title: β-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation.
abstract: β-Arrestins critically regulate G-protein-coupled receptor (GPCR) signalling, not only 'arresting' the G protein signal but also modulating endocytosis and initiating a discrete G-protein-independent signal through MAP kinase. Despite enormous recent progress towards understanding biophysical aspects of arrestin function, arrestin cell biology remains relatively poorly understood. Two key tenets underlie the prevailing current view: β-arrestin accumulates in clathrin-coated structures (CCSs) exclusively in physical complex with its activating GPCR, and MAP kinase activation requires endocytosis of formed GPCR-β-arrestin complexes. We show here, using β1-adrenergic receptors, that β-arrestin-2 (arrestin 3) accumulates robustly in CCSs after dissociating from its activating GPCR and transduces the MAP kinase signal from CCSs. Moreover, inhibiting subsequent endocytosis of CCSs enhances the clathrin- and β-arrestin-dependent MAP kinase signal. These results demonstrate β-arrestin 'activation at a distance', after dissociating from its activating GPCR, and signalling from CCSs. We propose a β-arrestin signalling cycle that is catalytically activated by the GPCR and energetically coupled to the endocytic machinery.
authors.affiliation: Program in Biochemistry and Molecular Biology, University of California, San Francisco, California 94158, USA.
authors.forename: K
authors.initials: K
authors.lastname: Eichel
authors.affiliation: Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jullié
authors.affiliation: Department of Psychiatry, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco School of Medicine, San Francisco, California 94158, USA.
authors.forename: M
authors.initials: M
authors.lastname: von Zastrow
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; D002966:Clathrin; D043562:Receptors, G-Protein-Coupled; C082333:arrestin3; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins
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