "P40337" } }, "belief": 0.2966006313418419, "evidence": [ { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": 24727459593869280, "agents": { "raw_text": [ null, "VHL" ], "raw_grounding": [ null, { "TEXT": "VHL", "HGNC": "12687", "EGID": "7428", "UP": "P40337" } ] }, "prior_uuids": [ "ae9a4f02-b912-4339-87a4-d7553dce0903" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "ae9a4f02-b912-4339-87a4-d7553dce0903", "matches_hash": "24727459593869280" }, { "type": "Methylation", "sub": { "name": "MAL2", "db_refs": { "TEXT": 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"text": "Promoter methylation of MEG3 , GSTP1 , and MAL2 has been shown to more commonly in higher grade meningiomas ( xref , xref , xref ).", "annotations": { "prior_hash": 19905421489784411, "agents": { "raw_text": [ null, "MEG3" ], "raw_grounding": [ null, { "TEXT": "MEG3", "HGNC": "14575", "EGID": "55384" } ] }, "prior_uuids": [ "8cb4bdf1-b93c-49ad-bb0e-04b774fa1228" ] }, "text_refs": { "PMID": "33194703", "TRID": 32390564, "PMCID": "PMC7645220", "DOI": "10.3389/FONC.2020.579599" }, "source_hash": 2386489888261898997 }, { "source_api": "sparser", "pmid": "33574795", "text": "In addition, the methylation of CDKN2A , MEG3 , and RASSF1A has also been detected in NF-PAs.", "annotations": { "prior_hash": 19905421489784411, "agents": { "raw_text": [ null, "MEG3" ], "raw_grounding": [ null, { "TEXT": "MEG3", "HGNC": "14575", "EGID": "55384" } ] }, "prior_uuids": [ "f0b8c7ed-2f51-478a-9fa5-b4288937f0e2" ] }, "text_refs": { "PMID": "33574795", "TRID": 32792872, "PMCID": "PMC7870789", "DOI": 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"text": "We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases.", "annotations": { "prior_hash": 12587818224858169, "agents": { "raw_text": [ null, "HIC1 (82%) and CASP8 (31%)" ], "raw_grounding": [ null, { "UP": "Q14790", "TEXT": "HIC1 (82%) and CASP8 (31%)", "HGNC": "1509", "EGID": "841" } ] }, "prior_uuids": [ "1e92e053-2ea1-46e3-b7c0-f56bbed8c3ce" ] }, "text_refs": { "PMID": "15788647", "DOI": "10.1677/ERC.1.00865", "TRID": 5563254 }, "source_hash": 8080989763907958035 }, { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": 12587818224858169, "agents": { "raw_text": [ null, "CASP8" ], "raw_grounding": [ null, { "TEXT": "CASP8", "HGNC": "1509", "EGID": "841", "UP": "Q14790" } ] }, "prior_uuids": [ "8580bb38-e2b6-4705-be49-55bd5cb83a4a" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "f3694c20-3311-4bb1-92b0-01bb32f28d0b", "matches_hash": "12587818224858169" }, { "type": "Methylation", "sub": { "name": "GOPC", "db_refs": { "TEXT": "FIG", "HGNC": "17643", "EGID": "57120", "UP": "Q9HD26" } }, "belief": 0.39435563094381954, "evidence": [ { "source_api": "sparser", "pmid": "1639394", "text": "Comparison of the\npublished genomic map (Fountain et al., 1989a) indicates that many of\nthe sites present in the YACs between the CpG islands must be\nmethylated in na NF1 YAC CONTIG 675 FIG.", "annotations": { "prior_hash": -36013065957696892, "agents": { "raw_text": [ null, "FIG" ], "raw_grounding": [ null, { "TEXT": "FIG", "HGNC": "17643", "EGID": "57120", "UP": "Q9HD26" } ] }, "prior_uuids": [ "39d4304e-d32a-4caa-b175-cf3083211184" ] }, "text_refs": { "PMID": "1639394", "DOI": "10.1016/0888-7543(92)90140-N", "TRID": 20563359 }, "source_hash": -1424643491271085773 } ], "id": "39d4304e-d32a-4caa-b175-cf3083211184", "matches_hash": "-36013065957696892" }, { "type": "Methylation", "sub": { "name": "CDK4", "db_refs": { "UP": "P11802", "TEXT": "ATM, p21 and CDK4", "HGNC": "1773", "EGID": "1019" } }, "belief": 0.3522659974197817, "evidence": [ { "source_api": "sparser", "pmid": "29426343", "text": "Differential methylation and 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THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": 7925644627604941, "agents": { "raw_text": [ null, "MGMT" ], "raw_grounding": [ null, { "TEXT": "MGMT", "HGNC": "7059", "EGID": "4255", "UP": "P16455" } ] }, "prior_uuids": [ "fdc07eef-2cd9-44c6-8b85-4581f1a3dd06" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 }, { "source_api": "sparser", "pmid": "24926470", "text": "There is a significant association between MGMT promoter methylation and the outcome of 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"annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "agents": { "raw_text": [ null, "MGMT" ], "raw_grounding": [ null, { "TEXT": "MGMT", "HGNC": "7059", "EGID": "4255", "UP": "P16455" } ] }, "prior_uuids": [ "1d2f2c3e-0429-4d09-a2d7-edc5167e8d72" ] }, "text_refs": { "PMID": "36418240", "TRID": 35863574, "DOI": "10.1097/PAS.0000000000001996" }, "source_hash": 5385768213308871840 } ], "id": "7afdc90d-aa14-4f50-a2e6-b8536211f626", "matches_hash": "7925644627604941" }, { "type": "Methylation", "sub": { "name": "MLH1", "db_refs": { "UP": "P40692", "TEXT": "HMLH1", "HGNC": "7127", "EGID": "4292" } }, "belief": 0.32689523042445057, "evidence": [ { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -14843184258824413, "agents": { "raw_text": [ null, "HMLH1" ], "raw_grounding": [ null, { "UP": "P40692", "TEXT": "HMLH1", "HGNC": "7127", "EGID": "4292" } ] }, "prior_uuids": [ "a8440f91-d8c8-4ace-8907-385ad39c3a11" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 }, { "source_api": "sparser", "pmid": "19639020", "text": "Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing.", "annotations": { "prior_hash": -14843184258824413, "agents": { "raw_text": [ null, "MLH1, MSH2, MSH6, and PMS2" ], "raw_grounding": [ null, { "UP": "P40692", "TEXT": "MLH1, MSH2, MSH6, and PMS2", "HGNC": "7127", "EGID": "4292" } ] }, "prior_uuids": [ "5beeaffb-df06-4d06-b4ae-623f8c1ea05a" ] }, "text_refs": { "PMID": "19639020", "PMCID": "PMC2987165", "DOI": "10.1038/EJHG.2009.129", "TRID": 21409341 }, "source_hash": 3368979015361838717 } ], "id": "f03df50e-baa8-48c6-99c4-1c969391101d", "matches_hash": "-14843184258824413" }, { "type": "Methylation", "sub": { "name": "MSH2", "db_refs": { "TEXT": "MSH2", "HGNC": "7325", "UP": "P43246", "EGID": "4436" } }, "belief": 0.3113955881388143, "evidence": [ { "source_api": "sparser", "pmid": "19639020", "text": "By contrast, we found promoter methylation of MSH2 with a higher rate of methylation in NF1 patients compared with controls.", "annotations": { "prior_hash": -24700331771108783, "agents": { "raw_text": [ null, "MSH2" ], "raw_grounding": [ null, { "TEXT": "MSH2", "HGNC": "7325", "UP": "P43246", "EGID": "4436" } ] }, "prior_uuids": [ "3ecea8a7-777f-4dc4-b1e9-bc0fdf3c393b" ] }, "text_refs": { "PMID": "19639020", "PMCID": "PMC2987165", "DOI": "10.1038/EJHG.2009.129", "TRID": 21409341 }, "source_hash": 5380512072029683007 }, { "source_api": "sparser", "pmid": "19639020", "text": "Leukocyte DNA of 79 controls and 79 NF1 patients was investigated for methylation of mismatch repair genes MLH1, MSH2, MSH6, and PMS2 by methylation-specific PCR and pyrosequencing.", "annotations": { "prior_hash": -24700331771108783, "agents": { "raw_text": [ null, "MLH1, MSH2, MSH6, and PMS2" ], "raw_grounding": [ null, { "UP": "P43246", "TEXT": "MLH1, MSH2, MSH6, and PMS2", "HGNC": "7325", "EGID": "4436" } ] }, "prior_uuids": [ "4cc33a45-50c0-46db-bbc4-bed7fdbbed83" ] }, "text_refs": { "PMID": "19639020", "PMCID": 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"PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": -7217855200927571159 }, { "source_api": "sparser", "pmid": "23139750", "text": "Moreover, PTEN promotor methylation correlated significantly with development of metastasis.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "417b1c5d-fc66-4e5b-9228-a86e3c835178" ] }, "text_refs": { "PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": 1578132822354150559 }, { "source_api": "sparser", "pmid": "25109740", "text": "In a methylation analysis of MPNSTs, although no significant methylation changes in the NF1 gene promoter were found in the MPNST tissues ( xref ), frequent PTEN promoter methylation was detected in NF1 -associated MPNST tissues and NF1 -deficient MPNST cell lines, although not in benign tumors ( xref ).", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "ad83ce5b-76bc-43d1-85bb-5a7b4d4fc4fb" ] }, "text_refs": { "PMID": "25109740", "PMCID": "PMC4148385", "DOI": "10.3892/OR.2014.3379", "TRID": 19935195 }, "source_hash": -3787545186317130221 }, { "source_api": "sparser", "pmid": "23139750", "text": "Next, we determined PTEN promotor methylation, a common mechanism for Pten down-regulation.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "dfa6d550-7768-41cb-9f4f-19908a4728e2" ] }, "text_refs": { "PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": -6163743503768790240 }, { "source_api": "sparser", "pmid": "23139750", "text": "PTEN methylation was significantly associated with early metastasis.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "450bdb5f-775e-49f8-a4fa-c784b87d20e1" ] }, "text_refs": { "PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": 7860159124926262938 }, { "source_api": "sparser", "pmid": "23139750", "text": "PTEN transcript expression did not correlate well with PTEN promotor methylation and Pten protein levels.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "dc7d3613-df50-43ae-9070-9898ccf8e3f4" ] }, "text_refs": { "PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": 2021004348846616321 }, { "source_api": "sparser", "pmid": "23139750", "text": "However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "686c49fe-3f2f-4ca6-88fe-bae1db0e5f3b" ] }, "text_refs": { "PMID": "23139750", "PMCID": "PMC3490977", "DOI": "10.1371/JOURNAL.PONE.0047595", "TRID": 16095904 }, "source_hash": 7422367118322654543 }, { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -3396638581171120, "agents": { "raw_text": [ null, "PTEN" ], "raw_grounding": [ null, { "UP": "P60484", "HGNC": "9588", "EGID": "5728", "TEXT": "PTEN" } ] }, "prior_uuids": [ "73630abb-5401-457b-9b85-29d5caa74147" ] }, "text_refs": { "PMID": "32150022", "PMCID": "PMC7547625", "DOI": "10.1097/MAO.0000000000002613", "MANUSCRIPT_ID": "NIHMS1631725", "TRID": 31260588 }, "source_hash": 1195708034834250738 } ], "id": "5d9fd52a-96c8-4c92-85af-9c98afced4fc", "matches_hash": "-3396638581171120" }, { "type": "Methylation", "sub": { "name": "Genes, Tumor Suppressor", "db_refs": { "TEXT": "tumor suppressor gene", "MESH": "D016147" } }, "belief": 0.18910128559582806, "evidence": [ { "source_api": "sparser", "pmid": "32150022", "text": "In particular, epigenetics may also play a role in the development of HL in VS.( xref ) A focused exploration into the methylation of 16 tumor-related genes suggest abnormal methylation of THBS1, TP73, MGMT, NF2, TIMP3, FASSF1A, VHL, PTEN, TP16, CASP8, TIMP3, DAPK, HMLH1, and GTSP1 in VS.( xref , xref , xref ) In particular, aberrant methylation of tumor suppressor gene (TP73) that encodes tumor protein 73 (p73) was associated with tumor-mediated HL.( xref ) The corrected hearing thresholds for VS patients with and without methylated TP73 were 43 decibels (dB) and 17 dB (p=0.04), respectively.", "annotations": { "prior_hash": -5649491645252104, "agents": { "raw_text": [ null, "tumor suppressor gene" ], "raw_grounding": [ null, { "TEXT": "tumor suppressor gene", "MESH": "D016147" } ] }, "prior_uuids": [ 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Stewart and P. Leder\n(1987) Parental legacy deter- mines methylation and expression of an\nautosomal transgene: a molecular mechanism for parental imprinting.", "annotations": { "prior_hash": 5964115598102752, "agents": { "raw_text": [ null, "transgene" ], "raw_grounding": [ null, { "MESH": "D019076", "TEXT": "transgene" } ] }, "prior_uuids": [ "7c056d77-d5e7-4e0d-8a34-b36e5cd3a321" ] }, "text_refs": { "PMID": "7650524", "DOI": "10.1016/0022-510X(94)00284-U", "TRID": 22737953 }, "source_hash": 1320896533871506647 } ], "id": "7c056d77-d5e7-4e0d-8a34-b36e5cd3a321", "matches_hash": "-9520021773657249", "supported_by": [ "1572032a-9512-4a2d-a095-130a9854cf4d" ] }, { "type": "Myristoylation", "sub": { "name": "AKT", "db_refs": { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } }, "belief": 0.277218663073286, "evidence": [ { "source_api": "sparser", "pmid": "21750658", "text": "The cDNAs of bovine myristoylated Akt\nand myristoylated kinase-dead Akt were kind gifts from Dr Rene H.\nMedema.", "annotations": { "prior_hash": 17168723315592487, "agents": { "raw_text": [ null, "Akt" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } ] }, "prior_uuids": [ "584f9862-fd9d-4147-9a81-31635fbd07cc" ] }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -5918185317251048381 }, { "source_api": "sparser", "pmid": "21750658", "text": "Finally, to study whether merlin S10 is an Akt substrate in\nvivo,merlin was expressed in COS-7 cells, which were either epidermal\ngrowth fac\u00adtor (EGF) stimulated to activate Akt or coexpressed with\nmyristoylated Akt (Akt myr), a constitutively activated and membrane-\ntargeted form of Akt.", "annotations": { "prior_hash": 17168723315592487, "agents": { "raw_text": [ null, "Akt" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } ] }, "prior_uuids": [ "0e80420a-fe0c-42b3-9528-97b2b1cefbf6" ] }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -2168071793257109254 }, { "source_api": "sparser", "pmid": "21750658", "text": "Akt1 is ubiquitously expressed at high\nlevels; Akt2 Abbreviations: Akt KD, kinase-dead Akt; Akt myr,\nmyristoylated Akt; DCAF1, DDB1\u00adand Cul4-associated factor 1; EGF,\nepidermal growth factor; MS, mass spectrometry; NF2, Neurofibromatosis\n2; PAK, p21-activated kinase; PI3K, phosphoinositide 3-kinase; PKA,\nprotein kinase A; PKC, protein kinase C Address all correspondence to:\nMinja Laulajainen, MSc, Biomedicum Helsinki, PL 63, 00014 University\nof Helsinki, Helsinki, Finland.", "annotations": { "prior_hash": 17168723315592487, "agents": { "raw_text": [ null, "Akt" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } ] }, "prior_uuids": [ "39db75b3-f2b9-4202-a952-b581df160b30" ] }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -759986107078765518 }, { "source_api": "sparser", "pmid": "21750658", "text": "To test this hypothesis, merlin WT\nand S10A were transfected into COS-7 cells together with either Akt\nmyr or myristoylated kinase dead Akt (Akt KD).", "annotations": { "prior_hash": 17168723315592487, "agents": { "raw_text": [ null, "Akt" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } ] }, "prior_uuids": [ "8a829abf-ca6c-47c0-88bc-7ddabf6988fa" ] }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -2948310889751586191 } ], "id": "bbe7a85d-f37f-447a-a925-394b6b1607e1", "matches_hash": "33329153428398473" }, { "type": "Myristoylation", "sub": { "name": "SRC", "db_refs": { "UP": "P12931", "HGNC": "11283", "EGID": "6714", "TEXT": "c-Src" } }, "belief": 0.6021797607327979, "evidence": [ { "source_api": "sparser", "pmid": "26483553", "text": "In fact, by expressing a version of Merlin tagged with the c-Src myristoylation sequence for membrane localization (Nf2 myr ), we confirmed that membrane-localized Merlin was sufficient for contact-dependent regulation of EGFR internalization ().", "annotations": { "prior_hash": -12885389936435400, "agents": { "raw_text": [ null, "c-Src" ], "raw_grounding": [ null, { "UP": "P12931", "HGNC": "11283", "EGID": "6714", "TEXT": "c-Src" } ] }, "prior_uuids": [ "38e70a22-c2c5-4356-9f20-7683e1e8d937" ] }, "text_refs": { "PMID": "26483553", "PMCID": "PMC4621825", "DOI": "10.1083/JCB.201503081", "TRID": 21172254 }, "source_hash": 5224997398167528047 } ], "id": "38e70a22-c2c5-4356-9f20-7683e1e8d937", "matches_hash": "-12885389936435400" }, { "type": "Palmitoylation", "sub": { "name": "TEAD", "db_refs": { "FPLX": "TEAD", "TEXT": "TEAD" } }, "belief": 0.328372579335072, "evidence": [ { "source_api": "sparser", "pmid": "33850002", "text": "Here we described the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD.", "annotations": { "emmaa": { "search_terms": [ { "type": "other", "name": "neurofibromatosis", "db_refs": {}, "search_term": "neurofibromatosis" } ], "metadata": { "internal": true } }, "prior_hash": -21862785584630002, "agents": { "raw_text": [ null, "TEAD" ], "raw_grounding": [ null, { "FPLX": "TEAD", "TEXT": "TEAD" } ] }, "prior_uuids": [ "26a30395-a2e2-4116-a7bf-7b8b67a03a42" ] }, "text_refs": { "PMID": "33850002", "TRID": 