Interaction of FoxO1 and TSC2 Induces Insulin Resistance through Activation of the Mammalian Target of Rapamycin/p70 S6K Pathway

University of Tsukuba, Tsukuba, Ibaraki, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2007; 281(52):40242-51. DOI: 10.1074/jbc.M608116200
Source: PubMed


Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles
in insulin signaling. However, little is known about the relationship between TSC2 and FoxO1. Here we identified TSC2 as a
FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. Among FoxOs, only FoxO1 can
be associated with TSC2. The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades
the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. Overexpression of wild type FoxO1
enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. Knockdown of endogenous FOXO1
in human vascular endothelial cells decreased phosphorylation of p70 S6K. Prolonged overexpression of wild type FoxO1 enhanced
phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum.
These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of
TSC2 function.

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    • "Furthermore, Akt-phosphorylated cytoplasmic FoxO1 binds to TSC2 and thereby dissociates the TSC1/TSC2 complex, which activates mTORC1 113. Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1, which in turn increases protein and lipid synthesis and induces insulin resistance 113. "
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    • "Hyperactivation of the mTOR-mediated pathway(s) has been observed in insulin desensitizing events and insulin resistant animal models [26-31]. This can be prevented or reversed by rapamycin [30,31]. "
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    • "Erk Serine/threonine kinase Raf-MEK1/2-Erk1/2 signaling (regulation of cell growth and differentiation) Not determined co-IP 293 [46] ERM Cytoskeletal anchor protein Regulation of cell–cell adhesion Hamartin aa 881–1084 Y2H, slot blot and blotoverly assay, co-IP, co-localization HUVEC [79] FIP200 Kinase binding protein Inhibition of FAK kinase (regulation of cell size, cell cycle progression, cell migration) Hamartin aa 403–787 Y2H, GST affinity precipitation, co-IP MEF, 293T [17] FoxO1 Transcription factor Cell signaling (regulation of cell cycle, cell survival, glucose and lipid metabolism) Tuberin aa 1280–1499 Y2H, co-IP co-localization Adipocytes, HEK293, hepatocytes [60] "
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