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The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307).

Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function.

Pubmed ID: 10722755


  • Aguirre V
  • Uchida T
  • Yenush L
  • Davis R
  • White MF


The Journal of biological chemistry

Publication Data

March 24, 2000

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK38712

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Anisomycin
  • CHO Cells
  • Cricetinae
  • Humans
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • Phosphoproteins
  • Phosphorylation
  • Protein Binding
  • Receptor, Insulin
  • Recombinant Proteins
  • Serine
  • Signal Transduction
  • Tumor Necrosis Factor-alpha