33090544, "DOI": "10.1158/1535-7163.MCT-20-0717" }, "source_hash": 5824292773189837579 } ], "id": "26a30395-a2e2-4116-a7bf-7b8b67a03a42", "matches_hash": "24587025709951681" }, { "type": "Palmitoylation", "sub": { "name": "SPR", "db_refs": { "TEXT": "SPR", "HGNC": "11257", "UP": "P35270", "EGID": "6697" } }, "belief": 0.26637608265875956, "evidence": [ { "source_api": "sparser", "pmid": "32697994", "text": "The SPR domain undergoes palmitoylation, causing SPRED proteins to localize in the membrane fraction ( xref ).", "annotations": { "prior_hash": 32319833127405463, "agents": { "raw_text": [ null, "SPR" ], "raw_grounding": [ null, { "TEXT": "SPR", "HGNC": "11257", "UP": "P35270", "EGID": "6697" } ] }, "prior_uuids": [ "d964ca01-f1a8-432d-aec3-6d8a6cb7b07d" ] }, "text_refs": { "PMID": "32697994", "PMCID": "PMC7437355", "DOI": "10.1016/J.CELREP.2020.107909", "PII": "S2211-1247(20)30890-1", "MANUSCRIPT_ID": "NIHMS1613940", "TRID": 31869230 }, "source_hash": -8760200321411753560 } ], "id": "d964ca01-f1a8-432d-aec3-6d8a6cb7b07d", "matches_hash": "35275229643075389" }, { "type": "Palmitoylation", "sub": { "name": "KRAS", "db_refs": { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "K-Ras" } }, "belief": 0.292607803448809, "evidence": [ { "source_api": "sparser", "pmid": "24294527", "text": "K-Ras4B is not palmitoylated.", "annotations": { "prior_hash": -22020554855386644, "agents": { "raw_text": [ null, "K-Ras" ], "raw_grounding": [ null, { "UP": "P01116", "EGID": "3845", "HGNC": "6407", "TEXT": "K-Ras" } ] }, "prior_uuids": [ "3e656670-1dbc-4738-91f2-d2ad6cf6f672" ] }, "text_refs": { "PMID": "24294527", "PMCID": "PMC3833460", "DOI": "10.1155/2013/536529", "TRID": 13449732 }, "source_hash": 2856728912984510285 } ], "id": "3e656670-1dbc-4738-91f2-d2ad6cf6f672", "matches_hash": "-22020554855386644" }, { "type": "Palmitoylation", "sub": { "name": "Membrane Proteins", "db_refs": { "TEXT": "membrane protein", "MESH": "D008565" } }, "belief": 0.2597351382278321, "evidence": [ { "source_api": "sparser", "pmid": "19144871", "text": "The erythrocyte p55 is a heavily palmitoylated peripheral membrane protein consisting of a single PDZ domain, a central SH3 domain, and the C-terminal GUK domain ( xref ).", "annotations": { "prior_hash": 18789069583523719, "agents": { "raw_text": [ null, "membrane protein" ], "raw_grounding": [ null, { "TEXT": "membrane protein", "MESH": "D008565" } ] }, "prior_uuids": [ 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"IP": "IPR033923", "TEXT": "PAK" } }, "belief": 0.3934874837721476, "evidence": [ { "source_api": "reach", "pmid": "18361411", "text": "PAK activation was elevated in DU145 cells and the addition of a PAK specific inhibitor peptide but not the Rac1 specific inhibitor NSC23766 inhibited both PAK and merlin phosphorylation.", "annotations": { "found_by": "Phosphorylation_syntax_4_noun", "agents": { "coords": [ [ 132, 140 ], [ 156, 159 ] ], "raw_text": [ "NSC23766", "PAK" ], "raw_grounding": [ { "TEXT": "NSC23766", "CHEBI": "CHEBI:144984", "CHEMBL": "CHEMBL257119", "PUBCHEM": "409805", "MESH": "C487513" }, { "FPLX": "PAK", "IP": "IPR033923", "TEXT": "PAK" } ] }, "prior_hash": 33147618571647036, "prior_uuids": [ "541ff2cb-56c0-498f-93e7-aea3836fec12" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": -6514635586376517, "belief": 0.3934874837721476, "source_counts": { "reach": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "18361411", "DOI": "10.1002/PROS.20760", "TRID": 26710672 }, "source_hash": 1339288792561660927 } ], "id": "541ff2cb-56c0-498f-93e7-aea3836fec12", "matches_hash": "-6514635586376517", "supported_by": [ "49b60a1d-38e5-4536-85be-eecfbeb49cb7" ] }, { "type": "Phosphorylation", "enz": { "name": "NSC 23766", "db_refs": { "TEXT": "NSC23766", "CHEBI": "CHEBI:144984", "CHEMBL": "CHEMBL257119", "PUBCHEM": "409805", "MESH": "C487513" } }, "sub": { "name": "NF2", "db_refs": { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } }, "belief": 0.3934874837721476, "evidence": [ { "source_api": "reach", "pmid": "18361411", "text": "PAK activation was elevated in DU145 cells and the addition of a PAK specific inhibitor peptide but not the Rac1 specific inhibitor NSC23766 inhibited both PAK and merlin phosphorylation.", "annotations": { "found_by": "Phosphorylation_syntax_4_noun", "agents": { "coords": [ [ 132, 140 ], [ 164, 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{ "type": "Phosphorylation", "enz": { "name": "AKT", "db_refs": { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } }, "sub": { "name": "NF2", "db_refs": { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } }, "residue": "T", "position": "230", "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "22912849", "text": "Phosphorylation of merlin by Akt at Thr230 and Ser315 can also target it for ubiquitination and subsequent degradation xref , which is a mechanism known to down-regulate merlin protein expression in breast cancer xref .", "annotations": { "prior_hash": -35456146245769838, "agents": { "raw_text": [ "Akt", "merlin" ], "raw_grounding": [ { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "669d2600-c668-4b17-b967-05142f3afa58" ], "indranet_edge": { "residue": "T", "position": "230", "stmt_type": "Phosphorylation", "evidence_count": 14, "stmt_hash": 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}, "prior_hash": -20985125539701186, "prior_uuids": [ "b0cb0e13-21ad-469c-a840-f5ba87ac50ec" ], "indranet_edge": { "residue": "T", "position": "230", "stmt_type": "Phosphorylation", "evidence_count": 14, "stmt_hash": -20985125539701186, "belief": 1, "source_counts": { "sparser": 5, "reach": 8, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "22750751", "PMCID": "PMC3459139", "DOI": "10.1016/J.BBCAN.2012.06.005", "PII": "S0304-419X(12)00052-2", "MANUSCRIPT_ID": "NIHMS396624", "TRID": 21002235 }, "source_hash": -4924072791879529044 }, { "source_api": "reach", "pmid": "24393766", "text": "In a positive feedback loop, activated AKT also binds and phosphorylates merlin on residues Thr230 and Ser315, which causes merlin to be ubiquitinated and targeted for degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 39, 42 ], [ 73, 79 ] ], "raw_text": [ "AKT", "merlin" ], "raw_grounding": [ { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": -20985125539701186, "prior_uuids": [ "b19055be-54f5-4345-a047-7eea3a293a95" ], "indranet_edge": { "residue": "T", "position": "230", "stmt_type": "Phosphorylation", "evidence_count": 14, "stmt_hash": -20985125539701186, "belief": 1, "source_counts": { "sparser": 5, "reach": 8, "trips": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "24393766", "PMCID": "PMC3960189", "DOI": "10.18632/ONCOTARGET.1557", "TRID": 12856661 }, "source_hash": -863350139172152155 }, { "source_api": "reach", "pmid": "19262146", "text": "Now, we show that merlin is a physiological substrate of Akt, which phosphorylates merlin on both T230 and S315 residues.", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 57, 60 ], [ 83, 89 ] ], "raw_text": [ "Akt", "merlin" ], "raw_grounding": [ { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": -20985125539701186, "prior_uuids": [ "69a92933-8bcf-477e-a6b5-083076c2c2e4" ], "indranet_edge": { "residue": "T", "position": "230", "stmt_type": "Phosphorylation", "evidence_count": 14, "stmt_hash": -20985125539701186, "belief": 1, "source_counts": { "sparser": 5, "reach": 8, "trips": 1 }, "internal": true } }, "epistemics": { "direct": false, "section_type": null }, "text_refs": { "PMID": "19262146", "PMCID": "PMC2634106", "DOI": "10.4161/CAM.1.4.5192", "TRID": 13958108 }, "source_hash": 2536646443648322384 }, { "source_api": "sparser", "pmid": "25893302", "text": "Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin\u2019s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).", "annotations": { "prior_hash": -35456146245769838, "agents": { "raw_text": [ "Akt", "Merlin" ], "raw_grounding": [ { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" }, { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "536fc785-0717-4b87-8363-6d360fdd4003" ], "indranet_edge": { "residue": "T", "position": "230", "stmt_type": "Phosphorylation", "evidence_count": 14, "stmt_hash": -20985125539701186, "belief": 1, "source_counts": { "sparser": 5, "reach": 8, "trips": 1 }, "internal": true } }, "text_refs": { "PMID": "25893302", "PMCID": "PMC4615258", "DOI": "10.1038/ONC.2015.125", "MANUSCRIPT_ID": "NIHMS672877", "TRID": 20517466 }, "source_hash": -3123948352887961575 }, { "source_api": "reach", "pmid": "29587439", "text": "Another protein kinase, AKT, phosphorylates merlin at Thr230 and Ser315, which appears to stimulate ubiquitin dependent protein degradation [XREF_BIBR].", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", 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has an additive\neffect on merlin degradation.", "annotations": { "prior_hash": -20249708656128221, "agents": { "raw_text": [ "PKA", "S10" ], "raw_grounding": [ { "FPLX": "PKA", "NCIT": "C16479", "ECCODE": "2.7.11.11", "TEXT": "PKA" }, { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" } ] }, "prior_uuids": [ "dbbb1969-4b85-4ba8-97e5-e6c071d47a78" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 3, "stmt_hash": 906285972236298, "belief": 0.48783677729382424, "source_counts": { "sparser": 3 }, "internal": true } }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -3695001759501766176 } ], "id": "4d0c62d0-6982-4f9b-a7e8-cf9aa821d0cd", "matches_hash": "906285972236298", "supported_by": [ "87976e63-9b64-44ce-ac94-1f8b8d52b586" ] }, { "type": "Phosphorylation", "enz": { "name": "PKA", "db_refs": { "FPLX": "PKA", "NCIT": "C16479", "ECCODE": 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cells, which are sensitive to the cyclic AMPPKA signalling axis xref .", "annotations": { "prior_hash": -17785280645434209, "agents": { "raw_text": [ "protein kinase A", "Merlin" ], "raw_grounding": [ { "FPLX": "PKA", "NCIT": "C16479", "ECCODE": "2.7.11.11", "TEXT": "protein kinase A" }, { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "b50238c8-d9ca-47c6-a56d-0c79545209b7" ], "indranet_edge": { "residue": "S", "position": "518", "stmt_type": "Phosphorylation", "evidence_count": 7, "stmt_hash": -4151656901438637, "belief": 0.7130225263884659, "source_counts": { "reach": 3, "sparser": 4 }, "internal": true } }, "text_refs": { "PMID": "27958595", "PMCID": "PMC5225790", "DOI": "10.14639/0392-100X-1093", "TRID": 18217419 }, "source_hash": -8111518461910307304 }, { "source_api": "sparser", "pmid": "20491622", "text": "Several kinases including p21-activated kinase 1 and 2 (PAK1/2) and cAMP-dependent protein kinase A (PKA) phosphorylate merlin at Ser518 [ xref - xref ], which leads to the open inactive conformation.", "annotations": { "prior_hash": -17785280645434209, "agents": { "raw_text": [ "protein kinase A", "merlin" ], "raw_grounding": [ { "FPLX": "PKA", "NCIT": "C16479", "ECCODE": "2.7.11.11", "TEXT": "protein kinase A" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "6f70cd0b-16dd-4ebc-ab8d-b3eadce7bb3d" ], "indranet_edge": { "residue": "S", "position": "518", "stmt_type": "Phosphorylation", "evidence_count": 7, "stmt_hash": -4151656901438637, "belief": 0.7130225263884659, "source_counts": { "reach": 3, "sparser": 4 }, "internal": true } }, "text_refs": { "PMID": "20491622", "PMCID": "PMC2946555", "DOI": "10.2174/138920310791824011", "MANUSCRIPT_ID": "NIHMS236013", "TRID": 3632152 }, "source_hash": 5868693419208495103 } ], "id": "59107226-e5fe-4e59-b84b-dc173018fc4f", "matches_hash": "-4151656901438637", "supported_by": [ "a516b9d4-d406-4533-a42c-7b734b90c634", 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three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA.", "annotations": { "prior_hash": 33345996243924298, "agents": { "raw_text": [ "PKA", "protein kinase" ], "raw_grounding": [ { "FPLX": "PKA", "NCIT": "C16479", "ECCODE": "2.7.11.11", "TEXT": "PKA" }, { "TEXT": "protein kinase", "MESH": "D011494" } ] }, "prior_uuids": [ "a5795ca3-a2c3-4866-ac2b-6e81dfecb2ca" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": -5608600849058706, "belief": 0.33814828361072025, "source_counts": { "sparser": 1 }, "internal": true } }, "text_refs": { "PMID": "10712197", "PMCID": "PMC1288164", "DOI": "10.1086/302809", "TRID": 1466487 }, "source_hash": -3691499948107300877 } ], "id": "a5795ca3-a2c3-4866-ac2b-6e81dfecb2ca", "matches_hash": "-5608600849058706", "supported_by": [ "44141afa-bc77-4b2c-96ef-2846e8ae3ddd" ] }, { "type": 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Akt, it is not phosphorylated by all AGC kinase family members because S10A mutations do not affect PKC mediated phosphorylation of merlin.", "annotations": { "found_by": "Phosphorylation_syntax_1a_noun", "agents": { "coords": [ [ 160, 163 ], [ 192, 198 ] ], "raw_text": [ "PKC", "merlin" ], "raw_grounding": [ { "FPLX": "PKC", "ECCODE": "2.7.11.13", "IP": "IPR012233", "NCIT": "C17017", "TEXT": "PKC" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": 18544584392424180, "prior_uuids": [ "6058485e-70ea-4771-a5cd-abe0dd96380b" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 4, "stmt_hash": -30258255817816073, "belief": 0.5783888137101326, "source_counts": { "reach": 3, "sparser": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": 5507561404532510534 }, { "source_api": "sparser", "pmid": "21750658", "text": "PKC phosphorylates merlin\nN-terminus in vitro, but the S10A mutation does not affect the\nphos\u00adphorylation (Figure 1B).", "annotations": { "prior_hash": 24770301638276429, "agents": { "raw_text": [ "PKC", "merlin" ], "raw_grounding": [ { "FPLX": "PKC", "ECCODE": "2.7.11.13", "IP": "IPR012233", "NCIT": "C17017", "TEXT": "PKC" }, { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "f9f3ab59-5b67-48c5-8b26-cf0ad1ac8aec" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 4, "stmt_hash": -30258255817816073, "belief": 0.5783888137101326, "source_counts": { "reach": 3, "sparser": 1 }, "internal": true } }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": 5404848176555978537 }, { "source_api": "reach", "pmid": "21750658", "text": "Merlin 1-314 is phosphorylated by PKC, but S10A mutation does not affect the phosphorylation.", "annotations": { "found_by": "Phosphorylation_syntax_2a_verb", "agents": { "coords": [ [ 34, 37 ], [ 0, 6 ] ], "raw_text": [ "PKC", "Merlin" ], "raw_grounding": [ { "FPLX": "PKC", "ECCODE": "2.7.11.13", "IP": "IPR012233", "NCIT": "C17017", "TEXT": "PKC" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "Merlin", "EGID": "4771" } ] }, "prior_hash": 18544584392424180, "prior_uuids": [ "958a8153-2410-4ceb-b295-52e7800c9a51" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 4, "stmt_hash": -30258255817816073, "belief": 0.5783888137101326, "source_counts": { "reach": 3, "sparser": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": -8801539199198635682 }, { "source_api": "reach", "pmid": "21750658", "text": "PKC phosphorylates merlin N-terminus in vitro, but the S10A mutation does not affect the phos phorylation.", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 0, 3 ], [ 19, 25 ] ], "raw_text": [ "PKC", "merlin" ], "raw_grounding": [ { "FPLX": "PKC", "ECCODE": "2.7.11.13", "IP": "IPR012233", "NCIT": "C17017", "TEXT": "PKC" }, { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": 18544584392424180, "prior_uuids": [ "3f250d29-025a-4a9f-bc84-55b8faebfc59" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 4, "stmt_hash": -30258255817816073, "belief": 0.5783888137101326, "source_counts": { "reach": 3, "sparser": 1 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": 969438371987877146 } ], "id": "733ab01c-bd34-4bb7-8257-c9676b3e8256", "matches_hash": "-30258255817816073", "supported_by": [ "2665ba5a-a912-4900-9c16-d7e3c879d105" ] }, { "type": "Phosphorylation", "enz": { "name": "PRKAC", "db_refs": { "TEXT": "PKA\ncatalytic subunit", "FPLX": "PRKAC" } }, "sub": { "name": "GST", "db_refs": { "FPLX": "GST", "NCIT": "C16641", "TEXT": "GST" } }, "belief": 0.7038084108836411, "evidence": [ { "source_api": "sparser", "pmid": "8612763", "text": "In vitro\nphosphorylation of GST-neurofibromin domain fu- sion proteins by PKA\ncatalytic subunit.", "annotations": { "prior_hash": 