{"corpus_id":39982271,"paper_sha":"5a28ff5601e4cd0b3bb26e2d7f7c2ae3a1cc29e0","doi":"10.1074/JBC.M008157200","arxiv_id":null,"pmid":11042184,"pmcid":null,"mag_id":2008745393,"dblp_id":null,"acl_id":null,"title":"Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) Suppresses TKR-Growth Factor Signaling Independent of Metalloproteinase Inhibition*","year":2001,"publication_date":"2001-02-02","venue":"Journal of Biological Chemistry","journal":{"name":"The Journal of Biological Chemistry","pages":"3203 - 3214","volume":"276"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article"],"s2_fields_of_study":["Biology","Medicine"],"reference_count":65,"citation_count":128,"influential_citation_count":4,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Adaptor Proteins, Signal Transducing","mj":true,"ui":"D048868"},{"d":"Adenylyl Cyclases","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D000262"},{"d":"Cell Division","mj":false,"qs":[{"q":"drug effects","mj":false,"ui":"Q000187"}],"ui":"D002455"},{"d":"Cyclic AMP-Dependent Protein Kinases","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D017868"},{"d":"Enzyme Activation","mj":false,"ui":"D004789"},{"d":"Epidermal Growth Factor","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D004815"},{"d":"ErbB Receptors","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D066246"},{"d":"GRB2 Adaptor Protein","mj":false,"ui":"D051380"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Matrix Metalloproteinase 1","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D020781"},{"d":"Matrix Metalloproteinase Inhibitors","mj":true,"ui":"D061965"},{"d":"Phosphorylation","mj":false,"ui":"D010766"},{"d":"Protein Phosphatase 1","mj":false,"ui":"D054645"},{"d":"Protein Tyrosine Phosphatases","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D017027"},{"d":"Proteins","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D011506"},{"d":"Receptor Protein-Tyrosine Kinases","mj":false,"qs":[{"q":"antagonists & inhibitors","mj":true,"ui":"Q000037"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D020794"},{"d":"Signal Transduction","mj":false,"qs":[{"q":"drug effects","mj":true,"ui":"Q000187"},{"q":"physiology","mj":false,"ui":"Q000502"}],"ui":"D015398"},{"d":"Tissue Inhibitor of Metalloproteinase-2","mj":false,"qs":[{"q":"pharmacology","mj":true,"ui":"Q000494"}],"ui":"D019716"},{"d":"Tumor Cells, Cultured","mj":false,"ui":"D014407"}],"chemicals":[{"n":"Adaptor Proteins, Signal Transducing","ui":"D048868","reg":"0"},{"n":"GRB2 Adaptor Protein","ui":"D051380","reg":"0"},{"n":"GRB2 protein, human","ui":"C495948","reg":"0"},{"n":"Matrix Metalloproteinase Inhibitors","ui":"D061965","reg":"0"},{"n":"Proteins","ui":"D011506","reg":"0"},{"n":"Tissue Inhibitor of Metalloproteinase-2","ui":"D019716","reg":"127497-59-0"},{"n":"Epidermal Growth Factor","ui":"D004815","reg":"62229-50-9"},{"n":"ErbB Receptors","ui":"D066246","reg":"EC 2.7.10.1"},{"n":"Receptor Protein-Tyrosine Kinases","ui":"D020794","reg":"EC 2.7.10.1"},{"n":"Cyclic AMP-Dependent Protein Kinases","ui":"D017868","reg":"EC 2.7.11.11"},{"n":"Protein Phosphatase 1","ui":"D054645","reg":"EC 3.1.3.16"},{"n":"Protein Tyrosine Phosphatases","ui":"D017027","reg":"EC 3.1.3.48"},{"n":"Matrix Metalloproteinase 1","ui":"D020781","reg":"EC 3.4.24.7"},{"n":"Adenylyl Cyclases","ui":"D000262","reg":"EC 4.6.1.1"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"http://www.jbc.org/article/S0021925818464964/pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/5a28ff5601e4cd0b3bb26e2d7f7c2ae3a1cc29e0","s2_open_access_license":"CCBY","s2_open_access_status":"HYBRID","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"The tissue inhibitors of metalloproteinases (TIMPs) block matrix metalloproteinase (MMP)-mediated increases in cell proliferation, migration, and invasion that are associated with extracellular matrix (ECM) turnover. Here we demonstrate a direct role for TIMP-2 in regulating tyrosine kinase-type growth factor receptor activation. We show that TIMP-2 suppresses the mitogenic response to tyrosine kinase-type receptor growth factors in a fashion that is independent of MMP inhibition. The TIMP-2 suppression of mitogenesis is reversed by the adenylate cyclase inhibitor SQ22536, and implicates cAMP as the second messenger in these effects. TIMP-2 neither altered the release of transforming growth factor α from the cell surface, nor epidermal growth factor (EGF) binding to the cognate receptor, EGFR. TIMP-2 binds to the surface of A549 cells in a specific and saturable fashion (K d = 147 pm), that is not competed by the synthetic MMP inhibitor BB-94 and is independent of MT-1-MMP. TIMP-2 induces a decrease in phosphorylation of EGFR and a concomitant reduction in Grb-2 association. TIMP-2 prevents SH2-protein-tyrosine phosphatase-1 (SHP-1) dissociation from immunoprecipitable EGFR complex and a selective increase in total SHP-1 activity. These studies represent a new functional paradigm for TIMP-2 in which TIMP suppresses EGF-mediated mitogenic signaling by short-circuiting EGFR activation.","claims":[{"public_id":"cl_d5cba815614b2f3aee0b20e1469d2b48","status":"active","text":"TIMP-2 binds specifically and saturably to A549 cell surfaces with a Kd of 147 pM, independently of MT-1-MMP and not competed by the synthetic MMP inhibitor BB-94.","confidence":0.95,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":2,"public_id":"4715169a40","public_label":"AK (4715169a40)","roles":["review"],"url":"https://sah.borca.ai/u/4715169a40"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale 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selectively increases total SHP-1 activity.","confidence":0.93,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani (b9tnx83g25)","roles":["extraction"],"url":"https://sah.borca.ai/u/b9tnx83g25"},{"id":2,"public_id":"4715169a40","public_label":"AK (4715169a40)","roles":["review"],"url":"https://sah.borca.ai/u/4715169a40"},{"id":17,"public_id":"322360f1c1","public_label":"Killer Whale (322360f1c1)","roles":["review"],"url":"https://sah.borca.ai/u/322360f1c1"}],"url":"https://sah.borca.ai/claims/cl_d2d7847d51011e0c8dbd277ef6db8aca"},{"public_id":"cl_c0b871d753603948e1e5d90f65e4e41b","status":"active","text":"TIMP-2 suppresses the mitogenic response to tyrosine kinase-type growth factor receptors in a manner independent of matrix metalloproteinase inhibition.","confidence":0.95,"contributors":[{"id":171,"public_id":"b9tnx83g25","public_label":"eunsjani 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