The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307

Tumor necrosis factor alpha (TNF alpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNF alpha promotes multipotential signal transduction cascades, including the activation of the Jun NH2-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-I, 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 TNF alpha on insulin-stimulated tyrosine phosphorylation of IRS-I. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNF alpha on IRS-I function.