30499167808901593, "agents": { "raw_text": [ "PKA\ncatalytic subunit", "GST" ], "raw_grounding": [ { "TEXT": "PKA\ncatalytic subunit", "FPLX": "PRKAC" }, { "FPLX": "GST", "NCIT": "C16641", "TEXT": "GST" } ] }, "prior_uuids": [ "ebf5286f-4e47-497a-948a-806130ab20dc" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": 23843198860565807, "belief": 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30499167808901593, "agents": { "raw_text": [ "PKA catalytic subunit", "the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins" ], "raw_grounding": [ { "FPLX": "PRKAC", "TEXT": "PKA catalytic subunit" }, { "GO": "GO:0004364", "TEXT": "the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins" } ] }, "prior_uuids": [ "d9f04a26-a1e9-4131-9681-3d402dd72971" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 2, "stmt_hash": 30499167808901593, "belief": 0.4994209923854587, "source_counts": { "sparser": 2 }, "internal": true } }, "text_refs": { "PMID": "14741381", "DOI": "10.1016/S0014-5793(03)01507-2", "TRID": 8361203 }, "source_hash": -7798492239389254062 }, { "source_api": "sparser", "pmid": "8612763", "text": "Furthermore,\nwe examined whether PKA catalytic subunit can phosphorylate\nimmunoprecipitated native neurofibromin as well as the GST fusion\nproteins.", "annotations": { "prior_hash": 30499167808901593, "agents": { "raw_text": [ "PKA catalytic subunit", "immunoprecipitated native neurofibromin as well as the GST fusion\nproteins" ], "raw_grounding": [ { "FPLX": "PRKAC", "TEXT": "PKA catalytic subunit" }, { "GO": "GO:0004364", "TEXT": "immunoprecipitated native neurofibromin as well as the GST fusion\nproteins" } ] }, "prior_uuids": [ "da3c72d3-645d-4d54-9eb6-a75835d5934c" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 2, "stmt_hash": 30499167808901593, "belief": 0.4994209923854587, "source_counts": { "sparser": 2 }, "internal": true } }, "text_refs": { "PMID": "8612763", "DOI": "10.1016/0014-5793(96)00137-8", "TRID": 14512886 }, "source_hash": 8598235103786106323 } ], "id": "bf374800-b214-41f3-8eec-4cf895971916", "matches_hash": "30499167808901593" }, { "type": "Phosphorylation", "enz": { "name": "PRKAC", "db_refs": { "FPLX": "PRKAC", "TEXT": "PKA catalytic subunit" } }, "sub": { "name": "NF1", "db_refs": { "UP": "P21359", "TEXT": "the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins", "HGNC": "7765", "EGID": "4763" } }, "belief": 0.510488077935079, "evidence": [ { "source_api": "sparser", "pmid": "14741381", "text": "We previously reported that PKA catalytic subunit phosphorylates the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins.", "annotations": { "prior_hash": 2464503966862867, "agents": { "raw_text": [ "PKA catalytic subunit", "the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins" ], "raw_grounding": [ { "FPLX": "PRKAC", "TEXT": "PKA catalytic subunit" }, { "UP": "P21359", "TEXT": "the immunoprecipitated native neurofibromin as well as the GST-CTD fusion proteins", "HGNC": "7765", "EGID": "4763" } ] }, "prior_uuids": [ "4a889ee6-c55a-434e-9f96-fc1bb2a2f29e" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 3, 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"EGID": "6204" } }, "belief": 0.35688225055014755, "evidence": [ { "source_api": "sparser", "pmid": "21750658", "text": "This form is subsequently phosphorylated on S10 by\neither Akt or PKA.", "annotations": { "prior_hash": -14677773029352370, "agents": { "raw_text": [ "Akt or PKA", "S10" ], "raw_grounding": [ { "TEXT": "Akt or PKA", "NXPFA": "03066", "FPLX": "RAC" }, { "TEXT": "S10", "HGNC": "10383", "UP": "P46783", "EGID": "6204" } ] }, "prior_uuids": [ "fff39ebe-e311-4c63-b276-a66f3f9e2ac2" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": 21881224931714255, "belief": 0.35688225055014755, "source_counts": { "sparser": 1 }, "internal": true } }, "text_refs": { "PMID": "21750658", "PMCID": "PMC3132850", "DOI": "10.1593/NEO.11356", "TRID": 4746808 }, "source_hash": 6079185261859490002 } ], "id": "fff39ebe-e311-4c63-b276-a66f3f9e2ac2", "matches_hash": "21881224931714255", "supported_by": [ 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Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": 33567530752742105, "agents": { "raw_text": [ "KIT, MAP, and Akt", "transfectants" ], "raw_grounding": [ { "TEXT": "KIT, MAP, and Akt", "NXPFA": "03066", "FPLX": "RAC" }, { "UP": "P22083", "TEXT": "transfectants", "HGNC": "4015", "EGID": "2526" } ] }, "prior_uuids": [ "598ff907-c734-411a-a0b9-7a9c6a1a49a3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": 33567530752742105, "belief": 0.37057654180202837, "source_counts": { "sparser": 1 }, "internal": true } }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 } ], "id": "598ff907-c734-411a-a0b9-7a9c6a1a49a3", "matches_hash": "33567530752742105" }, { "type": "Phosphorylation", "enz": { "name": "RAC", "db_refs": { "TEXT": "Akt and Erk", "NXPFA": "03066", "FPLX": "RAC" } }, "sub": { "name": "NCF1", "db_refs": { "UP": "P14598", "HGNC": "7660", "EGID": "653361", "TEXT": "p47 phox" } }, "belief": 0.29360831601798765, "evidence": [ { "source_api": "sparser", "pmid": "27266634", "text": "For example, the Ras-dependent kinases Akt and Erk directly phosphorylate the p47 phox subunit of NADPH oxidase 2 (NOX2) and facilitate Rac2-dependent recruitment of p67 phox to the transmembrane component of NOX2 to increase superoxide production in phagocytes [ xref \u2013 xref ].", "annotations": { "prior_hash": 34693439715807879, "agents": { "raw_text": [ "Akt and Erk", "p47 phox" ], "raw_grounding": [ { "TEXT": "Akt and Erk", "NXPFA": "03066", "FPLX": "RAC" }, { "UP": "P14598", "HGNC": "7660", "EGID": "653361", "TEXT": "p47 phox" } ] }, "prior_uuids": [ "d0040e74-d3fa-4cdc-9abd-4cd45a92b301" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 1, "stmt_hash": 34693439715807879, "belief": 0.29360831601798765, "source_counts": { "sparser": 1 }, "internal": true } }, "text_refs": { "PMID": "27266634", "PMCID": "PMC5765860", "DOI": "10.1016/J.FREERADBIOMED.2016.06.002", "PII": "S0891-5849(16)30289-1", "MANUSCRIPT_ID": "NIHMS926983", "TRID": 24501413 }, "source_hash": 2505373317783065642 } ], "id": "d0040e74-d3fa-4cdc-9abd-4cd45a92b301", "matches_hash": "34693439715807879", "supported_by": [ "aff60161-3972-4c9d-8ca2-a2c664626f83" ] }, { "type": "Phosphorylation", "enz": { "name": "RAC", "db_refs": { "TEXT": "Akt and PKA", "NXPFA": "03066", "FPLX": "RAC" } }, "sub": { "name": "PSMD6", "db_refs": { "TEXT": "S10", "HGNC": "9564", "EGID": "9861", "UP": "Q15008" } }, "belief": 0.4238694892779056, "evidence": [ { "source_api": "sparser", "pmid": "21750658", "text": "C-terminal Phosphorylation of Merlin Increases Serine 10\nPhosphorylation Because both Akt and PKA phosphorylate merlin S10,\nwe next looked at the interplay between PKA and Akt and their effect\non mer\u00adlin degradation.", "annotations": { "prior_hash": 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"belief": 0.8087929191461296, "evidence": [ { "source_api": "reach", "pmid": "29750912", "text": "Then, Raf phosphorylates and activates the MAPK kinase (MAPKK) MEKs (MEK1 and/or MEK2), which in turn phosphorylate and activate ERKs (ERK1 and/or ERK2).", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 6, 9 ], [ 69, 73 ] ], "raw_text": [ "Raf", "MEK1" ], "raw_grounding": [ { "FPLX": "RAF", "TEXT": "Raf" }, { "UP": "Q02750", "EGID": "5604", "HGNC": "6840", "TEXT": "MEK1" } ] }, "prior_hash": -30393650727415531, "prior_uuids": [ "1d96eb1a-499f-4ff5-b1cd-7e8368213ba0" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 4, "stmt_hash": -30393650727415531, "belief": 0.8087929191461296, "source_counts": { "reach": 2, "sparser": 2 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "29750912", "DOI": "10.1016/J.BBABIO.2018.05.003", "PII": 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91, 98 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "945a467c-39c0-402e-97f7-48fa44c80134" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 1701299833779547985 }, { "source_api": "reach", "pmid": "23082153", "text": "SecPH dose dependent inhibition of cofilin phosphorylation by LIMK2.", "annotations": { "found_by": "Phosphorylation_syntax_2_noun", "agents": { "coords": [ [ 62, 67 ], [ 35, 42 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "b0255e3a-5f3a-4f20-abde-645f65a73b82" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 6225985538553193462 }, { "source_api": "reach", "pmid": "23082153", "text": "Upon their activation by ROCK, LIMK2 and LIMK1 phosphorylate cofilin, resulting in its inactivation.", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 41, 46 ], [ 61, 68 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "b94b7ea8-113f-401d-a87a-dbb962d2cdc9" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 1266424025734060464 }, { "source_api": "sparser", "pmid": "23082153", "text": "As the constitutively active mutant LIMK2-TEE bypasses ROCK activation of LIMK2, these results suggest that SecPH might act upstream from LIMK2 and that its inhibitory effect on cofilin phosphorylation by LIMK2 might require the transient activation of LIMK2 by ROCK.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "e62a7834-0537-403b-a28d-9a1609820987" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": -1862303858366314921 }, { "source_api": "sparser", "pmid": "23082153", "text": "In an attempt to elucidate the mechanism of SecPH inhibition of cofilin phosphorylation by ROCK activated LIMK2, we postulated that SecPH might prevent LIMK2 from interacting with ROCK.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "adebcd9f-b527-418d-8218-db1faab38b97" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 3132644128448748575 }, { "source_api": "reach", "pmid": "23082153", "text": "Altogether these data suggest that SecPH inhibition of cofilin phosphorylation by LIMK2 is due to SecPH inhibition of LIMK2 phosphorylation and therefore activation by ROCK1.", "annotations": { "found_by": "Phosphorylation_syntax_2_noun", "agents": { "coords": [ [ 82, 87 ], [ 55, 62 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "7ed7670a-b8d2-4ccb-afd9-0dcc8ce8f371" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 569862529956109147 }, { "source_api": "sparser", "pmid": "23082153", "text": "These results suggest that SecPH partially inhibits cofilin phosphorylation by LIMK2.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "c7e71db5-dd37-4f0e-871b-b9db4e2c9811" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": -5317483610330050929 }, { "source_api": "reach", "pmid": "23082153", "text": "We also went further into the understanding of the molecular mechanism of Nf1 inhibition of the Rho/ROCK/LIMK2/cofilin pathway by suggesting that Nf1-SecPH might prevent LIMK2 activation by ROCK and therefore prevent LIMK2 phosphorylation and inhibition of cofilin.", "annotations": { "found_by": "Phosphorylation_syntax_1a_noun", "agents": { "coords": [ [ 217, 222 ], [ 257, 264 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "9b374e04-9fa8-4ccc-92d5-44f0d4fc88e3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": -5615298469245838133 }, { "source_api": "sparser", "pmid": "23082153", "text": "Altogether these data suggest that SecPH inhibition of cofilin phosphorylation by LIMK2 is due to SecPH inhibition of LIMK2 phosphorylation and therefore activation by ROCK1.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "e03fe3a8-4468-4bbc-bbe7-33e53acf75e6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 6805039209661636794 }, { "source_api": "sparser", "pmid": "23082153", "text": "In these conditions i.e. when ROCK1 was cotransfected with LIMK2, SecPH was still able to inhibit cofilin phosphorylation by LIMK2, although HA-LIMK2 immunoprecipitates showed an increased kinase activity on cofilin ( xref ).", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "db1c9f1f-b117-4bc4-9f80-0746cd2570c3" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": -871701204944980389 }, { "source_api": "reach", "pmid": "23082153", "text": "Upon activation by ROCK, LIMK2 phosphorylates cofilin, resulting in its inactivation.", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 25, 30 ], [ 46, 53 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "18929689-43f0-4b61-b7a4-661c9aa53ea4" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 3510984317580011098 }, { "source_api": "sparser", "pmid": "23082153", "text": "Consequently to T505 phosphorylation by ROCK, LIMK2 is activated and phosphorylates cofilin.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "0c3af8fa-bd83-4259-b778-19c30506e813" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 2126583819967239039 }, { "source_api": "sparser", "pmid": "23082153", "text": "SecPH inhibits LIMK2 phosphorylation of cofilin by preventing ROCK activation of LIMK2.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "765811d4-d680-4b1b-b173-ceada1119b94" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 7316338906392414854 }, { "source_api": "sparser", "pmid": "23082153", "text": "We also went further into the understanding of the molecular mechanism of Nf1 inhibition of the Rho/ROCK/LIMK2/cofilin pathway by suggesting that Nf1-SecPH might prevent LIMK2 activation by ROCK and therefore prevent LIMK2 phosphorylation and inhibition of cofilin.", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "TEXT": "LIMK2", "HGNC": "6614", "UP": "P53671", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_uuids": [ "f2c01de2-a70e-4081-a44c-991aba4a29f6" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 1957420694551316024 }, { "source_api": "reach", "pmid": "23082153", "text": "From a functional point of view, our data showed that SecPH is an inhibitor of LIMK2 : in the presence of SecPH, LIMK2 phosphorylates less efficiently its substrate cofilin.", "annotations": { "found_by": "Phosphorylation_syntax_1a_verb", "agents": { "coords": [ [ 112, 117 ], [ 164, 171 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "276f56a5-0349-4b49-a2d7-d678d836dadf" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 2992669944415921725 }, { "source_api": "reach", "pmid": "23082153", "text": "As the constitutively active mutant LIMK2 TEE bypasses ROCK activation of LIMK2, these results suggest that SecPH might act upstream from LIMK2 and that its inhibitory effect on cofilin phosphorylation by LIMK2 might require the transient activation of LIMK2 by ROCK.", "annotations": { "found_by": "Phosphorylation_syntax_2_noun", "agents": { "coords": [ [ 205, 210 ], [ 178, 185 ] ], "raw_text": [ "LIMK2", "cofilin" ], "raw_grounding": [ { "UP": "P53671", "HGNC": "6614", "TEXT": "LIMK2", "EGID": "3985" }, { "FPLX": "Cofilin", "IP": "IPR017904", "TEXT": "cofilin" } ] }, "prior_hash": 16543675418489204, "prior_uuids": [ "511843e5-7109-45e3-b4dc-2038990f4917" ], "indranet_edge": { "residue": null, "position": null, "stmt_type": "Phosphorylation", "evidence_count": 27, "stmt_hash": 16543675418489204, "belief": 1, "source_counts": { "reach": 12, "sparser": 15 }, "internal": true } }, "epistemics": { "direct": true, "section_type": null }, "text_refs": { "PMID": "23082153", "PMCID": "PMC3474823", "DOI": "10.1371/JOURNAL.PONE.0047283", "TRID": 1863062 }, "source_hash": 8015090024014847159 }, { "source_api": "sparser", "pmid": "22776759", "text": "Cofilin is phosphorylated mainly by LIMK1 and LIMK2[ xref - xref ].", "annotations": { "prior_hash": 16543675418489204, "agents": { "raw_text": [ "LIMK1 and LIMK2", "Cofilin" ], "raw_grounding": [ { "UP": "P53671", "TEXT": "LIMK1 and LIMK2", "HGNC": "6614", "EGID": "3985" }, { "TEXT": "Cofilin", "FPLX": "Cofilin", "IP": "IPR017904" } ] }, "prior_uuids": [ "542cd30d-031d-493e-85ea-dd5a84bb187d" ], "indranet_edge": { "residue": 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of these kinases can lead to enhanced protein biosynthesis ( xref ).", "annotations": { "prior_hash": -6301562238222832, "agents": { "raw_text": [ null, "AKT, ERK 1/2, and FAK" ], "raw_grounding": [ null, { "TEXT": "AKT, ERK 1/2, and FAK", "NXPFA": "03125" } ] }, "prior_uuids": [ "53fb99fb-dd9e-428b-ba89-9ac204c06a24" ] }, "text_refs": { "PMID": "28610844", "PMCID": "PMC5723558", "DOI": "10.1016/J.EXPNEUROL.2017.06.015", "PII": "S0014-4886(17)30154-1", "MANUSCRIPT_ID": "NIHMS886255", "TRID": 26238249 }, "source_hash": 7682288913726744360 }, { "source_api": "sparser", "pmid": "16405917", "text": "Interestingly, it is only when Nf1 is present and lipid rafts are intact\u2014as shown in MEF (+/+) cells not treated with MBCD ()\u2014that the phosphorylation of ERKs and FAK is completely turned off, and that the phosphorylation of Akt is turned down.", "annotations": { "prior_hash": -6301562238222832, "agents": { "raw_text": [ null, "ERKs and FAK" ], "raw_grounding": [ null, { "TEXT": "ERKs 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473 phosphorylation in K4622 Nf1 -deficient mouse glioma cells.", "annotations": { "prior_hash": 27449205828550069, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "46cc40b7-b271-4595-a46b-9835ce9cb20d" ] }, "text_refs": { "PMID": "21216928", "PMCID": "PMC3857701", "DOI": "10.1158/1535-7163.MCT-10-0654", "MANUSCRIPT_ID": "NIHMS533272", "TRID": 2501284 }, "source_hash": -9071409259725268232 } ], "id": "46cc40b7-b271-4595-a46b-9835ce9cb20d", "matches_hash": "2451748725511788", "supported_by": [ "9128253b-6993-4911-bec0-b88a82cf11d5" ] }, { "type": "Phosphorylation", "sub": { "name": "AKT", "db_refs": { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } }, "residue": "T", "position": "308", "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "30306639", "text": "Our previous analysis of uninjured nerves had revealed an increase in p-AKT in the cKO ( xref ), and at 1 d after injury, there was a similar increase in AKT phosphorylation at Thr308 and Ser473, which are catalyzed by PDK1 and mTORC2, respectively ( xref ; xref ) ( xref ).