Tumor necrosis factor ␣ (TNF␣) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNF␣ 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 TNF␣ 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 TNF␣ on IRS-1 function.The insulin signaling system is complex, and a common mechanism to explain the occurrence of insulin resistance during diabetes is difficult to resolve. So far, genetic approaches provide important insight into certain early onset forms of diabetes but fail to explain insulin resistance that is associated with common type 2 diabetes (1-4). Recent results support the notion that dysregulation of the insulin receptor and reduced tyrosine phosphorylation of the IRS 1 proteins might contribute significantly to peripheral insulin resistance and ␤-cell failure (5, 6).The principal insulin receptor substrates, IRS-1 and IRS-2, are phosphorylated on multiple tyrosine residues by the activated receptors for insulin, IGF-1, and various other cytokines (7). Tyrosine phosphorylation of IRS-1 and IRS-2 promotes their binding to the Src homology 2 domains in various downstream signaling proteins, including the phosphatidylinositol 3-kinase (PI 3-kinase), Grb-2, SHP2, and others (7,8). During association with IRS proteins, PI 3-kinase is activated, and its phospholipid products promote the recruitment of various serine kinases to the plasma membrane, where they are activated by phosphorylation (9). One of the membrane-associated kinases, protein kinase B/Akt, phosphorylates multiple downstream effectors that promote diverse biological responses, including stimulation of glucose transport, protein and glycogen synthesis, and the regulation of gene expression, which affects cellular proliferation and survival (10, 11).The insulin receptor and the IRS proteins might be counterregulated by degradation, differential expression, or modification by serine/threonine phosphorylation (12-15). Increased serine phosphorylation of IRS-1 is a common finding during insulin resistance and type 2 diabetes (16). However, the mechanism by which serine phosphorylation inhibits insulin signaling is difficult to establish, because IRS-1 contains more than 70 potential serine/threonine residues in consensus sequences for many protein kinases, including casein kinase II, cAMP-dependent protein kinase, prote...

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