Serine kinases of insulin receptor substrate proteins.

Signaling of insulin and insulin-like growth factor-I (IGF-1) at target tissues is essential for growth, development and for normal homeostasis of glucose, fat, and protein metabolism. Control over this process is therefore tightly regulated. It can be achieved by a negative-feedback control mechanism, whereby downstream components inhibit upstream elements along the insulin and IGF-1 signaling pathway or by signals from other pathways that inhibit insulin/IGF-1 signaling thus leading to insulin/IGF-1 resistance. Phosphorylation of insulin receptor substrates (IRS) proteins on serine residues has emerged as a key step in these control processes both under physiological and pathological conditions. The list of IRS kinases is growing rapidly, concomitant with the list of potential Ser/Thr phosphorylation sites in IRS proteins. Here we review a range of conditions that activate IRS kinases to phosphorylate IRS proteins on selected domains. The specificity of this reaction is discussed and its characteristic as an "array" phosphorylation is suggested. Finally, its implications on insulin/IGF-1 signaling, insulin/IGF-1 resistance and diabetes, an emerging epidemic of the twenty-first century are outlined.