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

Abstract

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...

Lipid signalling in disease

“…Mounting evidence indicates that activation of c-Jun N-terminal kinase (JNK), IKK and conventional PKC is central to the development of insulin resistance in response to obesity -mediated by the aforementioned fatty acidinduced ER stress, ROS production, TLR activation and inflammatory signalling by TNF . JNK, IKK and PKC have all been reported to inhibit insulin action by phosphorylating IRS1 on serine [80][81][82] . Serine phosphorylation of IRS1 disrupts insulin-receptor signalling through several distinct mechanisms and blocks insulin action 83,84 .…”

“…JNK is activated after exposure to cytokines, such as TNF , as well as by free fatty acids through the TLR pathway and internal cues such as ER stress, all of which might underlie its obesity-induced activity 60,80,85 . There is a striking increase in JNK activity at crucial metabolic sites such as adipose and liver tissue in mouse models of obesity 86 .…”

Autocrine insulin action activates Akt and increases survival of isolated human islets

“…Over the ensuing 24 h, JNK phosphorylation levels decrease concomitantly with a rise in Akt phosphorylation [11,31]. Since JNK is known to suppress insulin signalling [32], it is possible that the insulin signalling pathway is suppressed in islets immediately following isolation and Akt only becomes activated following suppression of the JNK pathway. We therefore examined whether exogenous insulin could induce Akt phosphorylation in islets immediately following isolation, at a time when JNK is highly activated.…”

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

“…In type 1 diabetes, JNK plays a central role in the intracellular events that signal beta cell loss after exposure to the proinflammatory cytokine IL-1β [24,25]. JNK is abnormally elevated in various tissues under diabetic conditions due to the phenomenon known as glucose toxicity, and it has been demonstrated that activation of the JNK pathway interferes with insulin action [26][27][28] and beta cell function [29,30], as well as with insulin biosynthesis [29]. Islet transplantation involves the exposure of islets to several forms of stress, not only as a result of pancreas preservation and islet isolation, but also of inflammation and glucose toxicity after transplantation.…”