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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.

Pubmed ID: 11287630


  • Ozes ON
  • Akca H
  • Mayo LD
  • Gustin JA
  • Maehama T
  • Dixon JE
  • Donner DB


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

April 10, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: CA67891
  • Agency: NCI NIH HHS, Id: CA73023
  • Agency: NIDDK NIH HHS, Id: DK 18849

Mesh Terms

  • Amino Acid Sequence
  • Cell Line
  • Chromatography, Liquid
  • Humans
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • Molecular Sequence Data
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases
  • 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
  • TOR Serine-Threonine Kinases
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Tyrosine