Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 107, Issue 2, Pages 181-189Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI10934
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- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR002635] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK040605, R01DK040936] Funding Source: NIH RePORTER
- NCRR NIH HHS [RR 02635] Funding Source: Medline
- NIDDK NIH HHS [R01 DK040936, R01 DK 40605] Funding Source: Medline
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Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser(307), which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. To monitor phosphorylation of Ser(307) in various cell and tissue backgrounds, we prepared a phosphospecific polyclonal antibody designated alpha pSer(307). This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser(307) in 3T3-L1 preadipocytes and adipocytes. Insulin injected into mice or rats also stimulated phosphorylation of Ser(307) on IRS-1 immunoprecipitated from muscle; moreover, Ser(307) was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser(307) was inhibited by LY294002 or wortmannin, whereas TNF-alpha -stimulated phosphorylation was inhibited by PD98059. Thus, distinct kinase pathways might converge at Ser(307) to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response.
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