Journal
MOLECULAR ENDOCRINOLOGY
Volume 21, Issue 9, Pages 2294-2302Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2007-0159
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- NIDDK NIH HHS [DK038712, DK067818] Funding Source: Medline
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Multisite phosphorylation of Irs1 on serine and threonine residues regulates insulin signaling that can contribute to insulin resistance. We identified by mass spectrometry the phosphorylation of Ser522 in rat Irs1 ( S522(Irs1)). The functional effects of this phosphorylation site were investigated in cultured cells using a sequencespecific phosphoserine antibody. Insulin stimulated the phosphorylation of S522(Irs1) in L6 myoblasts and myotubes. S522(Irs1) phosphorylation was inhibited by wortmannin, whereas PD98059, rapamycin, or glucose-starvation had no effect. Reducing Akt expression with small interfering RNA inhibited insulin-stimulated phosphorylation of S522(Irs1), suggesting the involvement of the phosphatidylinositol 3-kinase3 -> Akt cascade. A S522(Irs1)-> A522(Irs1) substitution increased insulinstimulated tyrosine phosphorylation of Irs1 and signaling, whereas a S522(Irs1)-> E522(Irs1) substitution reduced insulin-stimulated Irs1 tyrosine phosphorylation. Together, these results suggest the phosphatidylinositol 3-kinase -> Akt cascade can inhibit insulin signaling through the phosphorylation of S522(Irs1).
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