The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals.
beta-Arrestins are versatile adapter proteins that form complexes with most G-protein-coupled receptors (GPCRs) following agonist binding and phosphorylation of receptors by G-protein-coupled receptor kinases (GRKs). They play a central role in the interrelated processes of homologous desensitization and GPCR sequestration, which lead to the termination of G protein activation. beta-arrestin binding to GPCRs both uncouples receptors from heterotrimeric G proteins and targets them to clathrin-coated pits for endocytosis. Recent data suggest that beta-arrestins also function as GPCR signal transducers. They can form complexes with several signaling proteins, including Src family tyrosine kinases and components of the ERK1/2 and JNK3 MAP kinase cascades. By recruiting these kinases to agonist-occupied GPCRs, beta-arrestins confer distinct signaling activities upon the receptor. beta-arrestin-Src complexes have been proposed to modulate GPCR endocytosis, to trigger ERK1/2 activation and to mediate neutrophil degranulation. By acting as scaffolds for the ERK1/2 and JNK3 cascades, beta-arrestins both facilitate GPCR-stimulated MAP kinase activation and target active MAP kinases to specific locations within the cell. Thus, their binding to GPCRs might initiate a second wave of signaling and represent a novel mechanism of GPCR signal transduction.
Luttrell
Louis M
LM
The Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Lefkowitz
Robert J
RJ
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
D019390:Arrestins; D011956:Receptors, Cell Surface; D000071557:beta-Arrestins; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins