Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level

Mol Endocrinol. 1993 Nov;7(11):1445-55. doi: 10.1210/mend.7.11.7906861.


The insulin-dependent tyrosine kinase activity (TKA) of the insulin receptor (IR) plays an essential role in insulin signaling. Thus, dysregulation of IR-TKA might be an important element in the states of insulin resistance. A phosphorylated rat hepatic glycoprotein (pp63) acting as an inhibitor of IR-TK has been described. In search of the human homolog of pp63, we isolated a cDNA clone from a human liver lambda gt11 cDNA library. DNA sequence analysis reveals identity with the mRNA product of a human gene AHSG encoding a serum protein, alpha 2-Heremans Scmid-glycoprotein (alpha 2HSG), with heretofore unknown physiological function. Northern blot analysis demonstrates a 1.8-kilobase mRNA in human liver and HepG2 hepatoma cells. alpha 2HSG, purified from human serum, specifically inhibits insulin-stimulated IR autophosphorylation in vitro and in vivo as well as exogenous substrate tyrosine phosphorylation. alpha 2HSG also inhibits both insulin-induced tyrosine phosphorylation of IRS-1 and the association of IRS-1 with the p85 subunit of phosphatidylinositol-3 kinase in H-35 hepatoma cells. alpha 2HSG inhibits insulin-dependent mitogenesis, but does not affect insulin-stimulated induction of the metabolic enzyme tyrosine aminotransferase. alpha 2HSG does not compete with insulin for binding to IR. Finally, the action of alpha 2HSG is specific toward the IR-TK; its effect does not extend to insulin-like growth factor-I-stimulated TKA. Our results allow us to assign a biochemical function for human alpha 2HSG, namely regulation of insulin action at the IR-TK level.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blood Proteins / pharmacology*
  • CHO Cells
  • Cell Division / drug effects
  • Cricetinae
  • DNA, Complementary / genetics
  • Enzyme Induction / drug effects
  • Glycoproteins / chemistry
  • Humans
  • L Cells
  • Liver / metabolism
  • Mice
  • Molecular Sequence Data
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Rats
  • Receptor, Insulin / antagonists & inhibitors*
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Tyrosine Transaminase / biosynthesis
  • alpha-2-HS-Glycoprotein


  • AHSG protein, human
  • Ahsg protein, mouse
  • Ahsg protein, rat
  • Blood Proteins
  • DNA, Complementary
  • Glycoproteins
  • alpha-2-HS-Glycoprotein
  • Tyrosine Transaminase
  • Protein-Tyrosine Kinases
  • Receptor, Insulin