β-Arrestin-Dependent Formation of β2 Adrenergic Receptor-Src Protein Kinase Complexes

LM Luttrell, S Ferguson, Y Daaka, WE Miller… - Science, 1999 - science.org
LM Luttrell, S Ferguson, Y Daaka, WE Miller, S Maudsley, GJ Della Rocca, FT Lin…
Science, 1999science.org
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 …
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.
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