Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling.
Beta-arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated second messenger signalling pathways. The binding of beta-arrestins to 7MSRs also leads to new signals via activation of MAPKs (mitogen-activated protein kinases) such as JNK3 (c-Jun N-terminal kinase 3), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs. By binding to endocytic proteins [clathrin, AP2 (adapter protein 2), NSF (N -ethylmaleimide-sensitive fusion protein) and ARF6 (ADP-ribosylation factor 6)], beta-arrestins also serve as adapters to link the receptors to the cellular trafficking machinery. Agonist-promoted ubiquitination of beta-arrestins is a prerequisite for their role in receptor internalization, as well as a determinant of the differing trafficking patterns of distinct classes of receptors. Recently, beta-arrestins have also been implicated as playing novel roles in cellular chemotaxis and apoptosis. By virtue of their ability to bind, in a stimulus-dependent fashion, to 7MSRs as well as to different classes of cellular proteins, beta-arrestins serve as versatile adapter proteins that regulate the signalling and trafficking of the receptors.
Shenoy
Sudha K
SK
Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, Box 3821, Durham, NC 27710, USA.
Lefkowitz
Robert J
RJ
D000089982:ADP-Ribosylation Factor 6; D000818:Animals; D019390:Arrestins / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000071557:beta-Arrestins
D000089982:ADP-Ribosylation Factor 6; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C000715348:ARF6 protein, human