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.
Copyright The Rockerfeller University Press
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival
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Chemotaxis
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Fibroblasts / cytology
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Insulin / metabolism*
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / physiology
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Intracellular Signaling Peptides and Proteins
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Mice
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / metabolism*
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Phosphorylation
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Proteins / physiology
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Repressor Proteins / physiology
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Ribosomal Protein S6 Kinases / antagonists & inhibitors
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Ribosomal Protein S6 Kinases / metabolism
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Signal Transduction*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / physiology*
Substances
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Irs2 protein, mouse
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Phosphoproteins
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Proteins
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Repressor Proteins
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Insulin-Like Growth Factor I
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Phosphatidylinositol 3-Kinases
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Ribosomal Protein S6 Kinases