The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins.
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:
1-Phosphatidylinositol 3-Kinase, Animals, Cell Survival, Chemotaxis, Fibroblasts, Insulin, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Mice, Phosphoproteins, Phosphorylation, Proteins, Repressor Proteins, Ribosomal Protein S6 Kinases, Signal Transduction, Tumor Suppressor Proteins
1-Phosphatidylinositol 3-Kinase, Animals, Cell Survival, Chemotaxis, Fibroblasts, Insulin, Insulin Receptor Substrate Proteins, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Mice, Phosphoproteins, Phosphorylation, Proteins, Repressor Proteins, Ribosomal Protein S6 Kinases, Signal Transduction, Tumor Suppressor Proteins
J. Cell Biol.
Date: Jul. 19, 2004
PubMed ID: 15249583
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