A Phosphatidylinositol 3-Kinase/Akt/mTOR Pathway Mediates and PTEN Antagonizes Tumor Necrosis Factor Inhibition of Insulin Signaling through Insulin Receptor Substrate-1

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-04, Vol.98 (8), p.4640-4645
• Main Authors: Ozes, Osman Nidai, Akca, Hakan, Mayo, Lindsey D., Gustin, Jason A., Maehama, Tomohiko, Dixon, Jack E., Donner, David B.
• Format: Article
• Language: English
• Subjects: Adipocytes; Amino Acid Sequence; Antibodies; Biochemistry; Biological Sciences; Cell Line; Chromatography, Liquid; Enzymes; Humans; Immunology; Insulin; Insulin - metabolism; Insulin Receptor Substrate Proteins; Insulin Resistance; Memory interference; Microbiology; Molecular Sequence Data; Muscle fibers; NIH 3T3 cells; Phosphatases; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Kinases; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; PTEN gene; PTEN Phosphohydrolase; Receptors; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Suppressor Proteins; Tumors; Tyrosine - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.051042298

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 suppessor, 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.