| First Author | Waraich RS | Year | 2008 |
| Journal | J Biol Chem | Volume | 283 |
| Issue | 17 | Pages | 11226-33 |
| PubMed ID | 18285345 | Mgi Jnum | J:145810 |
| Mgi Id | MGI:3836105 | Doi | 10.1074/jbc.M708588200 |
| Citation | Waraich RS, et al. (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(17):11226-33 |
| abstractText | 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. |
