Bovine fetuin is an inhibitor of insulin receptor tyrosine kinase

Fetuin has been identified earlier as the bovine homolog of the human plasma protein, α2-Heremans Schmid grycoprotein (α2-HSG). Although bovine fetuin shares over 70% ammo acid sequence similarity with α2-HSG and rat fetuin, no common function(s) have been identified. We report that immunoaffinity purified bovine fetuin acts as an inhibitor of insulin receptor tyrosine kinase activity (IR-TKA) with half-maximal inhibition at 1.5 μM. In vitro, bovine fetuin (1.5 μM) blocked insulin-induced autophosphorylation of the human IR completely and the half-maximal inhibitory effect was observed at 0.5 μM. Incubation of HIRcB cells (ratl fibroblasts transfected with wild-type human insulin receptor cDNA) with bovine fetuin (1.5 μM) inhibited insulin-induced tyrosine phosphorylation of the IR β-subunit by 40%. In addition, bovine fetuin (2 μM) completely blocked insulin-stimulated DNA synthesis in H-35 rat hepatoma cells. Our results, together with earlier reports on rat fetuin and human α2-HSG, indicate a common IR-TK inhibitory function for fetuin homologs.