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Journal of Cell Science 115, 455-465 (2002)
© 2002 The Company of Biologists Limited

Commentary

The role of ß-arrestins in the termination and transduction of G-protein-coupled receptor signals

Louis M. Luttrell2,4 and Robert J. Lefkowitz1,2,3,*

1 The Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA
2 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
3 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA
4 The Geriatrics Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, Durham, NC 27705, USA

* Author for correspondence (e-mail: lefko001{at}receptor-biol.duke.edu)

ß-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. ß-arrestin binding to GPCRs both uncouples receptors from heterotrimeric G proteins and targets them to clathrin-coated pits for endocytosis. Recent data suggest that ß-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, ß-arrestins confer distinct signaling activities upon the receptor. ß-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, ß-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.

Key words: ß-arrestin, G-protein-coupled receptor, Desensitization, Sequestration, Tyrosine kinase, Mitogen-activated protein kinase


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ß-arrestins: terminators and scaffolds for GPCR signalling (p. 455)

JCS 2002 115: 301. [Full Text]  



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