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Phosphorylation of Ser357 of rat insulin receptor substrate-1 mediates adverse effects of protein kinase C-delta on insulin action in skeletal muscle cells.

Authors: Waraich, RS  Weigert, C  Kalbacher, H  Hennige, AM  Lutz, SZ  Haring, HU  Schleicher, ED  Voelter, W  Lehmann, R 
Citation: Waraich RS, etal., J Biol Chem. 2008 Apr 25;283(17):11226-33. doi: 10.1074/jbc.M708588200. Epub 2008 Feb 19.
Pubmed: (View Article at PubMed) PMID:18285345
DOI: Full-text: DOI:10.1074/jbc.M708588200

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.


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RGD Object Information
RGD ID: 8553881
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.