Inhibition of the activation and catalytic activity of insulin receptor kinase by zinc and other divalent metal ions.
The autophosphorylation reaction responsible for conversion of insulin receptor (from human placenta) to an active tyrosyl-protein kinase was shown to be inhibited by Zn2+ and other divalent metal ions. The order of inhibitory potency was found to be Cu2+ greater than Zn2+, Cd2+ greater than Co2+, Ni2+. Autophosphorylation of insulin receptor was almost completely blocked by 10 microM Zn2+. Zn2+, however, did not appear to affect the binding of insulin to its receptor. Histidine, a chelator of Zn2+, protected against the inhibitory effects of Zn2+. The failure of histidine to regenerate the competence of the Zn2+-inhibited receptor to undergo autophosphorylation suggested that the inhibition by Zn2+ was irreversible. In addition to inhibiting autophosphorylation, Zn2+ inhibited the tyrosyl-protein kinase activity of highly purified phosphorylated receptor. Zn2+ was also observed to inhibit phosphotyrosyl-protein phosphatase activity present in preparations of partially purified insulin receptor. These inhibitory effects of Zn2+ should be considered in the design of protocols for the isolation and handling of insulin receptor and possibly other tyrosine kinases. Additionally, the possible physiological significance of the inhibition of insulin receptor kinase by Zn2+ is discussed in light of the fact that Zn2+ is accumulated in and secreted from pancreatic islet cells together with insulin.
D002413:Cations, Divalent / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D010766:Phosphorylation; D010920:Placenta / Q000032:analysis; D011247:Pregnancy; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
D002413:Cations, Divalent; D012710:Serum Albumin, Bovine; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D015032:Zinc; D004229:Dithiothreitol