The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307

TLDR

Tumor necrosis factor alpha impairs insulin signaling by inducing serine phosphorylation of IRS proteins, but the specific sites were unknown; TNFα activates JNK, which associates with IRS‑1 and phosphorylates serine 307. Activation of JNK by anisomycin blocks insulin‑stimulated tyrosine phosphorylation of IRS‑1, and mutating serine 307 to alanine prevents JNK phosphorylation and rescues insulin signaling, indicating that Ser307 phosphorylation mediates TNFα‑induced IRS‑1 inhibition.

Abstract

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.