beta-arrestin-dependent formation of beta(2) adrenergic receptor Src protein kinase complexes

The Pas-dependent activation of mitogen-activated protein (MAP) kinase path ways by many receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) requires the activation of Src family tyrosine kinas es. Stimulation of beta(2) adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruit ment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-Arrestin 1 mutan ts, impaired either in c-Src binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta(2) a drenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. Th ese data suggest that beta-arrestin binding, which terminates receptor-C pr otein;coupling, also initiates a second wave of signal transduction in whic h the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex.