Protein Kinase C θ Inhibits Insulin Signaling by Phosphorylating IRS1 at Ser1101

Yu Li, Timothy J. Soos, Xinghai Li, Jiong Wu, Matthew DeGennaro, Xiaojian Sun, Dan R. Littman, Morris J. Birnbaum, Roberto D. Polakiewicz
2004 Journal of Biological Chemistry  
Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. The protein kinase C (PKC) is activated by free-fatty acids, and its activity is higher in muscle from obese diabetic patients. However, a molecular link between PKC and insulin resistance has not been defined yet. Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1
more » ... ine phosphorylation and downstream activation of the Akt pathway. Mutation of Ser 1101 to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. These results provide a novel mechanism linking the activation of PKC to the inhibition of insulin signaling.
doi:10.1074/jbc.c400186200 pmid:15364919 fatcat:pelpdybrcbcpnc462rkubg6mme