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Phosphorylation of Ser(24) 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

  1. Author:
    Kim, J. A.
    Yeh, D. C.
    Ver, M.
    Li, Y. H.
    Carranza, A.
    Conrads, T. P.
    Veenstra, T. D.
    Harrington, M. A.
    Quon, M. J.

  2. Author Address

    NCCAM, Diabet Unit, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Proteom & Analyt Technol, Mass Spectrometry Ctr, NCI,NIH, Frederick, MD 21702 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN 46202 USA Quon, MJ, NCCAM, Diabet Unit, NIH, Bldg 10,Rm 6C-205,10 Ctr Dr,MSC 1632, Bethesda, MD 20892 USA
    1. Year: 2005
    2. Date: JUN 17
  2. Journal: Journal of Biological Chemistry
    1. 280
    2. 24
    3. Pages: 23173-23183
  4. Type of Article: Article
  1. Abstract:

    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. Wildtype 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-3T3(IR) 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 Ser(24) 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 Ser(24)) 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 Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). We conclude that IRS-1 is a novel physiological substrate for mPLK. TNF-alpha-regulated phosphorylation at Ser(24) 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

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External Sources

  1. View record in Web of Science®
  2. WOS: 000229741800075

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