QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luttrell, L. M. Articles by Lefkowitz, R. J. Search for Related Content PubMed PubMed Citation Articles by Luttrell, L. M. Articles by Lefkowitz, R. J.

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

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

View larger version (36K): [in a new window]   Fig. 1. Role of ß-arrestins in the desensitization, sequestration and intracellular trafficking of GPCRs. Homologous desensitization of GPCRs (1) results from the binding of ß-arrestins (ß-arr) to agonist (H)-occupied receptors following phosphorylation of the receptor by GRKs. ß-arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors (E). Receptor-bound ß-arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, ß2-adaptin (AP-2) and NSF. Receptor sequestration (2) reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of ß-arrestin interaction. `Class A' GPCRs, for example the ß2 adrenergic receptor, rapidly dissociate from ß-arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane (3). `Class B' receptors, for example the angiotensin II AT1a receptor, form stable receptor-ß-arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes.

View larger version (28K): [in a new window]   Fig. 2. Putative domain architecture of the ß-arrestins. By analogy with the known crystal structure of visual arrestin, ß-arrestins are thought to be composed of two major structural domains, N and C, each comprising a seven-stranded ß sandwich. Based upon mutagenesis studies performed using both ß-arrestins and visual arrestin, the ß-arrestins are comprised of two major functional domains, an N-terminal (A) domain responsible for recognition of activated GPCRs and a C-terminal (B) domain responsible for secondary receptor recognition. The A and B domains are separated by a phosphate sensor domain (P). The functionally identified A and B domains correspond approximately to the N and C domains identified crystallographically. N (R1)- and C (R2)-terminal regulatory domains reside at either end of the protein. The R2 domain contains the primary site of ß-arrestin 1 phosphorylation, S412, as well as the LIEF binding motif for clathrin and the RXR binding motif for ß2-adaptin (AP2). The recognition domain for inositol phospholipids (IP6) resides within the B domain. One or more PXXP motifs located within the A domain of ß-arrestin 1 mediates binding to the c-Src-SH3 domain. The MAP kinase, JNK3, and possibly other MAP kinases (MAPKs), interact with ß-arrestin 2 via a consensus MAP kinase recognition sequence, RRSLHL, located within the B domain. Less precisely defined interactions, such as those between ß-arrestin 1 (1-185) and Ask1 and Src-SH1 domains, ß-arrestin 1 and NSF, and ß-arrestin 2 and Mdm2, are also shown. Regions of the protein involved in receptor or membrane recognition are shown in blue, those involved in controlling ß-arrestin interaction with the endocytic machinery are shown in red, while proposed interactions between ß-arrestins and signaling proteins are shown in green.

View larger version (39K): [in a new window]   Fig. 3. Proposed roles of ß-arrestin-dependent recruitment of Src kinases in GPCR signaling. The binding of ß-arrestins to agonist-occupied GPCRs coincides with the recruitment of Src family tyrosine kinases, including c-Src, Hck and c-Fgr (Src-TK), to the receptor—ß-arrestin complex. Several signaling events have been reported to involve ß-arrestin-dependent Src recruitment. These include the regulation of clathrin-dependent ß2-adrenergic receptor endocytosis by tyrosine phosphorylation of dynamin (1), Ras-dependent activation of the ERK1/2 MAP kinase cascade and stimulation of cell proliferation by ß2-adrenergic and neurokinin NK1 receptors (2), and stimulation of chemokine CXCR1 receptor-mediated neutrophil degranulation (3).

View larger version (33K): [in a new window]   Fig. 4. Proposed role of ß-arrestins in the activation and targeting of MAP kinases. The binding of ß-arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using ß-arrestin as a scaffold, with subsequent activation of a ß-arrestin-bound pool of ERK1/2. The receptor—ß-arrestin—ERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of ß-arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by ß-arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts ß-arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors.