Insulin receptor substrate 1 is one of the major substrates of the insulin receptor kinase. IRS-1 contains multiple tyrosine phosphorylation motifs that serve as docking sites for SH2-domain containing proteins that mediate the metabolic and growth-promoting functions of insulin. IRS-1 also contains over 30 potential serine/threonine phosphorylation sites. Ser307 of IRS-1 is phosphorylated by JNK and IKK while Ser789 is phosphorylated by SIK-2, a member of the AMPK family. The PKC and mTOR pathways mediate phosphorylation of IRS-1 at Ser612 and Ser636/639, respectively. Phosphorylation of IRS-1 at Ser1101 is mediated by PKCθ and results in an inhibition of insulin signaling in the cell, suggesting a potential mechanism for insulin resistance in some models of obesity.
[1] Sun, X.J. et al. (1991) Nature 352, 73-77.
[2] Sun, X.J. et al. (1992) J. Biol. Chem. 267, 22662-22672.
[3] Myers Jr., M.G. et al. (1993) Endocrinology 132, 1421-1430.
[4] Wang, L.M. et al. (1993) Science 261, 1591-1594.
[5] Rui, L. et al. (1997) J. Clin. Invest. 107, 181-189.
[6] Gao, Z. et al. (2002) J. Biol. Chem. 277, 48115-48121.
[7] Horike, N. et al. (2003) J. Biol. Chem. 278, 18440-18447.
[8] Ozes, O.N. et al. (2001) Proc. Natl. Acad. Sci. USA 98, 4640-4645.
[9] De Fea, K. and Ruth, R.A. (1997) Biochemistry 36, 12939-12947.
[10] Li, Y. et al. (2004) J. Biol. Chem. 279, 45304-45307.
