Interaction of the human insulin receptor with the ras oncogene product p21

Abstract

Autophosphorylation of the purified human insulin receptor tyrosyl kinase was found to be inhibited by the ras oncogene product p21 in a concentration- and GDP-dependent manner. GDP-β-S but not Gpp(NH)p could substitute for GDP in eliciting the ras-dependent inhibition. The inhibition was seen with both normal or mutant (Lys-61) p21^N-ras and normal or mutant (Val-12) p21^Ha-ras. Inhibition occurred at 23°C but not 4°C and was unaffected by the presence or absence of insulin although insulin stimulated the autophosphorylation rate of the receptor β-subunit some 2-fold. The insulin receptor did not phosphorylate native p21^Ha-ras in the presence or absence of added guanine nucleotide. After denaturation of p21^Ha-ras with urea it became a substrate, but then failed to inhibit receptor autophosphorylation even in the presence of added GDP.