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

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 β₂ 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 β₂ 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.