A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1.
Tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) by the insulin receptor permits this docking protein to interact with signaling proteins that promote insulin action. Serine phosphorylation uncouples IRS-1 from the insulin receptor, thereby inhibiting its tyrosine phosphorylation and insulin signaling. For this reason, there is great interest in identifying serine/threonine ... kinases for which IRS-1 is a substrate. Tumor necrosis factor (TNF) inhibited insulin-promoted tyrosine phosphorylation of IRS-1 and activated the Akt/protein kinase B serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase (PI 3-kinase). The effect of TNF on insulin-promoted tyrosine phosphorylation of IRS-1 was blocked by inhibition of PI 3-kinase and the PTEN tumor suppressor, which dephosphorylates the lipids that mediate PI 3-kinase functions, whereas constitutively active Akt impaired insulin-promoted IRS-1 tyrosine phosphorylation. Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt. Inhibition of IRS-1 tyrosine phosphorylation by TNF was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), a downstream target of Akt. mTOR induced the serine phosphorylation of IRS-1 (Ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that TNF impairs insulin signaling through IRS-1 by activation of a PI 3-kinase/Akt/mTOR pathway, which is antagonized by PTEN.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Cell Line, Chromatography, Liquid, Humans, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Molecular Sequence Data, PTEN Phosphohydrolase, Phosphoproteins, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, Spectrometry, Mass, Electrospray Ionization, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Tyrosine
1-Phosphatidylinositol 3-Kinase, Amino Acid Sequence, Cell Line, Chromatography, Liquid, Humans, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Molecular Sequence Data, PTEN Phosphohydrolase, Phosphoproteins, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Signal Transduction, Spectrometry, Mass, Electrospray Ionization, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins, Tyrosine
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 10, 2001
PubMed ID: 11287630
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