β-Arrestin-Dependent Formation of β ₂ Adrenergic Receptor-Src Protein Kinase Complexes

TLDR

Activation of MAP kinase pathways by G protein‑coupled receptors depends on Src family tyrosine kinases. β2‑adrenergic receptor stimulation recruits β‑arrestin, which bridges activated c‑Src to the receptor, forming a signaling complex. Mutant β‑arrestin 1 that cannot bind c‑Src or target receptors to clathrin‑coated pits blocks β2AR‑mediated Erk1/2 activation, indicating that β‑arrestin‑mediated recruitment of c‑Src to the desensitized receptor initiates a second wave of MAP‑kinase signaling.

Abstract

The Ras-dependent activation of mitogen-activated protein (MAP) kinase pathways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinases. Stimulation of β 2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by β-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. β-Arrestin 1 mutants, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of β 2 adrenergic receptor–mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that β-arrestin binding, which terminates receptor–G protein coupling, also initiates a second wave of signal transduction in which the “desensitized” receptor functions as a critical structural component of a mitogenic signaling complex.