Title

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

UMMS Affiliation

Program in Molecular Medicine and the Department of Biochemistry and Molecular Biology

Date

1-12-1996

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Biol Chem. 1996 Jan 12;271(2):1061-4.

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

8557631