β-Arrestin-Dependent Formation of β 2 Adrenergic Receptor-Src Protein Kinase ComplexesL. M. Luttrell, S. S. G. Ferguson, Y. Daaka, W. E. Miller, S. Maudsley, G. J. Della Rocca, F.-T. Lin, H. Kawakatsu, K. Owada, D. K. Luttrell, M. G. Caron, R. J. Lefkowitz
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.