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "74438307-4aed-4d7f-8f05-0dc50d53a448" ] }, "text_refs": { "PMID": "30306639", "PMCID": "PMC6289291", "DOI": "10.1002/GLIA.23500", "MANUSCRIPT_ID": "NIHMS992860", "TRID": 29424368 }, "source_hash": -4180563119640422335 }, { "source_api": "sparser", "pmid": "27755359", "text": "AKT, a master serine-threonine kinase downstream from phosphatidylinositol-3-kinases (PI3K), is phosphorylated at threonine 308 by its primary activator, PDK1 (phosphoinositide-dependent kinase 1).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "96ea305a-35d0-49f9-917c-910606c7c58a" ] }, "text_refs": { "PMID": "27755359", "PMCID": "PMC5154791", "DOI": "10.1097/MAO.0000000000001247", "MANUSCRIPT_ID": "NIHMS818227", "TRID": 12765455 }, "source_hash": -8779440856853409370 }, { "source_api": "sparser", "pmid": "27755359", "text": "PI-8 did not affect the phosphorylation of AKT at serine-473 but slightly decreased threonine-308 phosphorylation while PI-15 decreased the phosphorylation of AKT at both phosphorylation sites, Ser473 and Thr308.", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "e02f79c9-366f-412b-b037-14fd4dce3425" ] }, "text_refs": { "PMID": "27755359", "PMCID": "PMC5154791", "DOI": "10.1097/MAO.0000000000001247", "MANUSCRIPT_ID": "NIHMS818227", "TRID": 12765455 }, "source_hash": -8518124925321506784 }, { "source_api": "sparser", "pmid": "18199958", "text": "Immunohistochemical analysis of 14 VS tissue sections detected positive staining for activated AKT phosphorylated at both serine-473 and threonine-308 in all tumors.", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "1d6b1720-7c50-4e5c-a2df-0152ff34bc54" ] }, "text_refs": { "PMID": "18199958", "DOI": "10.1097/MAO.0B013E31816021F7", "TRID": 18141864 }, "source_hash": -901272775089851344 }, { "source_api": "sparser", "pmid": "27755359", "text": "In contrast, PI-15 effect is more potent in reducing the phosphorylation of both AKT-Thr308 and AKT-Ser473 phosphorylation in a dose dependent manner ( xref ).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "72a115d2-1008-4041-9f38-9410530977e9" ] }, "text_refs": { "PMID": "27755359", 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slightly AKT- Ser473 phosphorylation in a dose dependent manner.", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ "90b587c0-5e64-4d5a-926c-42ee73039387" ] }, "text_refs": { "PMID": "27755359", "PMCID": "PMC5154791", "DOI": "10.1097/MAO.0000000000001247", "MANUSCRIPT_ID": "NIHMS818227", "TRID": 12765455 }, "source_hash": 4268002600296349242 }, { "source_api": "sparser", "pmid": "21216928", "text": "No change in AKT phosphorylation at residue Thr-308 was observed following 0.75 nM rapamycin treatment ( xref ), and no increased in AKT Thr-308 phosphorylation was found in Nf1 -deficient astrocytes relative to their wild-type controls (data not shown).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, "prior_uuids": [ 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"However, the levels of Akt phosphorylation at residues T308\nand S473 did not appear to show significant difference by NF1 status ( xref ; xref ).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "Akt" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "Akt" } ] }, "prior_uuids": [ "00f8d4a4-625e-43cc-8a16-199ed8c27d5f" ] }, "text_refs": { "PMID": "30104415", "PMCID": "PMC6905494", "DOI": "10.1158/1940-6207.CAPR-18-0072", "PII": "CANPREVRES.0072.2018", "MANUSCRIPT_ID": "NIHMS1060344", "TRID": 29220938 }, "source_hash": 7753063940170887660 }, { "source_api": "sparser", "pmid": "23100325", "text": "Specifically, PIP 3 binds the pleckstrin homology domain of AKT, resulting in a conformational change that allows PDK1 to phosphorylate Thr 308 of AKT ( xref ).", "annotations": { "prior_hash": -6623285197120148, "agents": { "raw_text": [ null, "AKT" ], "raw_grounding": [ null, { "FPLX": "AKT", "NCIT": "C41625", "TEXT": "AKT" } ] }, 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the SRE through inhibiting the serum-induced phosphorylation of SRF.", "annotations": { "prior_hash": -11851434092324700, "agents": { "raw_text": [ null, "SRF" ], "raw_grounding": [ null, { "UP": "P11831", "HGNC": "11291", "EGID": "6722", "TEXT": "SRF" } ] }, "prior_uuids": [ "2f15efd6-f977-4d6d-963b-a7fa05f25bb9" ] }, "text_refs": { "PMID": "12604337", "DOI": "10.1016/S0006-291X(03)00124-4", "TRID": 7226896 }, "source_hash": -6602172310031634778 }, { "source_api": "sparser", "pmid": "12604337", "text": "At present, it is not known whether merlin regulates the serum-induced phosphorylation of SRF.", "annotations": { "prior_hash": -11851434092324700, "agents": { "raw_text": [ null, "SRF" ], "raw_grounding": [ null, { "UP": "P11831", "HGNC": "11291", "EGID": "6722", "TEXT": "SRF" } ] }, "prior_uuids": [ "4714b7fa-0787-4ce6-b7ec-f0a3239eedf9" ] }, "text_refs": { "PMID": "12604337", "DOI": "10.1016/S0006-291X(03)00124-4", "TRID": 7226896 }, "source_hash": 6847486441458610177 } ], "id": "81aab26b-f92d-491d-9c3c-558ab4e98756", "matches_hash": "-11851434092324700" }, { "type": "Phosphorylation", "sub": { "name": "STAT1", "db_refs": { "UP": "P42224", "HGNC": "11362", "EGID": "6772", "TEXT": "STAT1" } }, "belief": 0.7959682942630255, "evidence": [ { "source_api": "sparser", "pmid": "31650029", "text": "Since STAT1 phosphorylation was our determinant of oHSV resistance in an earlier study, xref we also evaluated p-STAT1 and found that, consistent with our TBK1 and IRF3 results, oHSV infection induced STAT1 phosphorylation within 6\u00a0h in the WT and 8814 shSCR cells.", "annotations": { "prior_hash": -1303812987759896, "agents": { "raw_text": [ null, "STAT1" ], "raw_grounding": [ null, { "UP": "P42224", "HGNC": "11362", "EGID": "6772", "TEXT": "STAT1" } ] }, "prior_uuids": [ "df14fa9d-72ca-484d-a50a-b025260874a7" ] }, "text_refs": { "PMID": "31650029", "PMCID": "PMC6804519", "DOI": "10.1016/J.OMTO.2019.09.001", "TRID": 30764180 }, "source_hash": -7574675649285568422 }, { "source_api": "sparser", "pmid": "31650029", "text": "Specifically, we have shown that resistant cell lines constitutively express a set of IFN-stimulated genes (ISGs) and respond to oHSV infection with rapid phosphorylation of STAT1 and that NF\u03baB-related signaling activity is involved in this basal ISG upregulation and oHSV resistance. xref , xref ", "annotations": { "prior_hash": -1303812987759896, "agents": { "raw_text": [ null, "STAT1" ], "raw_grounding": [ null, { "UP": "P42224", "HGNC": "11362", "EGID": "6772", "TEXT": "STAT1" } ] }, "prior_uuids": [ "4f066dcf-4c77-4123-9f76-7e0a9c6d04b7" ] }, "text_refs": { "PMID": "31650029", "PMCID": "PMC6804519", "DOI": "10.1016/J.OMTO.2019.09.001", "TRID": 30764180 }, "source_hash": 8756064744844832601 }, { "source_api": "sparser", "pmid": "31650029", "text": "Based upon this result and our previous data showing that oHSV induces STAT1 phosphorylation in resistant cell lines, we hypothesized that poly I:C would stimulate equivalent phosphorylation of STAT1 in our shSCR and shSTING cell lines but that HSV-60 would be less effective at stimulating p-STAT1 in our shSTING cell line.", "annotations": { "prior_hash": -1303812987759896, "agents": { "raw_text": [ null, "STAT1" ], "raw_grounding": [ null, { "UP": "P42224", "HGNC": "11362", "EGID": "6772", "TEXT": "STAT1" } ] }, "prior_uuids": [ "db56d41f-0a58-40ad-bd9f-7f8250826348" ] }, "text_refs": { "PMID": "31650029", "PMCID": "PMC6804519", "DOI": "10.1016/J.OMTO.2019.09.001", "TRID": 30764180 }, "source_hash": -141323561613797177 }, { "source_api": "sparser", "pmid": "22798428", "text": "Additionally, phosphorylation of p70S6 kinase, p90RSK, STAT5a/b, STAT1 and MSK1/2, proteins previously not considered as direct PAK substrates or effectors, were also decreased in PID-expressing and IPA-3-treated MM cells.", "annotations": { "prior_hash": -1303812987759896, "agents": { "raw_text": [ null, "kinase, p90RSK, STAT5a/b, STAT1 and MSK1/2" ], "raw_grounding": [ null, { "UP": "P42224", "TEXT": "kinase, p90RSK, STAT5a/b, STAT1 and MSK1/2", "HGNC": "11362", "EGID": "6772" } ] }, "prior_uuids": [ "3005ed2c-aee4-4d31-ba7f-a2c4f872142e" ] }, "text_refs": { "PMID": "22798428", "PMCID": "PMC3447107", "DOI": "10.1158/1541-7786.MCR-12-0082", "MANUSCRIPT_ID": "NIHMS394501", "TRID": 18097296 }, "source_hash": 9192998757447029259 } ], "id": "9cd6f787-c798-4d15-980b-6929c1ef86ef", "matches_hash": "-1303812987759896" }, { "type": "Phosphorylation", "sub": { "name": "STAT3", "db_refs": { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } }, "residue": "S", "position": "727", "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "20124472", "text": "In NF1 -deficient cells, we observed increased phosphorylation of STAT3 on Ser-727 and not Tyr-705.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "ee3d5442-acf1-4f65-907f-67d47238c8c2" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 4576577614965814370 }, { "source_api": "sparser", "pmid": "23318430", "text": "A recent in vitro study found STAT3 phosphorylated on Ser727 in an MPNST cell line ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "7aea3e65-dcc2-4db0-8c95-7a2ac5cb0ea7" ] }, "text_refs": { "PMID": "23318430", "PMCID": "PMC3923530", "DOI": "10.1038/ONC.2012.579", "MANUSCRIPT_ID": "NIHMS521689", "TRID": 7568332 }, "source_hash": -1224664768375647319 }, { "source_api": "sparser", "pmid": "20124472", "text": "Third, to show that Cucurbitacin-I inhibits Nf1 \u2212/\u2212 astrocyte cell proliferation as well as STAT3 activation, we examined the effect of Cucurbitacin-I treatment on [ 3 H]-thymidine incorporation and STAT3 Ser-727 phosphorylation in WT and Nf1 \u2212 / \u2212 astrocytes.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "c3d07aca-0763-482d-b29a-d7e9063938a4" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -2945022662148157390 }, { "source_api": "sparser", "pmid": "20124472", "text": "Finally, to determine whether STAT3 is also activated in brain tumors from patients with NF1, we examined STAT3 Ser-727 phosphorylation by immunohistochemistry in NF1-associated and sporadic pilocytic astrocytomas (PAs): Whereas 41% of NF1-associated PAs were phospho-STAT3-immunopositive, only 7% of the sporadic PAs were phospho-STAT3-immunoreactive ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "9ae253ae-4a66-4413-b655-432168810249" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 5826928560534509405 }, { "source_api": "sparser", "pmid": "20124472", "text": "Similarly, Rac1 N17 expression in Nf1 \u2212 / \u2212 astrocytes reduced STAT3 Ser-727 phosphorylation ( xref , bottom ), whereas Rac1 V12 expression in WT astrocytes increased STAT3 Ser-727 phosphorylation ( xref , top ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "49b14f43-aed9-44af-b7ad-1638311a29b1" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 1504067088631935367 }, { "source_api": "sparser", "pmid": "20124472", "text": "In this regard, Ser-727 STAT3 phosphorylation is associated with increased cyclin D1 expression ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "f53540b4-a1be-4f18-850b-f82ab55d38c9" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 2057628976446001489 }, { "source_api": "sparser", "pmid": "21216928", "text": "Following 0.75nM rapamycin treatment, S6-Ser 235/236 and STAT3-Ser 727 phosphorylation ( xref ) was significantly attenuated, and cell proliferation ( xref ) was reduced by ~36%.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "325d2cc1-6701-406f-8937-c2959fd197b4" ] }, "text_refs": { "PMID": "21216928", "PMCID": "PMC3857701", "DOI": "10.1158/1535-7163.MCT-10-0654", "MANUSCRIPT_ID": "NIHMS533272", "TRID": 2501284 }, "source_hash": 1009447418672430563 }, { "source_api": "sparser", "pmid": "21216928", "text": "In these experiments, we examined the effect of combined mTOR (rapamycin) and PI3-K inhibitor (LY294002) treatment on [ 3 H]-thymidine incorporation and S6-Ser 235/236 , STAT3-Ser 727 and AKT-Ser 473 phosphorylation in K4622 Nf1 -deficient mouse glioma cells.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "466f77ab-fa9f-4322-bf94-d51bdf1418ed" ] }, "text_refs": { "PMID": "21216928", "PMCID": "PMC3857701", "DOI": "10.1158/1535-7163.MCT-10-0654", "MANUSCRIPT_ID": "NIHMS533272", "TRID": 2501284 }, "source_hash": -9071409259725268232 }, { "source_api": "sparser", "pmid": "20124472", "text": "In addition, primary Nf1 \u2212/\u2212 neocortical neural stem cells likewise exhibited increased STAT3 Ser-727 phosphorylation relative to their WT counterparts ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "e60ed1f9-0c86-4a40-a24e-bbeb26d4fc93" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -2453196544972825663 }, { "source_api": "sparser", "pmid": "23318430", "text": "In contrast, STAT3 was phosphorylated at Ser727 in only a low percentage of cells, and in less than 20% of tested human and mouse tumors.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "65f42312-0891-4761-9e2c-ab45c5cb57fa" ] }, "text_refs": { "PMID": "23318430", "PMCID": "PMC3923530", "DOI": "10.1038/ONC.2012.579", "MANUSCRIPT_ID": "NIHMS521689", "TRID": 7568332 }, "source_hash": 7416019395085719593 }, { "source_api": "sparser", "pmid": "20124472", "text": "Moreover, phosphorylation of STAT3 at Ser-727 is sufficient for STAT3 activation in prostate cancer cells, independent of Tyr-705 phosphorylation ( xref ), and STAT3 Ser-727 phosphorylation is essential for postnatal survival and cell growth in mice, such that mice with a Stat3 allele in which the serine residue has been converted to alanine exhibit increased apoptosis ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "95a363df-f86f-48af-80f8-916fe4f70e6b" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 7169436101513350928 }, { "source_api": "sparser", "pmid": "20124472", "text": "Second, to directly demonstrate that neurofibromin regulates STAT3 activation, we examined STAT3 phosphorylation in Nf1 \u2212/\u2212 and WT astrocytes: STAT3 Ser-727 phosphorylation was increased 4.8-fold in Nf1 \u2212 / \u2212 compared to WT astrocytes ( xref , top ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "e58cba54-577b-4e95-b6d5-645bf7eb62ca" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": 4728997646164780054 }, { "source_api": "sparser", "pmid": "20124472", "text": "We observed a 1.4-fold reduction in cell proliferation ( xref ) and a 3-fold reduction in Ser-727 STAT3 phosphorylation ( xref ) in Nf1- deficient astrocytes following Cucurbitacin-I treatment.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "ae3c1696-4014-420a-b9dc-2b4dfe36942b" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -7811811778300792182 }, { "source_api": "sparser", "pmid": "20124472", "text": "Here, we showed that pharmacologic inhibition of either PI3-K (LY294002; xref ) or mTOR (rapamycin; xref , left ) blocked STAT3 Ser-727 phosphorylation in ST88-14 cells.", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "ccdbc025-47ec-448c-bbc6-1b5d19ba713e" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -5936252416231083037 }, { "source_api": "sparser", "pmid": "20124472", "text": "This is consistent with previous reports demonstrating that RAS activation increases STAT3 Ser-727 phosphorylation ( xref ).", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "cd50c212-2812-40f1-8ae2-8121464ddb45" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -3430276306211088172 }, { "source_api": "sparser", "pmid": "20124472", "text": "Second, we demonstrated that rapamycin blocks STAT3 Ser-727 phosphorylation (activation) in both human ST88-14 and mouse K1861 cells ( xref , right and xref ) as well as Rac1 activation in ST88-14 cells ( xref B, right) .", "annotations": { "prior_hash": -23188439215144623, "agents": { "raw_text": [ null, "STAT3" ], "raw_grounding": [ null, { "UP": "P40763", "HGNC": "11364", "EGID": "6774", "TEXT": "STAT3" } ] }, "prior_uuids": [ "07c9d682-5c2d-4b54-9568-eb482f7e7ca8" ] }, "text_refs": { "PMID": "20124472", "PMCID": "PMC5534849", "DOI": "10.1158/0008-5472.CAN-09-2178", "MANUSCRIPT_ID": "NIHMS881655", "TRID": 22993618 }, "source_hash": -8690522312413281677 } ], "id": 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xref ) and in in vitro GBM cell culture treated with media conditioned by cells transfected by CXCL12-lentiviral vector ( xref , see xref ).", "annotations": { "prior_hash": 19912867293090326, "agents": { "raw_text": [ null, "CXCR4" ], "raw_grounding": [ null, { "UP": "P61073", "HGNC": "2561", "EGID": "7852", "TEXT": "CXCR4" } ] }, "prior_uuids": [ "be495dab-dd98-4750-a841-ddc25cbcb62c" ] }, "text_refs": { "PMID": "20554030", "PMCID": "PMC2910179", "DOI": "10.1016/J.JNEUROIM.2010.05.002", "MANUSCRIPT_ID": "NIHMS207579", "TRID": 27974296 }, "source_hash": 8892842620494948511 } ], "id": "d9c5181a-df34-4985-9375-d622d6eca96c", "matches_hash": "19912867293090326" }, { "type": "Phosphorylation", "sub": { "name": "MAP7D3", "db_refs": { "UP": "Q8IWC1", "TEXT": "KIT, MAP, and Akt", "HGNC": "25742", "EGID": "79649" } }, "belief": 0.31848814392966895, "evidence": [ { "source_api": "sparser", "pmid": "18671247", "text": "Imatinib treatment markedly inhibited KIT, MAP, and Akt phosphorylation in all transfectants, leading to reduced glucose uptake via decreased levels of plasma membrane-bound Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": -30359312966809105, "agents": { "raw_text": [ null, "KIT, MAP, and Akt" ], "raw_grounding": [ null, { "UP": "Q8IWC1", "TEXT": "KIT, MAP, and Akt", "HGNC": "25742", "EGID": "79649" } ] }, "prior_uuids": [ "96eb2df3-eb84-4c2e-9105-f0a1df9ee9e1" ] }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 } ], "id": "96eb2df3-eb84-4c2e-9105-f0a1df9ee9e1", "matches_hash": "-30359312966809105" }, { "type": "Phosphorylation", "sub": { "name": "MAP9", "db_refs": { "UP": "Q49MG5", "TEXT": "KIT, MAP, and Akt", "HGNC": "26118", "EGID": "79884" } }, "belief": 0.5239401148924525, "evidence": [ { "source_api": "sparser", "pmid": "18671247", "text": "Imatinib treatment markedly inhibited KIT, MAP, and Akt phosphorylation in all transfectants, leading to reduced glucose uptake via decreased levels of plasma membrane-bound Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": 19560633956806225, "agents": { "raw_text": [ null, "KIT, MAP, and Akt" ], "raw_grounding": [ null, { "UP": "Q49MG5", "TEXT": "KIT, MAP, and Akt", "HGNC": "26118", "EGID": "79884" } ] }, "prior_uuids": [ "b40acc6e-6cfe-4862-8037-6e258a8dab3b" ] }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 } ], "id": "b40acc6e-6cfe-4862-8037-6e258a8dab3b", "matches_hash": "19560633956806225" }, { "type": "Phosphorylation", "sub": { "name": "DAB1", "db_refs": { "TEXT": "Dab1", "HGNC": "2661", "UP": "O75553", "EGID": "1600" } }, "belief": 0.6135249771151229, "evidence": [ { "source_api": "sparser", "pmid": "25083141", "text": "When bound by Reelin, signaling through these receptors results in phosphorylation of Dab1 and activation of the Src family of protein tyrosine kinases [ xref , xref ].", "annotations": { "prior_hash": -23845979792764994, "agents": { "raw_text": [ null, "Dab1" ], "raw_grounding": [ null, { "TEXT": "Dab1", "HGNC": "2661", "UP": "O75553", "EGID": "1600" } ] }, "prior_uuids": [ "93ff0fe7-dc1f-4518-ab55-3969a74549ec" ] }, "text_refs": { "PMID": "25083141", "PMCID": "PMC4114080", "DOI": "10.2217/FNL.10.80", "MANUSCRIPT_ID": "NIHMS269089", "TRID": 19469376 }, "source_hash": 2304301536703227293 } ], "id": "93ff0fe7-dc1f-4518-ab55-3969a74549ec", "matches_hash": "-23845979792764994" }, { "type": "Phosphorylation", "sub": { "name": "DDB1", "db_refs": { "UP": "Q16531", "TEXT": "its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1)", "HGNC": "2717", "EGID": "1642" } }, "belief": 0.25758854057282854, "evidence": [ { "source_api": "sparser", "pmid": "23267122", "text": "Upon stimulation by either growth factors or nutrients, mTORC1 assembles and promotes the phosphorylation of its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).", "annotations": { "prior_hash": -30171462918113972, "agents": { "raw_text": [ null, "its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1)" ], "raw_grounding": [ null, { "UP": "Q16531", "TEXT": "its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1)", "HGNC": "2717", "EGID": "1642" } ] }, "prior_uuids": [ "4c711f0f-5bda-47de-a1e1-0ae9a63d22e7" ] }, "text_refs": { "PMID": "23267122", "PMCID": "PMC3725758", "MANUSCRIPT_ID": "NIHMS494794", "TRID": 16129620 }, "source_hash": -906826060894133162 }, { "source_api": "sparser", "pmid": "21307646", "text": "mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K).", "annotations": { "prior_hash": -30171462918113972, "agents": { "raw_text": [ null, "the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K)" ], "raw_grounding": [ null, { "UP": "Q16531", "TEXT": "the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K)", "HGNC": "2717", "EGID": "1642" } ] }, "prior_uuids": [ "390b9477-dc26-4eec-b795-0b614d924d0c" ] }, "text_refs": { "PMID": "21307646", "PMCID": "PMC3154047", "DOI": "10.4161/OXIM.3.6.14787", "TRID": 19880770 }, "source_hash": -8202485149629148821 } ], "id": "10c5dc85-e20f-40af-a7bc-0ed63c4c6202", "matches_hash": "-30171462918113972" }, { "type": "Phosphorylation", "sub": { "name": "STING1", "db_refs": { "UP": "Q86WV6", "EGID": "340061", "HGNC": "27962", "TEXT": "STING" } }, "residue": "S", "position": "366", "belief": 0.28555096872837393, "evidence": [ { "source_api": "sparser", "pmid": "31650029", "text": "Previous work has shown that phosphorylation of STING at the serine-366 site is consistent with its activation and downstream IFN signaling. xref Therefore, in order to detect potential differences in STING signaling in these cell lines, we conducted an immunoblot-based screen using an antibody that is specific to STING S366 phosphorylation.", "annotations": { "prior_hash": -35878850377651746, "agents": { "raw_text": [ null, "STING" ], "raw_grounding": [ null, { "UP": "Q86WV6", "EGID": "340061", "HGNC": "27962", "TEXT": "STING" } ] }, "prior_uuids": [ "7d4a2c8b-cf51-46d6-a1c0-e1db353b2bed" ] }, "text_refs": { "PMID": "31650029", "PMCID": "PMC6804519", "DOI": "10.1016/J.OMTO.2019.09.001", "TRID": 30764180 }, "source_hash": 9068152690913553274 } ], "id": "7d4a2c8b-cf51-46d6-a1c0-e1db353b2bed", "matches_hash": "-35878850377651746", "supported_by": [ "48caccf4-18a4-4745-b24a-72aa569eba82" ] }, { "type": "Phosphorylation", "sub": { "name": "NFASC", "db_refs": { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } }, "belief": 0.5818739266864731, "evidence": [ { "source_api": "sparser", "pmid": "33414453", "text": "In the present study, KA decreased NF-S10 phosphorylation, which was reversed by PLPP/CIN deletion (Fig. xref ).", "annotations": { "prior_hash": -6408857572109351, "agents": { "raw_text": [ null, "NF" ], "raw_grounding": [ null, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ "cd353067-8848-4fb4-8b13-22340e555bd8" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 7123274747200941231 }, { "source_api": "sparser", "pmid": "33414453", "text": "Furthermore, NF-S10 phosphorylation increases NF2-actin binding and F-actin stability xref , although S518 phosphorylation weakens the NF2-cytoskeleton associations xref .", "annotations": { "prior_hash": -6408857572109351, "agents": { "raw_text": [ null, "NF" ], "raw_grounding": [ null, { "TEXT": "NF", "HGNC": "29866", "UP": "O94856", "EGID": "23114" } ] }, "prior_uuids": [ "62e69f36-123b-4fc5-8148-683162a1a40f" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -3434520322418749472 } ], "id": "9d9524eb-4952-48fe-a551-36302ab440f0", "matches_hash": "7153399996190305" }, { "type": "Phosphorylation", "sub": { "name": "DPYSL2", "db_refs": { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } }, "residue": "S", "position": "518", "belief": 0.7179198932687311, "evidence": [ { "source_api": "sparser", "pmid": "30915713", "text": "Proteomic analyses revealed that CRMP2 O -GlcNAcylation\nis located on the residue S517 and co-exists with CRMP2 phosphorylation on the\nneighboring residue S518 [ xref ].", "annotations": { "prior_hash": 14455435416502184, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "575e0d6f-27ca-4246-93ac-e64f838f2681" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -1447772676485181327 } ], "id": "575e0d6f-27ca-4246-93ac-e64f838f2681", "matches_hash": "14455435416502184", "supported_by": [ "5fd41c6a-be4f-4f54-a304-a1492156690f" ] }, { "type": "Phosphorylation", "sub": { "name": "DPYSL2", "db_refs": { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } }, "residue": "T", "position": "514", "belief": 0.6065692910910107, "evidence": [ { "source_api": "sparser", "pmid": "30915713", "text": "CRMP2 has recently been implicated in cancer progression, with CRMP2\nS522 or T514 phosphorylation increased in the tumors of several cancer variants,\nincluding glioblastoma, breast, lung, small intestinal neuroendocrine tumors,\nand lymphoma [ xref , xref , xref , xref , xref ].", "annotations": { "prior_hash": 12650205769066621, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "038624a8-2ba5-4c0b-ab4f-515b234d856d" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -8596099767376400094 } ], "id": "038624a8-2ba5-4c0b-ab4f-515b234d856d", "matches_hash": "12650205769066621", "supported_by": [ "5fd41c6a-be4f-4f54-a304-a1492156690f" ] }, { "type": "Phosphorylation", "sub": { "name": "DPYSL2", "db_refs": { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } }, "residue": "T", "position": "555", "belief": 0.605621755441964, "evidence": [ { "source_api": "sparser", "pmid": "30915713", "text": "In an animal model of multiple sclerosis (myelin oligodendrocyte glycoprotein\npeptide 25\u201335 (MOG 35\u201355 ) induced model of experimental\nautoimmune encephalomyelitis (EAE)), CRMP2 phosphorylation on T555 was increased\nin the axons located around inflammatory lesions in the spinal cord during the\nonset and the peak of EAE [ xref ].", "annotations": { "prior_hash": -14485031764057597, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "63c1355b-7a62-481b-8cae-e89cbe4fbd1a" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": 9104669836924438670 }, { "source_api": "sparser", "pmid": "30915713", "text": "Conversely,\nkainates, ephrins, lysophosphatidic acid (LPA), and lipids such as\nsphingosine-1-phosphate (S1P) can simulate CRMP2 phosphorylation at T555 via\ntheir association with their respective ligands.", "annotations": { "prior_hash": -14485031764057597, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "aebb0161-433a-4e32-9a42-396128a7c6ab" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -2640673871364132343 }, { "source_api": "sparser", "pmid": "30915713", "text": "Thus, CRMP2 phosphorylation at T555 plays a\nrole in regulating CRMP2 affinity for tubulin heterodimers but is probably\naccompanied by additional phosphorylations of CRMP2 (likely by Cdk5 and\nGSK3\u03b2) to induce growth cone collapse.", "annotations": { "prior_hash": -14485031764057597, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "5d9e2818-14ca-4fa9-bc18-73e1bf9f9afc" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", 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phosphorylating GSK3\u03b2 at S9.", "annotations": { "prior_hash": -33305704663350134, "agents": { "raw_text": [ null, "GSK3\u03b2" ], "raw_grounding": [ null, { "UP": "P49841", "EGID": "2932", "HGNC": "4617", "TEXT": "GSK3\u03b2" } ] }, "prior_uuids": [ "4be3f23d-dc36-47a3-9048-87979c56f073" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": 8291976178048015644 }, { "source_api": "sparser", "pmid": "23434321", "text": "We also examined GSK-3\u03b2 serine 9 inactivating phosphorylation and observed a reduction in CXCR4-depleted MPNST cells ( xref ).", "annotations": { "prior_hash": -33305704663350134, "agents": { "raw_text": [ null, "GSK-3\u03b2" ], "raw_grounding": [ null, { "UP": "P49841", "EGID": "2932", "HGNC": "4617", "TEXT": "GSK-3\u03b2" } ] }, "prior_uuids": [ "b19d6377-9de0-4521-b79e-0f80614f92cf" ] }, "text_refs": { "PMID": "23434321", "PMCID": "PMC3594500", 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KIT was phosphorylated and activated in all GISTs, but this amount was not correlated with the mutational GISTs status. xref These data suggested a transcriptional regulation of KIT overexpression in GISTs.", "annotations": { "prior_hash": -33249019699681166, "agents": { "raw_text": [ null, "KIT" ], "raw_grounding": [ null, { "TEXT": "KIT", "HGNC": "6342", "UP": "P10721", "EGID": "3815" } ] }, "prior_uuids": [ "f454da81-be50-4716-b906-6f7130b11b22" ] }, "text_refs": { "PMID": "23776354", "PMCID": "PMC3681166", "DOI": "10.2147/TACG.S7191", "TRID": 21211699 }, "source_hash": -2507446373824600066 } ], "id": "41933c45-0104-4c5d-9aea-9f34f201e15d", "matches_hash": "-33249019699681166" }, { "type": "Phosphorylation", "sub": { "name": "L1CAM", "db_refs": { "TEXT": "S10", "HGNC": "6470", "UP": "P32004", "EGID": "3897" } }, "belief": 0.5686774823242304, "evidence": [ { "source_api": "sparser", "pmid": "33414453", "text": "Since PKA simultaneously phosphorylates NF2 at S10 and S518 sites xref , 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of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { 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(4EBP1) and p70 ribosomal S6 kinase (p70S6K)" ], "raw_grounding": [ null, { "UP": "Q9UQF2", "TEXT": "the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K)", "HGNC": "6882", "EGID": "9479" } ] }, "prior_uuids": [ "4afa1343-4785-483d-9fca-11e862c44c17" ] }, "text_refs": { "PMID": "21307646", "PMCID": "PMC3154047", "DOI": "10.4161/OXIM.3.6.14787", "TRID": 19880770 }, "source_hash": -8202485149629148821 }, { "source_api": "sparser", "pmid": "23267122", "text": "Upon stimulation by either growth factors or nutrients, mTORC1 assembles and promotes the phosphorylation of its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).", "annotations": { "prior_hash": 22350099080849913, "agents": { "raw_text": [ null, "its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1)" ], "raw_grounding": [ null, { "UP": "Q9UQF2", "TEXT": "its two key effectors, p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1)", "HGNC": "6882", "EGID": "9479" } ] }, "prior_uuids": [ "a02c15e8-d3e3-4e26-84a6-1f993bf1715e" ] }, "text_refs": { "PMID": "23267122", "PMCID": "PMC3725758", "MANUSCRIPT_ID": "NIHMS494794", "TRID": 16129620 }, "source_hash": -906826060894133162 } ], "id": "f678ce11-5175-40bb-8633-fd8fd608a0e7", "matches_hash": "22350099080849913" }, { "type": "Phosphorylation", "sub": { "name": "MAPK9", "db_refs": { "UP": "P45984", "TEXT": "Erk1/2, Akt, and JNK", "HGNC": "6886", "EGID": "5601" } }, "belief": 0.7743278581086912, "evidence": [ { "source_api": "sparser", "pmid": "25289889", "text": "In keeping with our previous findings with tamoxifen and a potential overlap in tamoxifen and trifluoperazine action, trifluoperazine treatment resulted in decreases in the phosphorylation of Erk1/2, Akt, and JNK, demonstrating that tamoxifen and trifluoperazine target some of the same signaling cascades in MPNST cells.", "annotations": { "prior_hash": 19988065872122048, "agents": { "raw_text": [ null, "Erk1/2, Akt, and JNK" ], "raw_grounding": [ null, { "UP": "P45984", "TEXT": "Erk1/2, Akt, and JNK", "HGNC": "6886", "EGID": "5601" } ] }, "prior_uuids": [ "8367376d-8861-4d2b-964b-44d1f584f684" ] }, "text_refs": { "PMID": "25289889", "PMCID": "PMC4458069", "DOI": "10.1097/NEN.0000000000000126", "MANUSCRIPT_ID": "NIHMS625690", "TRID": 17613956 }, "source_hash": -7692543903193143613 } ], "id": "8367376d-8861-4d2b-964b-44d1f584f684", "matches_hash": "19988065872122048", "supported_by": [ "ed79926b-1706-4285-9065-4b85a8c46f7b", "5032c3d2-f887-4135-8933-e3b1024f4f1c" ] }, { "type": "Phosphorylation", "sub": { "name": "MAPRE1", "db_refs": { "UP": "Q15691", "TEXT": "KIT, MAP, and Akt", "HGNC": "6890", "EGID": "22919" } }, "belief": 0.6048402557226642, "evidence": [ { "source_api": "sparser", "pmid": "18671247", "text": "Imatinib treatment markedly inhibited KIT, MAP, and Akt phosphorylation in all transfectants, leading to reduced glucose uptake via decreased levels of plasma membrane-bound Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": -16858833179287227, "agents": { "raw_text": [ null, "KIT, MAP, and Akt" ], "raw_grounding": [ null, { "UP": "Q15691", "TEXT": "KIT, MAP, and Akt", "HGNC": "6890", "EGID": "22919" } ] }, "prior_uuids": [ "c0d66e24-f89f-4f16-9b68-7a061dde7650" ] }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 } ], "id": "c0d66e24-f89f-4f16-9b68-7a061dde7650", "matches_hash": "-16858833179287227" }, { "type": "Phosphorylation", "sub": { "name": "MAPRE3", "db_refs": { "UP": "Q9UPY8", "TEXT": "KIT, MAP, and Akt", "HGNC": "6892", "EGID": "22924" } }, "belief": 0.5851928070315653, "evidence": [ { "source_api": "sparser", "pmid": "18671247", "text": "Imatinib treatment markedly inhibited KIT, MAP, and Akt phosphorylation in all transfectants, leading to reduced glucose uptake via decreased levels of plasma membrane-bound Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": -6315831128530194, "agents": { "raw_text": [ null, "KIT, MAP, and Akt" ], "raw_grounding": [ null, { "UP": "Q9UPY8", "TEXT": "KIT, MAP, and Akt", "HGNC": "6892", "EGID": "22924" } ] }, "prior_uuids": [ "bb6814a4-f0bd-4607-a19f-e1b964432607" ] }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 } ], "id": "bb6814a4-f0bd-4607-a19f-e1b964432607", "matches_hash": "-6315831128530194" }, { "type": "Phosphorylation", "sub": { "name": "MAPT", "db_refs": { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } }, "belief": 0.7669895863210118, "evidence": [ { "source_api": "sparser", "pmid": "30915713", "text": "LKE treatment also reduced\npathology in a mouse model of Alzheimer\u2019s disease (AD), in which it\nreduced amyloid deposition, phospho-tau accumulation, and the density of\nIba1 stained microglial cells [ xref ].", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "tau" ], "raw_grounding": [ null, { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } ] }, "prior_uuids": [ "c904ef7e-f2dd-4317-863a-f87906b9c464" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": 3716895938676310546 }, { "source_api": "sparser", "pmid": "19333415", "text": "Alzheimer\u2019s disease (AD) is the most common neurodegenerative disease characterized by extracellular accumulation of A\u00df peptide in senile plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles and neuropil threads [ xref , xref ].", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "tau" ], "raw_grounding": [ null, { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } ] }, "prior_uuids": [ "8a86618a-0c10-4f59-97f5-d4597e8e20c6" ] }, "text_refs": { "PMID": "19333415", "PMCID": "PMC2660653", "DOI": "10.3390/IJMS10020407", "TRID": 15634799 }, "source_hash": -9082333260138268664 }, { "source_api": "sparser", "pmid": "19333415", "text": "When wildtype human tau (4R isoform) was coexpressed with the fly homolog of GSK-3\u03b2 (shaggy), presumably involved in hyperphosphorylation of tau, neurodegeneration was enhanced and insoluble intraneuronal NFT formation, positive for AT100 antibody was observed.", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "tau" ], "raw_grounding": [ null, { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } ] }, "prior_uuids": [ "f4bc914a-d6a1-4dea-8769-cb998c1032d6" ] }, "text_refs": { "PMID": "19333415", "PMCID": "PMC2660653", "DOI": "10.3390/IJMS10020407", "TRID": 15634799 }, "source_hash": 2628482535022376361 }, { "source_api": "sparser", "pmid": "19333415", "text": "Thus, Drosophila tau models replicate several important features of human tauopathies, including tau hyperphosphorylation, accumulation, NFT formation and neuronal degeneration.", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "tau" ], "raw_grounding": [ null, { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } ] }, "prior_uuids": [ "865f6122-005f-47ac-bbfe-5c15d67ff4a1" ] }, "text_refs": { "PMID": "19333415", "PMCID": "PMC2660653", "DOI": "10.3390/IJMS10020407", "TRID": 15634799 }, "source_hash": -3592396543555937655 }, { "source_api": "sparser", "pmid": "18671247", "text": "Imatinib treatment markedly inhibited KIT, MAP, and Akt phosphorylation in all transfectants, leading to reduced glucose uptake via decreased levels of plasma membrane-bound Glut4 and induction of apoptosis and/or growth arrest. xref Long-term results from a randomized phase II trial by Blanke et al. showed that nearly 50% of patients with advanced GIST who were treated with imatinib survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose. xref Chen et al. found the effect of imatinib on KIT(820Tyr) was weaker than that on KIT(del559\u2013560) or KIT(642Glu), indicating varying biological effects of imatinib on GISTs that have different KIT and PDGFRA mutational settings. xref In the recently published randomized EORTC phase III trial study, tumors with mutation in KIT exon 11 showed response rates of up to 80%, whereas fewer than 50% of tumors with mutation in KIT exon 9 responded. xref The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% and the relative risk of death by 190% when compared with KIT exon 11 mutants.", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "KIT, MAP, and Akt" ], "raw_grounding": [ null, { "UP": "P10636", "TEXT": "KIT, MAP, and Akt", "HGNC": "6893", "EGID": "4137" } ] }, "prior_uuids": [ "537877c7-f47e-4c45-82e4-c7b0ff2c7d58" ] }, "text_refs": { "PMID": "18671247", "PMCID": "PMC2651090", "DOI": "10.1002/CNCR.23778", "MANUSCRIPT_ID": "NIHMS64614", "TRID": 2170736 }, "source_hash": -4630390173052933765 }, { "source_api": "sparser", "pmid": "19333415", "text": "Neurofibrillary tangles (NFT), neuritic plaques and neuropil threads composed of hyperphosphorylated tau forming intraneuronal inclusions are characteristic of AD, but tau inclusions are also associated with other neurodegenerative diseases such as Pick\u2019s disease, corticobasal degeneration, argyrophilic grain disease, progressive supranuclear palsy and fronto-temporal lobar degeneration (FTLD) [ xref ] characterized by diverse clinico-pathological phenotypes from aphasia to dementia syndromes [ xref ].", "annotations": { "prior_hash": -7600514167452466, "agents": { "raw_text": [ null, "tau" ], "raw_grounding": [ null, { "UP": "P10636", "HGNC": "6893", "EGID": "4137", "TEXT": "tau" } ] }, "prior_uuids": [ "a57b6290-7139-4e28-96a4-7554f57c1ad8" ] }, "text_refs": { "PMID": "19333415", "PMCID": "PMC2660653", "DOI": "10.3390/IJMS10020407", "TRID": 15634799 }, "source_hash": -1015292954458236614 } ], "id": "30ba7d23-cda0-4fd4-a3cf-bfa6f5c9ebaa", "matches_hash": "-7600514167452466" }, { "type": "Phosphorylation", "sub": { "name": "MDM2", "db_refs": { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } }, "residue": "S", "position": "166", "belief": 0.7621682892796044, "evidence": [ { "source_api": "sparser", "pmid": "33414453", "text": "KA also reduced Mdm2-S166 phosphorylation to 0.66- and 0.47-fold of control WT levels in WT mice and PLPP/CIN Tg mice, respectively ( F (3,24) \u2009=\u200952.87, p \u2009<\u20090.0001, one-way ANOVA, n \u2009=\u20097, respectively; Fig. xref a and f).", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "09377394-53c7-41ca-b6e7-1e296d2a78f6" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 268619026282842956 }, { "source_api": "sparser", "pmid": "33414453", "text": "Considering no effect of NF2 knockdown on Mdm2-S166 phosphorylation, these findings indicate that Mdm2-S166 phosphorylation may be required for Mdm2-mediated PSD95 degradation.", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "c5e9f550-3854-440a-821b-7ff12a6dec26" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -61272109006105675 }, { "source_api": "sparser", "pmid": "33414453", "text": "Therefore, it is excluded the possibility that the NF2-mediated AKT regulation would affect Mdm2-S166 phosphorylation in PLPP/CIN Tg and PLPP/CIN \u2212/\u2212 mice.", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "69f2a586-d5b3-4e3c-90f9-4e7b6821af68" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -348250658353127281 }, { "source_api": "sparser", "pmid": "33414453", "text": "However, the present data show that NF2 siRNA did not change Mdm2-S166 phosphorylation under physiological condition.", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "4367a328-1c30-4836-ad71-e3b481119486" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": -7407292192191825018 }, { "source_api": "sparser", "pmid": "33414453", "text": "Thus, it is plausible that NF2 itself and/or NF2-S10 phosphorylation would directly affect AKT-mediated Mdm2-S166 phosphorylation.", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "26724b80-85d9-441c-9acc-40cf4d0107d3" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 4594688431359186799 }, { "source_api": "sparser", "pmid": "33414453", "text": "Interestingly, NF2 also decreases Mdm2-S166 phosphorylation by inhibiting AKT activity xref .", "annotations": { "prior_hash": 14897846701546320, "agents": { "raw_text": [ null, "Mdm2" ], "raw_grounding": [ null, { "UP": "Q00987", "EGID": "4193", "HGNC": "6973", "TEXT": "Mdm2" } ] }, "prior_uuids": [ "e078d19b-724d-402b-bada-c97b4e1c07ad" ] }, "text_refs": { "PMID": "33414453", "TRID": 32626669, "PMCID": "PMC7791067", "DOI": "10.1038/S41419-020-03325-9" }, "source_hash": 4357605236410241841 } ], "id": "f6624cdf-6e46-4216-b6aa-804905007b87", "matches_hash": "14897846701546320" }, { "type": "Phosphorylation", "sub": { "name": "MET", "db_refs": { "UP": "P08581", "TEXT": "EGFR, MET, PDGFRA, PDGFRB, AXL and TYRO3", "HGNC": "7029", "EGID": "4233" } }, "belief": 0.7766988995792896, "evidence": [ { "source_api": "sparser", "pmid": "25551830", "text": "The results from phosphorylated RTK protein array showed that the levels of phosphorylated EGFR, MET, PDGFRA, PDGFRB, AXL and TYRO3 were increased in at least three of the four MPNST cell lines tested ( xref ).", "annotations": { "prior_hash": -19072182362961226, "agents": { "raw_text": [ null, "EGFR, MET, PDGFRA, PDGFRB, AXL and TYRO3" ], "raw_grounding": [ null, { "UP": "P08581", "TEXT": "EGFR, MET, PDGFRA, PDGFRB, AXL and TYRO3", "HGNC": "7029", "EGID": "4233" } ] }, "prior_uuids": [ "6168fd11-2393-4abf-8941-0fb23ea11b91" ] }, "text_refs": { "PMID": "25551830", "PMCID": "PMC4281253", "DOI": "10.1371/JOURNAL.PONE.0115916", "TRID": 16641348 }, "source_hash": -7156215868636227722 }, { "source_api": "sparser", "pmid": "29720369", "text": "Currently, it is difficult to define the size or makeup of\nthe \u201cMET-addicted\u201d clinical subset in the neurofibromatosis population\ndue to the lack of suitable biomarkers, however MET Y1234/35 phosphorylation has\nbeen proposed as a candidate immunohistochemical marker to define MET-activated\nMPNSTs, and predict MET inhibitor response ( xref ).", "annotations": { "prior_hash": -19072182362961226, "agents": { "raw_text": [ null, "MET" ], "raw_grounding": [ null, { "UP": "P08581", "EGID": "4233", "HGNC": "7029", "TEXT": "MET" } ] }, "prior_uuids": [ "cef4810b-926b-4e64-80df-ed995a05c1ae" ] }, "text_refs": { "PMID": "29720369", "PMCID": "PMC6235171", "DOI": "10.1158/0008-5472.CAN-17-3167", "PII": "CANRES.3167.2017", "MANUSCRIPT_ID": "NIHMS995301", "TRID": 28678666 }, "source_hash": -2276558562585641274 }, { "source_api": "sparser", "pmid": "29720369", "text": "MET phosphorylation (Tyr1234/35)\nwas demonstrated in at least half of MPNSTs, and was recently proposed as a\nbiomarker for MET-activated MPNSTs ( xref ).", "annotations": { "prior_hash": -19072182362961226, "agents": { "raw_text": [ null, "MET" ], "raw_grounding": [ null, { "UP": "P08581", "EGID": "4233", "HGNC": "7029", "TEXT": "MET" } ] }, "prior_uuids": [ "297301af-178a-46e8-93fb-cc6720ca7097" ] }, "text_refs": { "PMID": "29720369", "PMCID": "PMC6235171", "DOI": "10.1158/0008-5472.CAN-17-3167", "PII": "CANRES.3167.2017", "MANUSCRIPT_ID": "NIHMS995301", "TRID": 28678666 }, "source_hash": 5190701960155620766 }, { "source_api": "sparser", "pmid": "24371224", "text": "Immunoblot analysis demonstrated that SU11274 treatment blocks phosphorylation of c-Met and ERK1/2 in both MM cell lines tested, although AKT phosphorylation, a known substrate of c-Met, was downregulated in only one cell line (MM 87; xref ).", "annotations": { "prior_hash": -19072182362961226, "agents": { "raw_text": [ null, "c-Met and ERK1/2" ], "raw_grounding": [ null, { "UP": "P08581", "TEXT": "c-Met and ERK1/2", "HGNC": "7029", "EGID": "4233" } ] }, "prior_uuids": [ "c98f83d2-6588-4303-ac6c-6accc17f855d" ] }, "text_refs": { "PMID": "24371224", "PMCID": "PMC3945416", "DOI": "10.1158/0008-5472.CAN-13-2062", "MANUSCRIPT_ID": "NIHMS552351", "TRID": 12851870 }, "source_hash": 3168327291086253503 } ], "id": "147cb843-58fd-4854-b3df-3692c68d103a", "matches_hash": "-19072182362961226" }, { "type": "Phosphorylation", "sub": { "name": "MST1", "db_refs": { "UP": "P26927", "TEXT": "MST1 or MST2", "HGNC": "7380", "EGID": "4485" } }, "belief": 0.6046253577886147, "evidence": [ { "source_api": "sparser", "pmid": "25026211", "text": "Unexpectedly, neither expression of Merlin nor silencing of DCAF1 increased phosphorylation of the activation loop of MST1 or MST2 ( xref ).", "annotations": { "prior_hash": 9506171976074362, "agents": { "raw_text": [ null, "MST1 or MST2" ], "raw_grounding": [ null, { "UP": "P26927", "TEXT": "MST1 or MST2", "HGNC": "7380", "EGID": "4485" } ] }, "prior_uuids": [ "3f2ab294-87f6-4cf9-b749-a085f8fc8842" ] }, "text_refs": { "PMID": "25026211", "PMCID": "PMC4126592", "DOI": "10.1016/J.CCR.2014.05.001", "PII": "S1535-6108(14)00189-5", "MANUSCRIPT_ID": "NIHMS593760", "TRID": 23759943 }, "source_hash": -6978151997253512533 } ], "id": "3f2ab294-87f6-4cf9-b749-a085f8fc8842", "matches_hash": "9506171976074362" }, { "type": "Phosphorylation", "sub": { "name": "MYL2", "db_refs": { "TEXT": "myosin light chain 2", "HGNC": "7583", "EGID": "4633", "UP": "P10916" } }, "residue": "S", "position": "19", "belief": 0.6627867044811734, "evidence": [ { "source_api": "sparser", "pmid": "20442305", "text": "As further evidence that the Rho signaling pathway is disrupted, KR158 cells treated with SA and EGF were immunostained for phosphorylation of Ser 19 on myosin light chain 2 (MLC2), which is downstream of Rho/Rock signaling.", "annotations": { "prior_hash": -31419499978101348, "agents": { "raw_text": [ null, "myosin light chain 2" ], "raw_grounding": [ null, { "TEXT": "myosin light chain 2", "HGNC": "7583", "EGID": "4633", "UP": "P10916" } ] }, "prior_uuids": [ "659c0d59-33c2-4e11-86b1-349bdc3d01ba" ] }, "text_refs": { "PMID": "20442305", "PMCID": "PMC3268685", "DOI": "10.1158/1535-7163.MCT-09-0834", "MANUSCRIPT_ID": "NIHMS187633", "TRID": 6028049 }, "source_hash": -870521820063443125 }, { "source_api": "sparser", "pmid": "20442305", "text": "As further evidence that the Rho signaling pathway is disrupted, KR158 cells treated with SA and EGF were immunostained for phosphorylation of Ser 19 on myosin light chain 2 (MLC2), which is downstream of 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(an ADP ribosyl transferase that selectively ribosylates RhoA, RhoB, and