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.
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
J. Biol. Chem.
Date: Mar. 24, 2000
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