Article

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)

University of Chicago, Chicago, Illinois, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2004; 279(44):45304-7. DOI: 10.1074/jbc.C400186200
Source: 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.

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    • "Ser-29 Krasel et al. (2001); Malhotra et al. (2010) PKCα GTPase activating protein (GAP) p190A Ser-1221 and Thr-1226 Lévay et al. (2009) PKCδ Heat-shock protein-25/27 Ser-15 and Ser-86 Maizels et al. (1998) PKCζ Heterogeneous ribonucleoprotein A1 Ser-199 + three unknown sites Municio et al. (1995) cPKCs and PKCδ High-mobility-group protein-1 Ser-44 and Ser-64 Xiao et al. (2000) PKCβΙ Histone H3 Thr-6 Metzger et al. (2010) PKCε and β Ser-10 Huang et al. (2004) PKCζ Insulin-responsive aminopeptidase (IRAP) Ser-80 and Ser-91 Ryu et al. (2002) PKCδ Insulin receptor substrate-1 (IRS-1) (human) Ser-24, Ser-307, Ser-323, and Ser-574 Greene et al. (2004) (2006) PKCθ IRS-1 (human) Ser-1101 Li et al. (2004) PKCβII IRS-1 (mouse) Ser-336 Liberman et al. (2008) PKCδ IRS-1 (rat) Ser 357 Waraich et al. (2008) PKCζ IRS-1 (rat) Ser-318, Ser-498, Ser-570, and Ser-612 (a major phosphorylation site is Ser-318) Beck et al. (2003); Moeschel et al. (2004) "
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