RhoC proteins on asparagine residue 41, rendering them inactive), Y-27632 (a specific inhibitor of the ROCK family of protein kinases), or a Rac1 inhibitor to examine which member in the Rho family GTPase is responsible for the induction of SEMA3F and TSP2 on the reintroduction of merlin / NF2.", "annotations": { "found_by": "Ribosylation_syntax_1a_verb", "agents": { "coords": [ [ 75, 78 ], [ 144, 148 ] ], "raw_text": [ "transferase", "RhoC" ], "raw_grounding": [ { "TEXT": "transferase", "MESH": "D014166" }, { "UP": "P08134", "EGID": "389", "HGNC": "669", "TEXT": "RhoC" } ] }, "prior_hash": -12857352450572943, "prior_uuids": [ "54a0d522-6e4f-47fe-94fc-bf4dde834891" ], "indranet_edge": { "residue": null, "position": "41", "stmt_type": "Ribosylation", "evidence_count": 1, "stmt_hash": -2975774728243501, "belief": 0.20369829545922236, "source_counts": { "reach": 1 }, "internal": true } }, "epistemics": { "direct": 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regulates microtubule dynamics [ xref , xref , xref , xref ].", "annotations": { "prior_hash": -7357585100784017, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "75e13ea7-7066-4be1-9001-faaff9bfe250" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -5633753686741058677 }, { "source_api": "sparser", "pmid": "30915713", "text": "Similarly, SUMOylation of CRMP2 at Lys 374 also decreases CaV2.2-mediated\ncalcium influx in sensory neurons [ xref ].", "annotations": { "prior_hash": -7357585100784017, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "8630d5e1-c13f-43d9-b131-cfe5637ce18d" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": 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"position": "522", "belief": 0.2746754993076932, "evidence": [ { "source_api": "sparser", "pmid": "30915713", "text": "CRMP2 S522 phosphorylation and SUMOylation are\nregulatory events of these channels\u2019 pre-synaptic localization [ xref , xref ].", "annotations": { "prior_hash": 30269761861822557, "agents": { "raw_text": [ null, "CRMP2" ], "raw_grounding": [ null, { "TEXT": "CRMP2", "HGNC": "3014", "UP": "Q16555", "EGID": "1808" } ] }, "prior_uuids": [ "0f0985bd-69cc-40b2-ad85-98499a21f70d" ] }, "text_refs": { "PMID": "30915713", "PMCID": "PMC6728212", "DOI": "10.1007/S12035-019-1568-4", "MANUSCRIPT_ID": "NIHMS1525514", "TRID": 30037397 }, "source_hash": -6336036578583042456 } ], "id": "0f0985bd-69cc-40b2-ad85-98499a21f70d", "matches_hash": "30269761861822557", "supported_by": [ "9ef0f799-e572-4a6e-abaf-b27c2b272dd8" ] }, { "type": "Sumoylation", "sub": { "name": "NF1", "db_refs": { "TEXT": "Nf1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } }, "belief": 0.38542168017160217, "evidence": [ { "source_api": "sparser", "pmid": "22293200", "text": "Nf1 sumoylation might be antagonistic or synergistic to its ubiquitinylation as described for many other proteins involved in different cellular processes [37] and its localization in PML bodies might promote and regulate its sumoylation.", "annotations": { "prior_hash": -17017529897290209, "agents": { "raw_text": [ null, "Nf1" ], "raw_grounding": [ null, { "TEXT": "Nf1", "HGNC": "7765", "EGID": "4763", "UP": "P21359" } ] }, "prior_uuids": [ "b6bbb344-dfdc-44fc-9299-e8bcf79d61d9" ] }, "text_refs": { "PMID": "22293200", "DOI": "10.1016/J.BBRC.2012.01.079", "TRID": 16926969 }, "source_hash": -6056836781891658647 }, { "source_api": "sparser", "pmid": "22293200", "text": "Our attempts to demonstrate a sumoylation of Nf1 using anti-SUMO-1 Ab after Nf1 immunoprecipitation have been unsuccessful.", "annotations": { "prior_hash": -17017529897290209, "agents": { "raw_text": [ null, "Nf1" ], "raw_grounding": [ null, { "TEXT": 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"S1383-5742(14)00074-X", "TRID": 165507 }, "source_hash": 7280521838356801185 }, { "source_api": "sparser", "pmid": "25795125", "text": "Moreover, deletion of ELG1 resulted in the accumulation of SUMOylated PCNA on the chromatin, suggesting a role for Elg1 in either PCNA unloading or de-SUMOylation [62] .", "annotations": { "prior_hash": -28693517133649807, "agents": { "raw_text": [ null, "PCNA" ], "raw_grounding": [ null, { "UP": "P12004", "EGID": "5111", "HGNC": "8729", "TEXT": "PCNA" } ] }, "prior_uuids": [ "86da6c54-5c1f-4a7f-83a0-ee33dc168920" ] }, "text_refs": { "PMID": "25795125", "DOI": "10.1016/J.MRREV.2014.11.007", "PII": "S1383-5742(14)00074-X", "TRID": 165507 }, "source_hash": -5337144749296860275 }, { "source_api": "sparser", "pmid": "25795125", "text": "Recently, it was found that mammalian PCNA undergoes SUMOylation [149,150] , as well as modification by ISG15, another ubiquitin-like small molecule that is believed to serve in terminating PRR [80] .", "annotations": { "prior_hash": -28693517133649807, "agents": { "raw_text": [ null, "PCNA" ], "raw_grounding": [ null, { "UP": "P12004", "EGID": "5111", "HGNC": "8729", "TEXT": "PCNA" } ] }, "prior_uuids": [ "aeb8179c-d41b-48b4-8290-a35ab27ee42c" ] }, "text_refs": { "PMID": "25795125", "DOI": "10.1016/J.MRREV.2014.11.007", "PII": "S1383-5742(14)00074-X", "TRID": 165507 }, "source_hash": 8118732407392476000 }, { "source_api": "sparser", "pmid": "25795125", "text": "Although the yeast Elg1 protein was found to preferentially interact with SUMOylated PCNA [56,63] , its human counterpart was found to regulate the levels of PCNA ubiquitination, not SUMOylation [95] .", "annotations": { "prior_hash": -28693517133649807, "agents": { "raw_text": [ null, "PCNA" ], "raw_grounding": [ null, { "UP": "P12004", "EGID": "5111", "HGNC": "8729", "TEXT": "PCNA" } ] }, "prior_uuids": [ "d772bf41-1da7-4ed2-bd4f-975e9abdd785" ] }, "text_refs": { "PMID": "25795125", "DOI": "10.1016/J.MRREV.2014.11.007", "PII": 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pre-requisite for cohesin activation.", "annotations": { "prior_hash": -28693517133649807, "agents": { "raw_text": [ null, "PCNA" ], "raw_grounding": [ null, { "UP": "P12004", "EGID": "5111", "HGNC": "8729", "TEXT": "PCNA" } ] }, "prior_uuids": [ "bb0d5355-3176-4705-bc69-3331558fed7d" ] }, "text_refs": { "PMID": "25795125", "DOI": "10.1016/J.MRREV.2014.11.007", "PII": "S1383-5742(14)00074-X", "TRID": 165507 }, "source_hash": -1521360082595190576 }, { "source_api": "sparser", "pmid": "25795125", "text": "PCNA SUMOylation may thus act as a local signal to coordinate unloading by the Elg1-RLC, and the Ctf18-RLC may participate in re-loading.", "annotations": { "prior_hash": -28693517133649807, "agents": { "raw_text": [ null, "PCNA" ], "raw_grounding": [ null, { "UP": "P12004", "EGID": "5111", "HGNC": "8729", "TEXT": "PCNA" } ] }, "prior_uuids": [ "08339598-1bfa-4a76-9a41-489f8d3e0628" ] }, "text_refs": { "PMID": "25795125", "DOI": "10.1016/J.MRREV.2014.11.007", "PII": 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of Sav on Hippo signaling output in S2R+ cells.", "annotations": { "location": "GO:0016020", "prior_hash": 34239774276905451, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ "3bcccfb0-93af-4fc0-9bfb-73ea57e4d31c" ] }, "text_refs": { "PMID": "24012335", "PMCID": "PMC3835333", "DOI": "10.1016/J.CELL.2013.08.025", "PII": "S0092-8674(13)01019-2", "MANUSCRIPT_ID": "NIHMS526293", "TRID": 26758113 }, "source_hash": -3245627054310925906 }, { "source_api": "sparser", "pmid": "24012335", "text": "To investigate the functional role of Sav-induced membrane recruitment of Hpo, we analyzed the effect of Sav on Hippo signaling output in S2R+ cells.", "annotations": { "location": "GO:0016020", "prior_hash": -35520100318249632, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ "e92e9d58-4df6-4f25-a266-184a1c748f15" ] }, "text_refs": { "PMID": "24012335", "PMCID": "PMC3835333", "DOI": "10.1016/J.CELL.2013.08.025", "PII": "S0092-8674(13)01019-2", "MANUSCRIPT_ID": "NIHMS526293", "TRID": 26758113 }, "source_hash": -3245627054310925906 }, { "source_api": "sparser", "pmid": "24012335", "text": "Sav-induced membrane translocation of Hpo is mediated by direct binding, since it was abolished by mutation of Sav\u2019s SARAH domain ( xref ), which is known to mediate Sav-Hpo binding ( xref ).", "annotations": { "location": "GO:0016020", "prior_hash": 34239774276905451, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ "dd2c8824-2605-496b-8b9f-8d7dc464f1bc" ] }, "text_refs": { "PMID": "24012335", "PMCID": "PMC3835333", "DOI": "10.1016/J.CELL.2013.08.025", "PII": "S0092-8674(13)01019-2", "MANUSCRIPT_ID": "NIHMS526293", "TRID": 26758113 }, "source_hash": -1315576901739586188 }, { "source_api": "sparser", "pmid": "24012335", "text": "Sav-induced membrane translocation of Hpo is mediated by direct binding, since it was abolished by mutation of Sav\u2019s SARAH domain ( xref ), which is known to mediate Sav-Hpo binding ( xref ).", "annotations": { "location": "GO:0016020", "prior_hash": -35520100318249632, "agents": { "raw_text": [ "Hpo" ], "raw_grounding": [ { "TEXT": "Hpo", "CHEBI": "CHEBI:32363" } ] }, "prior_uuids": [ "1e5bf9e9-b6e4-413e-b077-45abb5c8fd5a" ] }, "text_refs": { "PMID": "24012335", "PMCID": "PMC3835333", "DOI": "10.1016/J.CELL.2013.08.025", "PII": "S0092-8674(13)01019-2", "MANUSCRIPT_ID": "NIHMS526293", "TRID": 26758113 }, "source_hash": -1315576901739586188 } ], "id": "f0eb701d-92b9-4d68-b6ef-b2fdab02db32", "matches_hash": "17365225489649403" }, { "type": "Translocation", "agent": { "name": "messenger RNA", "db_refs": { "TEXT": "mRNA", "CHEBI": "CHEBI:33699" } }, "to_location": "cytoplasm", "belief": 0.4451393329684825, "evidence": [ { "source_api": "sparser", "pmid": "11072063", "text": "ApoB mRNA editing is a predominantly intra-nuclear event and is completed before the mature apoB mRNA is exported into the cytoplasm .", "annotations": { "location": "GO:0005737", "prior_hash": -22586685571826573, "agents": { "raw_text": [ "mRNA" ], "raw_grounding": [ { "TEXT": "mRNA", "CHEBI": "CHEBI:33699" } ] }, "prior_uuids": [ "96b80f65-b489-4c0d-a4c6-c8cfb05e5fd3" ] }, "text_refs": { "PMID": "11072063", "DOI": "10.1016/S0167-4781(00)00219-0", "TRID": 5913852 }, "source_hash": -2316491748935204592 } ], "id": "96b80f65-b489-4c0d-a4c6-c8cfb05e5fd3", "matches_hash": "-22586685571826573" }, { "type": "Translocation", "agent": { "name": "ERK", "db_refs": { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } }, "to_location": "nucleus", "belief": 0.8030653032529445, "evidence": [ { "source_api": "sparser", "pmid": "19595305", "text": "Following phosphorylation, ERK translocates to the nucleus where it activates various transcription factors and cell cycle regulatory proteins ( Downward, 2003; Garnett and Marais, 2004; Wellbrock et al. , 2004 ).", "annotations": { "location": "GO:0005634", "prior_hash": -31546789898613594, "agents": { "raw_text": [ "ERK" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } ] }, "prior_uuids": [ "fcff3af7-2873-48b6-9d6b-e5013383382f" ] }, "text_refs": { "PMID": "19595305", "DOI": "10.1016/S0065-230X(09)02001-6", "TRID": 1799050 }, "source_hash": 1577157446374791009 }, { "source_api": "sparser", "pmid": "24132643", "text": "Smith et al (2010) reported that lower KPNB1 expression in normal cells restricts the nuclear translocation of phospho-ERK after pathway stimulation, thereby limiting cell proliferation and maintaining a differentiated phenotype of ovarian and mammary epithelial cells, suggesting that KPNB1 levels are a rate-limiting step of RAS\u2013MAPK pathway activation.", "annotations": { "location": "GO:0005634", "prior_hash": -31546789898613594, "agents": { "raw_text": [ "ERK" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } ] }, "prior_uuids": [ "7d1d7dfc-10df-4a76-9528-01f4820c02ea" ] }, "text_refs": { "PMID": "24132643", "PMCID": "PMC4166508", "DOI": "10.1002/PATH.4294", "MANUSCRIPT_ID": "NIHMS620495", "TRID": 9061143 }, "source_hash": 4815350857058869501 }, { "source_api": "sparser", "pmid": "12604337", "text": "ERK proteins activated through signal transduction translocate to the nucleus [26] , where they can activate transcription factors, and thereby, regulate gene expression.", "annotations": { "location": "GO:0005634", "prior_hash": -31546789898613594, "agents": { "raw_text": [ "ERK" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } ] }, "prior_uuids": [ "70f3a805-57d7-4199-b8ca-edd810b39a1b" ] }, "text_refs": { "PMID": "12604337", "DOI": "10.1016/S0006-291X(03)00124-4", "TRID": 7226896 }, "source_hash": 7906208013205566806 }, { "source_api": "reach", "pmid": "19595305", "text": "Following phosphorylation, ERK translocates to the nucleus where it activates various transcription factors and cell cycle regulatory proteins (Downward, 2003; Garnett and Marais, 2004; Wellbrock et al., 2004).", "annotations": { "found_by": "translocation_8b_verb_active_no_cause", "agents": { "coords": [ [ 27, 30 ] ], "raw_text": [ "ERK" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } ] }, "prior_hash": -31546789898613594, "prior_uuids": [ "782c81a5-41c6-47a1-b2c0-2aa81bd3a722" ] }, "epistemics": { "direct": false, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005634" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "6239" } }, "type": "bio" }, "text_refs": { "PMID": "19595305", "DOI": "10.1016/S0065-230X(09)02001-6", "TRID": 1799050 }, "source_hash": -300467545263121412 }, { "source_api": "sparser", "pmid": "30302932", "text": "Active ERK translocates into the nucleus to phosphorylate transcription factors that turn on the production of proteins that, in turn, drive cells through the cell cycle into S-phase.", "annotations": { "location": "GO:0005634", "prior_hash": -31546789898613594, "agents": { "raw_text": [ "ERK" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "ERK" } ] }, "prior_uuids": [ "ae6ad5ec-28c7-4c23-aba1-7ac3e4da5e8b" ] }, "text_refs": { "PMID": "30302932", "PMCID": "PMC6312476", "DOI": "10.1002/AJMG.A.40632", "MANUSCRIPT_ID": "NIHMS998809", "TRID": 29419901 }, "source_hash": -124913046731327780 }, { "source_api": "reach", "pmid": "22077553", "text": "Erk1/2 phosphorylate cytoplasmic targets (e.g. p90 rsk), translocate to the nucleus, and activate multiple mitogenic transcription factors (e.g. c-Fos, Elk1, C/EBP), although Erk dependent transcriptional events and gene products are largely undocumented for the SCF stimulated Nf1 +/- mast cell.", "annotations": { "found_by": "translocation_8b_verb_active_no_cause", "agents": { "coords": [ [ 0, 6 ] ], "raw_text": [ "Erk1/2" ], "raw_grounding": [ { "FPLX": "ERK", "IP": "IPR008349", "NCIT": "C26360", "TEXT": "Erk1/2" } ] }, "prior_hash": -31546789898613594, "prior_uuids": [ "be3314f9-621d-4b7e-bf9d-f9be350edb10" ] }, "epistemics": { "direct": false, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005634" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "10090" } }, "type": "bio" }, "text_refs": { "PMID": "22077553", "PMCID": "PMC3694738", "DOI": "10.1146/ANNUREV-PATHOL-011811-132441", "MANUSCRIPT_ID": "NIHMS478542", "TRID": 7139777 }, "source_hash": 4825972064771610162 } ], "id": "6edcbb2f-3e10-4d24-9c53-4a78b5d684f8", "matches_hash": "-31546789898613594", "supported_by": [ "8e8c86e2-7005-4f48-9532-8f706998b4b5" ] }, { "type": "Translocation", "agent": { "name": "ERK", "db_refs": { "FPLX": "ERK", "TEXT": "MEK1/2, ERK1/2 and Raf", "IP": "IPR008349", "NCIT": "C26360" } }, "to_location": "plasma membrane", "belief": 0.649585697231348, "evidence": [ { "source_api": "sparser", "pmid": "26549023", "text": "KSR1 translocates to the plasma membrane upon growth factor stimulation, where it forms a complex with activated MEK1/2, ERK1/2 and Raf, which also translocates to the plasma membrane through association with Ras-GTP ( xref ).", "annotations": { "location": "GO:0005886", "prior_hash": -30038581230761295, "agents": { "raw_text": [ "MEK1/2, ERK1/2 and Raf" ], "raw_grounding": [ { "FPLX": "ERK", "TEXT": "MEK1/2, ERK1/2 and Raf", "IP": "IPR008349", "NCIT": "C26360" } ] }, "prior_uuids": [ "5a41e4db-ae05-4288-be98-92f79fad017e" ] }, "text_refs": { "PMID": "26549023", "PMCID": "PMC4861249", "DOI": "10.1038/ONC.2015.404", "MANUSCRIPT_ID": "EMS66778", "TRID": 27183378 }, "source_hash": 6467111499514678252 } ], "id": "5a41e4db-ae05-4288-be98-92f79fad017e", "matches_hash": "-30038581230761295" }, { "type": "Translocation", "agent": { "name": "MAPK", "db_refs": { "FPLX": "MAPK", "ECCODE": "2.7.11.24", "NCIT": "C16376", "TEXT": "MAP