The insulin receptor substrate-1 (IRS1) is an adaptor protein that is one of the major substrates of the insulin receptor kinase. IRS1 is phosphorylated on serine, threonine and tyrosine residues in a variety of tissues. IRS1 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 IRS1, which is responsible for the interaction with the insulin receptor. The association of 14-3-3 with IRS1 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 IRS1.
