PMID:18285345

Citation	Waraich, RS, Weigert, C, Kalbacher, H, Hennige, AM, Lutz, SZ, Häring, HU, Schleicher, ED, Voelter, W and Lehmann, R (2008) Phosphorylation of Ser357 of rat insulin receptor substrate-1 mediates adverse effects of protein kinase C-delta on insulin action in skeletal muscle cells. J. Biol. Chem. 283:11226-33
Abstract	The activation of the protein kinase C (PKC) family of serine/threonine kinases contributes to the modulation of insulin signaling, and the PKC-dependent phosphorylation of insulin receptor substrate (IRS)-1 has been implicated in the development of insulin resistance. Here we demonstrate Ser(357) of rat IRS-1 as a novel PKC-delta-dependent phosphorylation site in skeletal muscle cells upon stimulation with insulin and phorbol ester using Ser(P)(357) antibodies and active and kinase dead mutants of PKC-delta. Phosphorylation of this site was simulated using IRS-1 Glu(357) and shown to reduce insulin-induced tyrosine phosphorylation of IRS-1, to decrease activation of Akt, and to subsequently diminish phosphorylation of glycogen synthase kinase-3. When the phosphorylation was prevented by mutation of Ser(357) to alanine, these effects of insulin were enhanced. When the adjacent Ser(358), present in mouse and rat IRS-1, was mutated to alanine, which is homologous to the human sequence, the insulin-induced phosphorylation of glycogen synthase kinase-3 or tyrosine phosphorylation of IRS-1 was not increased. Moreover, both active PKC-delta and phosphorylation of Ser(357) were shown to be necessary for the attenuation of insulin-stimulated Akt phosphorylation. The phosphorylation of Ser(357) could lead to increased association of PKC-delta to IRS-1 upon insulin stimulation, which was demonstrated with IRS-1 Glu(357). Together, these data suggest that phosphorylation of Ser(357) mediates at least in part the adverse effects of PKC-delta activation on insulin action.
Links	PubMed Online version:10.1074/jbc.M708588200
Keywords	Adaptor Proteins, Signal Transducing/metabolism; Animals; Cricetinae; Humans; Insulin/metabolism; Insulin Receptor Substrate Proteins; Kidney/metabolism; Mice; Models, Biological; Muscle, Skeletal/metabolism; Mutation; Phosphorylation; Protein Kinase C-delta/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Rats; Serine/chemistry
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