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 beta2 adrenergic receptors resulted in the assembly of a protein complex containing activated c-Src and the receptor. Src recruitment was mediated by beta-arrestin, which functions as an adapter protein, binding both c-Src and the agonist-occupied receptor. beta-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 beta2 adrenergic receptor-mediated activation of the MAP kinases Erk1 and Erk2. These data suggest that beta-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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adrenergic beta-Agonists / metabolism
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Adrenergic beta-Agonists / pharmacology
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Animals
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Arrestins / genetics
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Arrestins / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Cell Membrane / metabolism
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Enzyme Activation
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GTP-Binding Proteins / metabolism
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Humans
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Isoproterenol / metabolism
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Isoproterenol / pharmacology
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases*
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Models, Biological
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Phosphorylation
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Point Mutation
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Precipitin Tests
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Proto-Oncogene Proteins pp60(c-src) / metabolism*
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Receptor Cross-Talk
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Receptors, Adrenergic, beta-2 / metabolism*
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Receptors, Cell Surface / metabolism
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Signal Transduction*
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Transfection
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beta-Arrestin 1
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beta-Arrestins
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src Homology Domains
Substances
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ARRB1 protein, human
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Adrenergic beta-Agonists
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Arrestins
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Receptors, Adrenergic, beta-2
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Receptors, Cell Surface
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beta-Arrestin 1
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beta-Arrestins
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Proto-Oncogene Proteins pp60(c-src)
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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GTP-Binding Proteins
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Isoproterenol