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

Laura S Harrington, Greg M Findlay, Alexander Gray, Tatiana Tolkacheva, Simon Wigfield, Heike Rebholz, Jill Barnett, Nick R Leslie, Susan Cheng, Peter R Shepherd, Ivan Gout, C Peter Downes, Richard F Lamb

Research output: Contribution to journalArticlepeer-review

963 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)213-223
Number of pages11
JournalJournal of Cell Biology
Issue number2
Publication statusPublished - 19 Jul 2004


  • Animals
  • Cell Survival
  • Chemotaxis
  • Fibroblasts
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins
  • Phosphorylation
  • Proteins
  • Repressor Proteins
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • Tumor Suppressor Proteins


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