Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).
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Li Y, Soos TJ, Li X, Wu J, Degennaro M, Sun X, Littman DR, Birnbaum MJ, Polakiewicz RD
Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).
J Biol Chem. 2004 Oct 29;279(44):45304-7. Epub 2004 Sep 10.
- PubMed ID
- 15364919 [ View in PubMed]
- Abstract
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 tyrosine 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.