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Originally published In Press as doi:10.1074/jbc.M501439200 on April 22, 2005

J. Biol. Chem., Vol. 280, Issue 24, 23173-23183, June 17, 2005
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Phosphorylation of Ser24 in the Pleckstrin Homology Domain of Insulin Receptor Substrate-1 by Mouse Pelle-like Kinase/Interleukin-1 Receptor-associated Kinase

CROSS-TALK BETWEEN INFLAMMATORY SIGNALING AND INSULIN SIGNALING THAT MAY CONTRIBUTE TO INSULIN RESISTANCE*

Jeong-a Kim{ddagger}, Deborah C. Yeh{ddagger}, Marel Ver{ddagger}, Yunhua Li{ddagger}, Andrea Carranza{ddagger}, Thomas P. Conrads§, Timothy D. Veenstra§, Maureen A. Harrington¶, and Michael J. Quon{ddagger}||

From the {ddagger}Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892, §SAIC-Frederick, Inc., Laboratory of Proteomics and Analytical Technologies, Mass Spectrometry Center, NCI, National Institutes of Health, at Frederick, Frederick, Maryland 21702-1201, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and Walther Cancer Institute, Indianapolis, Indiana 46202

Inflammation contributes to insulin resistance in diabetes and obesity. Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-{alpha}-treated cells. In NIH-3T3IR cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. This association was increased by treatment of cells with TNF-{alpha}. Using mass spectrometry, we identified Ser24 in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser24) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. Importantly, endogenous mPLK/IRAK was activated in response to TNF-{alpha} or interleukin 1 treatment of primary adipose cells. In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser24, we found that interleukin-1 or TNF-{alpha} treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser24. We conclude that IRS-1 is a novel physiological substrate for mPLK. TNF-{alpha}-regulated phosphorylation at Ser24 in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance.

Received for publication, February 7, 2005 , and in revised form, March 21, 2005.

* This work was supported by a Research Award from the American Diabetes Association (to M. J. Q.). The mass spectrometry was funded in part with Federal funds from NCI, National Institutes of Health, under Contract NO1-CO-12400. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Diabetes Unit, NC-CAM, National Institutes of Health, Bldg. 10, Rm. 6C-205, 10 Center Dr. MSC 1632, Bethesda, MD 20892-1632. Tel.: 301-496-6269; Fax: 301-402-1679; E-mail: quonm{at}nih.gov.


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