Serine Phosphorylation of Insulin Receptor Substrate 1 by Inhibitor κB Kinase Complex* 210

By Zhanguo Gao, D. Hwang, Fredly Bataille, M. Lefevre, D. York, M. Quon, Jianping Ye. Journal of Biological Chemistry, 2002

689 citations recorded by the source corpus.

Insulin resistance contributes importantly to the pathophysiology of type 2 diabetes mellitus. One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor κB kinase (IKK) complex. However, the precise molecular mechanisms by which IKK may contribute to the development of insulin resistance are not well understood. In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser307 (equivalent to Ser312 in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-α or calyculin A treatment that paralleled surrogate markers for IKK activation. The phosphorylation of human IRS-1 at Ser312 in response to tumor necrosis factor-α was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J2 as well as in cells derived from IKK knock-out mice. We observed interactions between endogenous IRS-1 and IKK in intact cells using a co-immunoprecipitation approach. Moreover, this interaction between IRS-1 and IKK in the basal state was reduced upon IKK activation and increased serine phosphorylation of IRS-1. Data from in vitro kinase assays using recombinant IRS-1 as a substrate were consistent with the ability of IRS-1 to function as a direct substrate for IKK with multiple serine phosphorylation sites in addition to Ser312. Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser312 (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/987f9ab6339d6e71cdd0480874577e47781171c7

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Citations in the corpus

Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance (2007, background): “has become a molecular indicator of insulin resistance (3,4,43,44).”
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 (2012, background): “In contrast, in mammalian cells, IKKβ physically associates with IRS1, and its TNFα-stimulated activity correlates with phosphorylation of mS307/hS312—consistent with IKKβ phosphorylation of this residue in vitro [167].”
The Molecular Bases of Training Adaptation (2007, background): “TNFα appears to exert its effect on IRS-1 by activation of IKK in a p38 MAPK-dependent manner (Del Aguila et al. 2000; Gao et al. 2002; de Alvaro et al. 2004).”
Diabetes associated cell stress and dysfunction: role of mitochondrial and non‐mitochondrial ROS production and activity (2007, background): “…are reported to be involved in IRS-mediated insulin resistance include the mammalian target of rapamycin (mTOR) (Mussig et al. 2005), several isozymes of PKC, including PKCβ and PKC (Ishizuka et al. 2004; Dey et al. 2005; Greene et al. 2006), and the IKKβ–NFκB signalling cascades (Gao et al. 2002).”
Nutrient sensing and inflammation in metabolic diseases (2008, background): “The modifications that impair the action of insulin can be triggered by cytokines, such as TNF , indicating that immune mediators can have a crucial regulatory role in systemic glucose homeostasi”
Adipocytokines in Obesity and Metabolic Disease (2014, neutral): “JNK1 can directly inhibit insulin signaling by phosphorylating insulin receptor substrate 1 (IRS1) on serine residues (Aguirre et al. 2002) and can also potentiate fatty acid- induced cytokine production (Nguyen et al. 2005).”
Mechanisms of insulin resistance in obesity (2013, background): “Activation of IKKβ and JNK1 involves in IRS-1 inhibition by TNF-α [8,12,13].”