SERUM ALPHA(2)-HS-GLYCOPROTEIN IS AN INHIBITOR OF THE HUMAN INSULIN-RECEPTOR AT THE TYROSINE KINASE LEVEL

The insulin-dependent tyrosine kinase activity (TKA) of the insulin re ceptor (IR) plays an essential role in insulin signaling. Thus, dysreg ulation of IR-TKA might be an important element in the states of insul in resistance. A phosphorylated rat hepatic glycoprotein (pp63) acting as an inhibitor of IR-TK has been described. In search of the human h omolog of pp63, we isolated a cDNA clone from a human liver lambda gt1 1 cDNA library. DNA sequence analysis reveals identity with the mRNA p roduct of a human gene AHSG encoding a serum protein, alpha(2)-Hereman s Scmid-glycoprotein (alpha(2)HSG), with heretofore unknown physiologi cal function. Northern blot analysis demonstrates a 1.8-kilobase mRNA in human liver and HepG2 hepatoma cells. alpha(2)HSG, purified from hu man serum, specifically inhibits insulin-stimulated IR autophosphoryla tion in vitro and in vivo as well as exogenous substrate tyrosine phos phorylation. alpha(2)HSG also inhibits both insulin-induced tyrosine p hosphorylation of IRS-1 and the association of IRS-1 with the p85 subu nit of phosphatidylinositol-3 kinase in H-35 hepatoma cells. alpha(2)H SG inhibits insulin-dependent mitogenesis, but does not affect insulin -stimulated induction of the metabolic enzyme tyrosine aminotransferas e. alpha(2)HSG does not compete with insulin for binding to IR. Finall y, the action of alpha(2)HSG is specific toward the IR-TK; its effect does not extend to insulin-like growth factor-I-stimulated TKA. Our re sults allow us to assign a biochemical function for human alpha(2)HSG, namely regulation of insulin action at the IR-TK level.