Specificity
The Insulin receptor substrate-1 (IRS-1), a protein major substrate of the Insulin receptor, is phosphorylated in response to stimulation of cells by Insulin, Insulin-like growth factor 1 (IGF-1) and interleukin 4 (IL-4). IRS-1 is phosphorylated on serine, threonine and tyrosine residues in a variety of tissues. An Insulin-sensitive serine/threonine kinase casein kinase II mediates a portion of the Insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. Thr 502 is identified as the major casein kinase IIcatalyzed phosphorylation site in rat IRS-1, and Ser 99 is an additional phosphorylation site catalyzed by casein kinase II. Thus, casein kinase IIcatalyzed phosphorylation of IRS-1 may be a component of the intracellular Insulin signaling cascade. IRS-1 contains three putative binding sites for 14-3-3 (Ser 270, Ser 374 and Ser 641) and the motif around Ser 270 is located in the phosphotyrosine binding domain of IRS-1, which is responsible for the interaction with the Insulin receptor. The association of 14-3-3 with IRS-1 increases significantly upon treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. Therefore, the association of 14-3-3 protein may play a role in the regulation of Insulin sensitivity by interrupting the association between the Insulin receptor and IRS-1.
