| Background |
Insulin receptor substrate 1 (IRS-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.GSK-3-mediated IRS-1 serine phosphorylation leads to inhibition of insulin-stimulated IRS-1 signaling. Ser332 and Ser336 of IRS-1 are situated in a glycogen synthase kinase-3 (GSK-3) consensus motif (SXXXS), and it has been shown that Ser332 is the actual GSK-3 phosphorylation site while Ser336 provides a " priming" site necessary for GSK-3 action.
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