A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1

Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4640-5. doi: 10.1073/pnas.051042298. Epub 2001 Apr 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Chromatography, Liquid
  • Humans
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • Molecular Sequence Data
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Kinases*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction*
  • Spectrometry, Mass, Electrospray Ionization
  • TOR Serine-Threonine Kinases
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Suppressor Proteins*
  • Tyrosine / metabolism

Substances

  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Proteins
  • Tyrosine
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human