Structure and function of the insulin receptor-a personal perspective

Immunoprecipitation with autoantibodies to the insulin receptor derived from patients with extreme insulin resistance and acanthosis nigricans revealed that the receptor is comprised of two subunits of 135 kDa (alpha subunit) and 95 kDa (beta subunit) and that insulin induces the rapid phosphorylation of the beta subunit in intact cells. Incubation of a highly purified insulin receptor preparation with [gamma P-32]ATP also resulted in tyrosine phosphorylation of the beta subunit in an insulin-dependent manner, suggesting that the receptor itself is a tyrosine-specific protein kinase. Furthermore, a Japanese boy with insulin resistance and acanthosis nigricans was found to be heterozygous for a mutation of the insulin receptor gene that resulted in the replacement of glycine-996 with valine in the ATP binding site of the receptor. Expression of the mutant receptor in cultured cells revealed it to be deficient in tyrosine kinase activity and mediation of insulin action, suggesting that the tyrosine kinase activity of the insulin receptor is essential for insulin action in vivo.