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 journalArticle

834 Citations (Scopus)

Abstract

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
Volume166
Issue number2
DOIs
Publication statusPublished - 19 Jul 2004

Keywords

  • 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

Fingerprint Dive into the research topics of 'The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins'. Together they form a unique fingerprint.

  • Cite this

    Harrington, L. S., Findlay, G. M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., Gout, I., Downes, C. P., & Lamb, R. F. (2004). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. Journal of Cell Biology, 166(2), 213-223. https://doi.org/10.1083/jcb.200403069