Cytosolic Substrates for the Insulin Receptor Kinase

Abstract

Insulin receptor belongs to a family of cell surface receptors possessing ligand-activated tyrosine kinase activity. In the case of the insulin receptor, phosphorylation of tyrosine residues in its β subunit is stimulated by the binding of insulin to the ∝subunit (1–8), resulting in an increased receptor tyrosine phosphotransferase activity towards several artificial substrates (9–14). That receptor kinase activity is involved in insulin action is supported by the observation that the effect of insulin was abolished in intact cells when their insulin receptor kinase was inhibited (15) or in transfectant cells expressing insulin receptors deficient in kinase activity (16). As is the case with other receptor kinase, the exact relationship between receptor kinase activity and insulin action remains unresolved. It is possible that the activated insulin receptor may initially phosphorylate one or more membrane or cytosolic proteins which catalyze subsequent changes in the activities of key enzymes. The identification of such cellular substrate(s) for the insulin receptor kinase, or for the receptor kinase of other growth factors, is an important step to understanding the mechanism of action of insulin or other growth factors. Since the same tissue can possess more than one kind of receptor with kinase activity, for example, receptors for both EGF and insulin are present in hepatocyte, and since different tissues or target organs respond differently to the same hormone, for example the different actions of insulin on fat and liver tissue, it is reasonable to postulate that endogenous substrates would be both tissue and hormone specific. Thus an endogenous substrate S of the insulin receptor in the liver would not be phosphorylated by the EGF receptor, and substrate S may not be found in fat tissue. Several putative substrates of the insulin receptor kinase have been detected recently. These are listed in Table I. They were detected primarily as additional insulin-stimulated phosphorylated components in membrane preparations or in preparations of partially purified insulin receptors. The role of these proteins in the action of insulin is not known, except the 15-kDa protein detected in the 3T3-L1 adipocytes. This protein was linked circumstantially to the insulin-stimulated glucose oxidation by the 3T3-L1 adipocytes.