β-Arrestins and Cell Signaling

Upon their discovery, β-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows that β-arrestins can also function to activate signaling cascades independently of G protein activation. By serving as multiprotein scaffolds, the β-arrestins bring elements of specific signaling pathways into close proximity. β-Arrestin regulation has been demonstrated for an everincreasing number of signaling molecules, including the mitogenactivated protein kinases ERK, JNK, and p38 as well as Akt, PI3 kinase, and RhoA. In addition, investigators are discovering new roles for β-arrestins in nuclear functions. Here, we review the signaling capacities of these versatile adapter molecules and discuss the possible implications for cellular processes such as chemotaxis and apoptosis. 483 A nn u. R ev . P hy si ol . 2 00 7. 69 :4 83 -5 10 . D ow nl oa de d fr om a rj ou rn al s. an nu al re vi ew s. or g by U ni ve rs ity o f Pa ri s 5 R en e D es ca rt es o n 11 /1 8/ 08 . F or p er so na l u se o nl y. ANRV300-PH69-21 ARI 8 January 2007 17:37 7TMR: seventransmembrane receptor GPCR: G protein–coupled receptor GRK: G protein–coupled receptor kinase β2AR: β-2 adrenergic receptor Adapter: a protein that enhances cellular responses by recruiting key proteins into a complex AT1AR: angiotensin II receptor type 1A β-ARRESTINS: DISCOVERY, BIOLOGY, AND CLASSICAL FUNCTIONS The classic paradigm of signal transduction in response to stimulation of seventransmembrane receptors (7TMRs), also known as G protein–coupled receptors (GPCRs), involves an agonist-induced conformational change that allows the receptor to interact with and dissociate the Gα from the Gβγ subunits of heterotrimeric G proteins (for a historical review, see Reference 1). Distinct subtypes of Gαproteins, such as Gαs, Gαq, and Gαi, signal through discrete pathways via second messenger molecules such as cyclic AMP, inositol triphosphate, diacylglycerol, and calcium. Members of a protein family known as the G protein–coupled receptor kinases (GRKs) initiate the termination of this signaling response (for reviews see References 2–4). GRKs rapidly phosphorylate the receptor, typically on its cytoplasmic tail. β-Arrestins then bind the phosphorylated receptor, which blocks further G protein–initiated signaling through a steric mechanism. Discovery of β-Arrestins The discovery of β-arrestins in the late 1980s resulted from the observation that increasingly pure preparations of GRK2 (then referred to as β adrenergic receptor kinase) progressively lost the ability to desensitize G protein activation in a reconstituted β-2 adrenergic receptor (β2AR) system (5). The loss of desensitization could be rescued by addition of high molar excesses of visual arrestin (S-antigen or 48-kDa protein) (6), which researchers had recently discovered to function together with rhodopsin kinase to desensitize rhodopsin signaling. This implied that a homologous protein could exist in nonretinal tissues (5). Molecular cloning confirmed this and revealed two isoforms of the hypothesized protein, termed β-arrestins 1 and 2 (or arrestins 2 and 3) because of their homology with arrestin and their functional regulation of the β2AR (7, 8). β-Arrestins as Adapters for Internalization β-Arrestins are expressed ubiquitously in all cells and tissues and function in the desensitization of most 7TMRs except rhodopsin. Although their role in the termination of signaling led to their discovery, later research appreciated thatβ-arrestins serve a second function in receptor internalization [for a review, see Benovic et al. (8a) in this volume]. By acting as adapters for β(2) adaptin, better known as AP2, and clathrin (9–11), β-arrestins bring activated receptors to clathrin-coated pits for endocytosis, a process critical for receptor recycling and degradation.β-Arrestins also bind to various other proteins implicated in receptor internalization. For example, β-arrestin2 is constitutively bound to the guanine nucleotide exchange factor ARNO (ARF nucleotide binding site opener) and serves as a switch to regulate the activity of the small G protein ARF6 (ADP-ribosylation factor 6), which is bound to β-arrestin2 only upon receptor stimulation (12, 13). When ARNO activates ARF6, the latter is released by βarrestin2 and assists in the endocytosis of the receptor. Isoform Differences Between β-Arrestins 1 and 2 The amino acid sequences of the two βarrestin isoforms are 78% identical; most of the coding differences appear in the C termini. Knockout studies show that mice lacking either β-arrestin1 or -2 are viable (14, 15), whereas the double-knockout phenotype is embryonic lethal (16; R.J. Lefkowitz & F.T. Lin, unpublished data), implying that each βarrestin functionally substitutes for the other isoform to some degree. However, the molecular studies reviewed here do not support redundant roles for all β-arrestin-mediated functions. For example, internalization of 484 DeWire et al. A nn u. R ev . P hy si ol . 2 00 7. 69 :4 83 -5 10 . D ow nl oa de d fr om a rj ou rn al s. an nu al re vi ew s. or g by U ni ve rs ity o f Pa ri s 5 R en e D es ca rt es o n 11 /1 8/ 08 . F or p er so na l u se o nl y. ANRV300-PH69-21 ARI 8 January 2007 17:37 Table 1 7TMRs and their β-arrestin-dependent propertiesa