The role of β-arrestins in the termination and transduction of G-protein-coupled receptor signals
Abstract
β-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. β-arrestin binding to GPCRs both uncouples receptors from heterotrimeric
G proteins and targets them to clathrincoated pits for endocytosis. Recent data suggest
that β-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, β-arrestins confer distinct signaling activities upon the receptor. β-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, β-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.
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Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the

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