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PMID: 15249583 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of cell biology ·Vol. 166 ·No. 2 ·2004-07-19 ·Pages 213-23

Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, Downes CP, Lamb RF

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.

MeSH Terms
Animals Cell Survival Chemotaxis Fibroblasts/cytology Insulin/metabolism Insulin Receptor Substrate Proteins Insulin-Like Growth Factor I/physiology Intracellular Signaling Peptides and Proteins Mice Phosphatidylinositol 3-Kinases/metabolism Phosphoproteins/antagonists & inhibitors,metabolism Phosphorylation Proteins/physiology Repressor Proteins/physiology Ribosomal Protein S6 Kinases/antagonists & inhibitors,metabolism Signal Transduction Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins/physiology
Chemicals
Insulin Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs1 protein, mouse Irs2 protein, mouse Phosphoproteins Proteins Repressor Proteins Tsc1 protein, mouse Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Insulin-Like Growth Factor I Phosphatidylinositol 3-Kinases Ribosomal Protein S6 Kinases
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Harrington Laura S
Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Rd., London SW3 6JB, England, UK.
Findlay Greg M
Gray Alex
Tolkacheva Tatiana
Wigfield Simon
Rebholz Heike
Barnett Jill
Leslie Nick R
Cheng Susan
Shepherd Peter R
Gout Ivan
Downes C Peter
Lamb Richard F
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200403069
Published
2004-07-19
Epub
2004-00-12
Pages
213-23
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2172316
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200403069 PMC Full Text View journal details
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