The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

doi:10.1083/jcb.200403069

Published online 12 July 2004. doi:10.1083/jcb.200403069
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 2, 213-223

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The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

Laura S. Harrington¹, Greg M. Findlay¹, Alex Gray², Tatiana Tolkacheva¹, Simon Wigfield¹, Heike Rebholz³, Jill Barnett², Nick R. Leslie², Susan Cheng⁴, Peter R. Shepherd⁴, Ivan Gout³, C. Peter Downes², and Richard F. Lamb¹

¹ Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, London SW3 6JB, England, UK
² School of Life Sciences Research Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, UK
³ Ludwig Institute for Cancer Research, Royal Free and University College Medical School Branch, London W1W 7BS, England, UK
⁴ Department of Biochemistry, University College London, London WC1E 6BT, England, UK

Address correspondence to Richard F. Lamb, Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK. Tel.: (44) 207-970-6096. Fax: (44) 207-352-5630. email: Richard.Lamb{at}icr.ac.uk

Insulin-like growth factors elicit many responses through activationof phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosiscomplex (TSC1-2) suppresses cell growth by negatively regulatinga protein kinase, p70S6K (S6K1), which generally requires PI3Ksignals for its activation. Here, we show that TSC1-2 is requiredfor insulin signaling to PI3K. TSC1-2 maintains insulin signalingto PI3K by restraining the activity of S6K, which when activatedinactivates insulin receptor substrate (IRS) function, via repressionof IRS-1 gene expression and via direct phosphorylation of IRS-1.Our results argue that the low malignant potential of tumorsarising from TSC1-2 dysfunction may be explained by the failureof TSC mutant cells to activate PI3K and its downstream effectors.

Key Words: TSC1-2; PI3K; IRS proteins; S6K; insulin

L.S. Harrington and G.M. Findlay contributed equally to thispaper.

Abbreviations used in this paper: IRS, insulin receptor substrate;MEF, mouse embryo fibroblast; mTOR, mammalian target of rapamycin;PI3K, phosphoinositide 3-OH kinase; PIP3, phosphatidylinositol3,4,5-trisphosphate; PTB, phosphotyrosine-binding domain; siRNA,small interfering RNA; TSC, tuberous sclerosis complex.

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