{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:43:38Z","timestamp":1776401018355,"version":"3.51.2"},"reference-count":56,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,7,19]]},"abstract":"<jats:p>Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.<\/jats:p>","DOI":"10.1083\/jcb.200403069","type":"journal-article","created":{"date-parts":[[2004,7,13]],"date-time":"2004-07-13T00:15:05Z","timestamp":1089677705000},"page":"213-223","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":947,"title":["The TSC1-2 tumor suppressor controls insulin\u2013PI3K signaling via regulation of IRS proteins"],"prefix":"10.1083","volume":"166","author":[{"given":"Laura S.","family":"Harrington","sequence":"first","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK"}]},{"given":"Greg M.","family":"Findlay","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK"}]},{"given":"Alex","family":"Gray","sequence":"additional","affiliation":[{"name":"2School of Life Sciences Research Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, UK"}]},{"given":"Tatiana","family":"Tolkacheva","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK"}]},{"given":"Simon","family":"Wigfield","sequence":"additional","affiliation":[{"name":"1Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK"}]},{"given":"Heike","family":"Rebholz","sequence":"additional","affiliation":[{"name":"3Ludwig Institute for Cancer Research, Royal Free and University College Medical School Branch, London W1W 7BS, England, UK"}]},{"given":"Jill","family":"Barnett","sequence":"additional","affiliation":[{"name":"2School of Life Sciences Research Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, UK"}]},{"given":"Nick R.","family":"Leslie","sequence":"additional","affiliation":[{"name":"2School of Life Sciences Research Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, UK"}]},{"given":"Susan","family":"Cheng","sequence":"additional","affiliation":[{"name":"4Department of Biochemistry, University College London, London WC1E 6BT, England, UK"}]},{"given":"Peter R.","family":"Shepherd","sequence":"additional","affiliation":[{"name":"4Department of Biochemistry, University College London, London WC1E 6BT, England, UK"}]},{"given":"Ivan","family":"Gout","sequence":"additional","affiliation":[{"name":"3Ludwig Institute for Cancer Research, Royal Free and University College Medical School Branch, London W1W 7BS, England, UK"}]},{"given":"C. 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