The beta-adrenergic receptor is a substrate for the insulin receptor tyrosine kinase

J Biol Chem. 1996 Jan 12;271(2):1061-4. doi: 10.1074/jbc.271.2.1061.


G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on beta-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of beta 2-adrenergic receptors. Phosphorylation of tyrosyl residues 350/354 of beta 2-adrenergic receptors is obligatory for counter-regulation by insulin (Karoor, V., Baltensperger, K., Paul, H., Czech, M., and Malbon, C. C. (1995) J. Biol. Chem. 270, 25305-25308), suggesting the hypothesis that G-protein-linked receptors themselves may act as substrates for the insulin receptor and other growth factor receptors. This hypothesis was evaluated directly using recombinant human insulin receptor, hamster beta 2-adrenergic receptor, and an vitro reconstitution and phosphorylation assay. Insulin is shown to stimulate insulin receptor-catalyzed phosphorylation of the beta 2-adrenergic receptor. Phosphoamino acid analysis establishes that insulin receptor-catalyzed phosphorylation of the beta 2-adrenergic receptor in vitro is confined to phosphotyrosine. High pressure liquid chromatography and two-dimensional mapping reveal insulin receptor-catalyzed phosphorylation of the beta 2-adrenergic receptor at residues Tyr132/Tyr141, Tyr350/Tyr354, and Tyr364, known sites of phosphorylation in response to insulin in vivo. Insulin-like growth factor-I receptor as well as the insulin receptor displays the capacity to phosphorylate the beta 2-adrenergic receptor in vitro, establishing a new paradigm, i.e. G-protein-linked receptors acting as substrates for intrinsic tyrosine kinase growth factor receptors.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • GTP-Binding Proteins / metabolism
  • Humans
  • Molecular Sequence Data
  • Phosphorylation
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, IGF Type 1 / metabolism*
  • Receptor, Insulin / metabolism*
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Recombinant Proteins / metabolism
  • Substrate Specificity


  • Receptors, Adrenergic, beta-2
  • Recombinant Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • GTP-Binding Proteins