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J Cell Biol. 2004 Jul 19;166(2):213-23. Epub 2004 Jul 12.

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

Author information

1
Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK.

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.

PMID:
15249583
PMCID:
PMC2172316
DOI:
10.1083/jcb.200403069
[Indexed for MEDLINE]
Free PMC Article

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