kinases" } }, "from_location": "cytoplasm", "to_location": "nucleus", "belief": 0.6319788812241817, "evidence": [ { "source_api": "sparser", "pmid": "7542926", "text": "In rat fibroblasts, a translocation of MAP kinases from\ncytoplasm to nucleus occurs in parallel with the activation of the\nenzymes.", "annotations": { "location": "GO:0005634", "prior_hash": 29306396420449101, "agents": { "raw_text": [ "MAP kinases" ], "raw_grounding": [ { "FPLX": "MAPK", "ECCODE": "2.7.11.24", "NCIT": "C16376", "TEXT": "MAP kinases" } ] }, "prior_uuids": [ "1c365d55-a65d-4800-8ff1-0218a22f55b1" ] }, "text_refs": { "PMID": "7542926", "DOI": "10.1016/0304-419X(95)00005-Z", "TRID": 18560812 }, "source_hash": -5890627392691939562 } ], "id": "1c365d55-a65d-4800-8ff1-0218a22f55b1", "matches_hash": "13840150378694753", "supported_by": [ "8e8c86e2-7005-4f48-9532-8f706998b4b5" ] }, { "type": "Translocation", "agent": { "name": "MEK", "db_refs": { "FPLX": "MEK", "TEXT": "MEK1/2, ERK1/2 and Raf" } }, "to_location": "plasma membrane", "belief": 0.5245532333249894, "evidence": [ { "source_api": "sparser", "pmid": "26549023", "text": "KSR1 translocates to the plasma membrane upon growth factor stimulation, where it forms a complex with activated MEK1/2, ERK1/2 and Raf, which also translocates to the plasma membrane through association with Ras-GTP ( xref ).", "annotations": { "location": "GO:0005886", "prior_hash": 2766207833466275, "agents": { "raw_text": [ "MEK1/2, ERK1/2 and Raf" ], "raw_grounding": [ { "FPLX": "MEK", "TEXT": "MEK1/2, ERK1/2 and Raf" } ] }, "prior_uuids": [ "a707ed0b-299a-4b09-8820-b6a34f9e9116" ] }, "text_refs": { "PMID": "26549023", "PMCID": "PMC4861249", "DOI": "10.1038/ONC.2015.404", "MANUSCRIPT_ID": "EMS66778", "TRID": 27183378 }, "source_hash": 6467111499514678252 } ], "id": "a707ed0b-299a-4b09-8820-b6a34f9e9116", "matches_hash": "2766207833466275" }, { "type": "Translocation", "agent": { "name": "NFkappaB", "db_refs": { "FPLX": "NFkappaB", "IP": "IPR000451", "NCIT": "C17380", "TEXT": "NF-\u03baB" } }, "to_location": "nucleus", "belief": 0.5837008781018218, "evidence": [ { "source_api": "sparser", "pmid": "12207915", "text": "Although the induced nuclear translocation of NF-\u03baB has been highly regarded as the principal method to activate NF-\u03baB, an alternative mechanism is indicated that regulates the transactivation potential of p65 by phosphorylating p65.", "annotations": { "location": "GO:0005634", "prior_hash": 24287877331001014, "agents": { "raw_text": [ "NF-\u03baB" ], "raw_grounding": [ { "FPLX": "NFkappaB", "IP": "IPR000451", "NCIT": "C17380", "TEXT": "NF-\u03baB" } ] }, "prior_uuids": [ "c416e304-baee-4192-9de7-74e7e4f278b8" ] }, "text_refs": { "PMID": "12207915", "DOI": "10.1016/S0006-291X(02)02077-6", "TRID": 21340987 }, "source_hash": 3844481509037142638 }, { "source_api": "sparser", "pmid": "12207915", "text": "The activated IKK complex phosphorylates I\u03baB and leads to degradation of I\u03baB by ubiquitination pathway and nuclear translocation of NF-\u03baB.\nHere, to explore the effect of merlin on these signaling intermediate molecules, we overexpressed NIK, IKK\u03b1, and an increasing amount of in NIH3T3 cells.", "annotations": { "location": "GO:0005634", "prior_hash": 24287877331001014, "agents": { "raw_text": [ "NF-\u03baB" ], "raw_grounding": [ { "FPLX": "NFkappaB", "IP": "IPR000451", "NCIT": "C17380", "TEXT": "NF-\u03baB" } ] }, "prior_uuids": [ "9c17ab53-f256-4dcb-a918-9788bb0c8195" ] }, "text_refs": { "PMID": "12207915", "DOI": "10.1016/S0006-291X(02)02077-6", "TRID": 21340987 }, "source_hash": 8915863819023396157 } ], "id": "9e2fcc91-5e33-44d5-bad5-0a330feea355", "matches_hash": "24287877331001014" }, { "type": "Translocation", "agent": { "name": "PAK", "db_refs": { "TEXT": "PAKs", "FPLX": "PAK", "IP": "IPR033923" } }, "to_location": "focal adhesion", "belief": 0.41838476907009237, "evidence": [ { "source_api": "sparser", "pmid": "22798428", "text": "Interestingly, Merlin was also shown to negatively regulate PAKs by directly interacting with the PBD domain and preventing recruitment of PAKs to focal adhesions ( xref ).", "annotations": { "location": "GO:0005925", "prior_hash": -12835864083653084, "agents": { "raw_text": [ "PAKs" ], "raw_grounding": [ { "TEXT": "PAKs", "FPLX": "PAK", "IP": "IPR033923" } ] }, "prior_uuids": [ "1698456a-6715-4c22-930c-77216c4991f6" ] }, "text_refs": { "PMID": "22798428", "PMCID": "PMC3447107", "DOI": "10.1158/1541-7786.MCR-12-0082", "MANUSCRIPT_ID": "NIHMS394501", "TRID": 18097296 }, "source_hash": 7572330387610830734 } ], "id": "1698456a-6715-4c22-930c-77216c4991f6", "matches_hash": "-12835864083653084" }, { "type": "Translocation", "agent": { "name": "RAC", "db_refs": { "FPLX": "RAC", "TEXT": "Rac" } }, "to_location": "plasma membrane", "belief": 1, "evidence": [ { "source_api": "sparser", "pmid": "22247700", "text": "Merlin/NF-2 mediates contact\ninhibition of growth by suppressing recruitment of Rac to the plasma\nmembrane.", "annotations": { "location": "GO:0005886", "prior_hash": 18698146268219666, "agents": { "raw_text": [ "Rac" ], "raw_grounding": [ { "FPLX": "RAC", "TEXT": "Rac" } ] }, "prior_uuids": [ "48288845-9c65-4563-91cd-e5fb5b01e49e" ] }, "text_refs": { "PMID": "22247700", "PMCID": "PMC3257450", "DOI": "10.1593/NEO.111060", "TRID": 8573546 }, "source_hash": 3220110563402581142 }, { "source_api": "sparser", "pmid": "20491622", "text": "Furthermore, merlin mediates contact inhibition of cell growth through its interaction with CD44 [ xref , xref ] or by blocking recruitment of Rac to the plasma membrane [ xref ].", "annotations": { "location": "GO:0005886", "prior_hash": 18698146268219666, "agents": { "raw_text": [ "Rac" ], "raw_grounding": [ { "FPLX": "RAC", "TEXT": "Rac" } ] }, "prior_uuids": [ "b7a40b66-8760-4f5b-bf20-c72e4965c747" ] }, "text_refs": { "PMID": "20491622", "PMCID": "PMC2946555", "DOI": "10.2174/138920310791824011", "MANUSCRIPT_ID": "NIHMS236013", "TRID": 3632152 }, "source_hash": 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the promotion of cell growth.", "annotations": { "location": "GO:0005634", "prior_hash": 31025405255273335, "agents": { "raw_text": [ "YAP" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" } ] }, "prior_uuids": [ "7163b771-697d-4b36-b0b9-b7a36ea34111" ] }, "text_refs": { "PMID": "25243094", "PMCID": "PMC4163293", "DOI": "10.1155/2014/915725", "TRID": 18162520 }, "source_hash": 5022261654416750644 }, { "source_api": "sparser", "pmid": "22329991", "text": "Dephosphorylated YAP translocates into the nucleus, where it binds to TEAD and activates the transcription of target genes.", "annotations": { "location": "GO:0005634", "prior_hash": 31025405255273335, "agents": { "raw_text": [ "YAP" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" } ] }, "prior_uuids": [ "bcc7171a-b4f9-4e7d-8df1-2577856b3327" ] }, "text_refs": { "PMID": "22329991", "PMCID": "PMC3302232", "DOI": "10.1084/JEM.20111653", "TRID": 7073691 }, "source_hash": -4718681698115382442 }, { "source_api": "sparser", "pmid": "28052036", "text": "These observations suggest that overexpression of AMOTp80 could increase nuclear translocation of YAP, likely due to decreases in the levels of pYAP.", "annotations": { "location": "GO:0005634", "prior_hash": 31025405255273335, "agents": { "raw_text": [ "YAP" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" } ] }, "prior_uuids": [ "80b85e57-6d19-4d94-8a75-801635da43d3" ] }, "text_refs": { "PMID": "28052036", "PMCID": "PMC5354648", "DOI": "10.18632/ONCOTARGET.14358", "TRID": 13615653 }, "source_hash": 4409481755838012784 }, { "source_api": "sparser", "pmid": "25433207", "text": "Inactivation of Mst1/2 or Lats1/2 kinases or overexpression of Yap leads to accumulation of unphosphorylated Yap, which translocates into the nucleus and activates genes that promote proliferation and survival.", "annotations": { "location": "GO:0005634", "prior_hash": 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"annotations": { "location": "GO:0005634", "prior_hash": 31025405255273335, "agents": { "raw_text": [ "YAP and TAZ" ], "raw_grounding": [ { "UP": "P46937", "TEXT": "YAP and TAZ", "HGNC": "16262", "EGID": "10413" } ] }, "prior_uuids": [ "f9426d3e-b990-4d00-936e-d46b95042c43" ] }, "text_refs": { "PMID": "26923924", "DOI": "10.1016/J.BBAGRM.2016.02.010", "PII": "S1874-9399(16)30032-3", "TRID": 12257638 }, "source_hash": 5752079543313044855 }, { "source_api": "sparser", "pmid": "28052036", "text": "We further showed that AMOTp80 could signal through the Hippo pathway by promoting the nuclear translocation of YAP to increase YAP target protein expression.", "annotations": { "location": "GO:0005634", "prior_hash": 31025405255273335, "agents": { "raw_text": [ "YAP" ], "raw_grounding": [ { "UP": "P46937", "HGNC": "16262", "EGID": "10413", "TEXT": "YAP" } ] }, "prior_uuids": [ "3fde174b-a837-41e2-8d21-6dba396c5bfa" ] }, "text_refs": { "PMID": "28052036", "PMCID": "PMC5354648", "DOI": 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"MANUSCRIPT_ID": "NIHMS672877", "TRID": 20517466 }, "source_hash": -9191899053208633908 }, { "source_api": "sparser", "pmid": "23267122", "text": "Phosphorylated, cytoplasmic NF2 loses its ability to control the cell cycle in schwannoma and mesothelioma cells, suggesting that nuclear translocation of NF2 is critical for its affect on the cell cycle xref , xref .", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "NF2" ], "raw_grounding": [ { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "8a721417-5605-47e4-8b1e-a357cb3758b5" ] }, "text_refs": { "PMID": "23267122", "PMCID": "PMC3725758", "MANUSCRIPT_ID": "NIHMS494794", "TRID": 16129620 }, "source_hash": 6548948233080829090 }, { "source_api": "sparser", "pmid": "24726726", "text": "In contrast to Merlin's cortex-specific roles that largely influence cell junctions and Rac signaling, intercellular and cortical cues lead to accumulation of dephosphorylated Merlin, which translocates to the nucleus and attenuates oncogenic gene expression via inhibition of CRL4 DCAF1 [ xref ] As CRL4 DCAF1 regulates several proteins that broadly control transcription and epigenetics [ xref , xref , xref ], Merlin is poised to dramatically alter the expression of genes in response to adhesion signaling.", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "Merlin" ], "raw_grounding": [ { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "ef377922-a347-4ac1-95fc-300288300636" ] }, "text_refs": { "PMID": "24726726", "PMCID": "PMC4111995", "DOI": "10.1016/J.FEBSLET.2014.04.001", "PII": "S0014-5793(14)00276-2", "MANUSCRIPT_ID": "NIHMS584477", "TRID": 15307121 }, "source_hash": 7102387771515862426 }, { "source_api": "sparser", "pmid": "25026211", "text": "To examine if nuclear translocation of Merlin is required to induce proliferation arrest, we used mutational analysis.", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "Merlin" ], "raw_grounding": [ { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "78658e98-259e-4117-b0f2-7c03a469786c" ] }, "text_refs": { "PMID": "25026211", "PMCID": "PMC4126592", "DOI": "10.1016/J.CCR.2014.05.001", "PII": "S1535-6108(14)00189-5", "MANUSCRIPT_ID": "NIHMS593760", "TRID": 23759943 }, "source_hash": -3713113036455483414 }, { "source_api": "sparser", "pmid": "24726726", "text": "Notably, Merlin translocates to the nucleus where it directly inhibits the CRL4 DCAF1 E3 ubiquitin ligase, thereby suppressing inhibition of the Lats kinases.", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "Merlin" ], "raw_grounding": [ { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "74849e60-5c35-4d33-b8f1-71204db36d02" ] }, "text_refs": { "PMID": "24726726", "PMCID": "PMC4111995", "DOI": "10.1016/J.FEBSLET.2014.04.001", "PII": "S0014-5793(14)00276-2", "MANUSCRIPT_ID": "NIHMS584477", "TRID": 15307121 }, "source_hash": 5977285364732293591 }, { "source_api": "sparser", "pmid": "25893302", "text": "Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "merlin" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "e98e6b62-fa8e-47f2-a399-b5b8e1870dfc" ] }, "text_refs": { "PMID": "25893302", "PMCID": "PMC4615258", "DOI": "10.1038/ONC.2015.125", "MANUSCRIPT_ID": "NIHMS672877", "TRID": 20517466 }, "source_hash": 499007952307973983 }, { "source_api": "sparser", "pmid": "23267122", "text": "The nuclear translocation of NF2 appears to be mediated by both its phosphorylation status and the phase of the cell cycle.", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "NF2" ], "raw_grounding": [ { "TEXT": "NF2", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "bbb04306-0216-48fe-ba4a-88bc4a499801" ] }, "text_refs": { "PMID": "23267122", "PMCID": "PMC3725758", "MANUSCRIPT_ID": "NIHMS494794", "TRID": 16129620 }, "source_hash": 6740519938065436050 }, { "source_api": "sparser", "pmid": "21084862", "text": "We have recently observed that Merlin translocates into the nucleus and binds to and inhibits the E3 ubiquitin ligase CRL4 (DCAF1) .", "annotations": { "location": "GO:0005634", "prior_hash": 15629283540963835, "agents": { "raw_text": [ "Merlin" ], "raw_grounding": [ { "TEXT": "Merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "6be88b00-21c1-4f68-8e04-7f28f43684b1" ] }, "text_refs": { "PMID": "21084862", "PMCID": 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and suppress the E3 ubiquitin ligase CRL4 DCAF1 [XREF_BIBR, XREF_BIBR], and may also regulate protein and fatty acid syntheses via interactions with mTOR signaling [XREF_BIBR].", "annotations": { "found_by": "translocation_8b_verb_active_no_cause", "agents": { "coords": [ [ 53, 59 ] ], "raw_text": [ "merlin" ], "raw_grounding": [ { "UP": "P35240", "HGNC": "7773", "TEXT": "merlin", "EGID": "4771" } ] }, "prior_hash": 15629283540963835, "prior_uuids": [ "22335e02-34e3-4340-a7c4-40c4f8328773" ] }, "epistemics": { "direct": false, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0005634" } }, "cell_line": { "name": null, "db_refs": { "CELLOSAURUS": "CVCL_8467" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "31161239", "PMCID": "PMC7038792", "DOI": "10.1007/S00401-019-02029-5", "MANUSCRIPT_ID": "NIHMS1537896", "TRID": 30276902 }, "source_hash": 5098253386318417939 } ], "id": 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"pmid": "24726726", "text": "This notion was supported in Drosophila by the observation that nascent Merlin is recruited to the plasma membrane [XREF_BIBR, XREF_BIBR].", "annotations": { "found_by": "translocation_3b_verb_passive", "agents": { "coords": [ [ 72, 78 ] ], "raw_text": [ "Merlin" ], "raw_grounding": [ { "UP": "P35240", "HGNC": "7773", "TEXT": "Merlin", "EGID": "4771" } ] }, "prior_hash": -34410759473812523, "prior_uuids": [ "5e6b5594-dda4-4595-97b2-2967917b9268" ] }, "epistemics": { "direct": false, "section_type": null }, "context": { "location": { "name": null, "db_refs": { "GO": "GO:0016020" } }, "cell_type": { "name": null, "db_refs": { "CL": "CL:0000312" } }, "organ": { "name": null, "db_refs": { "UBERON": "UBERON:0019204" } }, "species": { "name": null, "db_refs": { "TAXONOMY": "9606" } }, "type": "bio" }, "text_refs": { "PMID": "24726726", "PMCID": "PMC4111995", "DOI": "10.1016/J.FEBSLET.2014.04.001", "PII": "S0014-5793(14)00276-2", "MANUSCRIPT_ID": "NIHMS584477", "TRID": 15307121 }, "source_hash": -7226130991526074567 }, { "source_api": "sparser", "pmid": "27871951", "text": "Furthermore, silencing of TIMAP in our experiments, not only initiated translocation of merlin to the plasma membrane, but resulted in a significant increase as well in the phosphorylation level of Ser518 side chain of merlin.", "annotations": { "location": "GO:0005886", "prior_hash": -34410759473812523, "agents": { "raw_text": [ "merlin" ], "raw_grounding": [ { "TEXT": "merlin", "HGNC": "7773", "EGID": "4771", "UP": "P35240" } ] }, "prior_uuids": [ "fb142415-da34-4249-8e58-9c94c3c0a3cc" ] }, "text_refs": { "PMID": "27871951", "DOI": "10.1016/J.BIOCEL.2016.11.010", "PII": "S1357-2725(16)30347-8", "TRID": 5222224 }, "source_hash": -2130837506640118606 }, { "source_api": "reach", "pmid": "24012335", "text": "Active Merlin recruits Wts and Lats to plasma membrane through direct protein protein interaction.", "annotations": { "found_by": 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