- Protein family review
- Open Access
Arrestins: ubiquitous regulators of cellular signaling pathways
Genome Biology volume 7, Article number: 236 (2006)
In vertebrates, the arrestins are a family of four proteins that regulate the signaling and trafficking of hundreds of different G-protein-coupled receptors (GPCRs). Arrestin homologs are also found in insects, protochordates and nematodes. Fungi and protists have related proteins but do not have true arrestins. Structural information is available only for free (unbound) vertebrate arrestins, and shows that the conserved overall fold is elongated and composed of two domains, with the core of each domain consisting of a seven-stranded β-sandwich. Two main intramolecular interactions keep the two domains in the correct relative orientation, but both of these interactions are destabilized in the process of receptor binding, suggesting that the conformation of bound arrestin is quite different. As well as binding to hundreds of GPCR subtypes, arrestins interact with other classes of membrane receptors and more than 20 surprisingly diverse types of soluble signaling protein. Arrestins thus serve as ubiquitous signaling regulators in the cytoplasm and nucleus.
Gene organization and evolutionary history
The arrestin family has four members in mammals: arrestin1 (called visual or rod arrestin in some species, and previously called S-antigen or 48 kDa protein), arrestin2 (also known as β-arrestin or β-arrestin1), arrestin3 (β-arrestin2) and arrestin4 (cone arrestin or X-arrestin). Structurally and functionally the family can be subdivided into two subfamilies: visual or sensory (arrestin1 and arrestin4) and non-visual (arrestin2 and arrestin3) . Fish and amphibians have a rod arrestin, a cone arrestin and at least one non-visual arrestin; insects have at least two sensory arrestins and one non-sensory arrestin (called Kurtz in Drosophila melanogaster), whereas other invertebrates (such as Caenorhabditis elegans) and protochordates (such as Ciona intestinalis) have only one arrestin homolog. Chromosomal locations and accession numbers are shown in Tables 1 and 2, respectively.
In vertebrates, arrestins are encoded by large (13-50 kilobases) genes containing 14-17 exons, some of which are only 10 nucleotides long [2, 3]. This multi-exon structure appears to be ancient, as the sole arrestin in the protochordate C. intestinalis is encoded by 13 exons, with the positions of nine introns corresponding to those in bovine rod arrestin (arrestin1) . The arrestin gene in C. elegans has ten exons , whereas the genes in D. melanogaster are simpler, having only three or four exons . The positions of five introns are identical in C. elegans, C. intestinalis and bovine rod arrestin, suggesting that they were acquired by a common ancestor gene. The exons do not correspond to known structural elements of arrestins, which consist of two domains and a variable carboxy-terminal tail [7–9], with one interesting exception: one of the exons conserved from C. elegans to mammals contains the phosphate-binding motif homologous to a motif in ataxin-7, a protein mutated in olivopontocerebellar atrophy with retinal degeneration . The multi-exon structure of vertebrate arrestins gives rise to splice variants of rod arrestin and both non-visual subtypes . The short splice variant of rod arrestin lacks most of the carboxy-terminal tail and has functional characteristics distinct from the longer variant: it binds unphosphorylated rhodopsin  and has a different subcellular localization in rod photoreceptors. The long and short forms of the two non-visual arrestins differ by 8 or 11 residues in the proximal carboxy-terminal tail; the functional significance of this is unclear [11, 13].
Ancestors of arrestin proteins probably appeared early in the evolution of eukaryotes, before the separation of animals, plants and fungi. Yeast and several other species of fungi have related proteins of the PalF family . These proteins of about 80 kDa have two approximately 150-residue regions that are homologous to the cores of the two arrestin domains. Three predicted proteins (accession numbers EAS01748, EAS01749 and YP_053990) from two species of Ciliophora - Paramecium tetraurelia and Tetrahymena thermophila - show homology with the same central part of arrestin that has homology to PalF proteins. These proteins and members of the PalF family lack most of the structural features that are the hallmarks of 'true' arrestins, however. So far, no arrestin-related proteins of plant origin have been described.
Analysis of the phylogenetic tree of arrestins (Figure 1) shows that vertebrate arrestins are divided into visual and non-visual branches; the visual branch further subdivides into rod and cone arrestins (arrestin1 and arrestin4) and the non-visual branch into arrestin2 and arrestin3. Vertebrate non-visual arrestins are the least diverse group. They are closer to the invertebrate non-sensory subtypes than to any other group (Additional data file 1). Arrestin2 has so far been found only in mammals; it is much more abundant than arrestin3 in mammalian cells, especially in mature neurons, where overall non-visual arrestin expression levels are the highest . The greater homology within the arrestin2 group than among arrestin3 proteins in mammals suggests that arrestin2 may be the latest evolutionary addition to the family. Arrestins from C. elegans and C. intestinalis and Kurtz in Drosophila seem to be 'hybrids': they are expressed throughout the nervous system and support receptor internalization, similarly to the vertebrate non-visual arrestins, yet participate in olfaction and vision, similarly to the visual/sensory subtypes [4, 5, 16]. Thus, the first proto-arrestins apparently emerged before the separation of the main branches of eukaryotes. True arrestins in animals evolved before the separation between the vertebrate and invertebrate lineages and then diverged into visual and non-visual groups early in the evolution of both lineages (Additional data file 1).
Characteristic structural features
Arrestins are ubiquitous (that is, every cell in animals has at least one arrestin subtype) regulators of G-protein-coupled receptors (GPCRs), the largest known family of signaling proteins. Arrestins bind to the cytoplasmic side of active phosphorylated forms of their cognate receptors, usually engaging the carboxyl terminus and several cytoplasmic loops of the receptor . Arrestins shut off G-protein-mediated signaling, target receptors to coated pits for internalization and redirect GPCR signaling to a variety of G-protein-independent pathways, such as the activation of the protein tyrosine kinase Src, mitogen-activated protein (MAP) kinase cascades, and so on [1, 17]. The length of arrestin proteins is fairly well conserved from C. elegans to humans, in the range of 360-470 residues.
Crystal structures of three out of the four subtypes of vertebrate arrestins have been solved: bovine rod arrestin , bovine arrestin2  and salamander cone arrestin . Each of these arrestins is an elongated molecule with two domains (amino-terminal and carboxy-terminal) and an extended carboxy-terminal tail that makes a strong contact with the body of the amino-terminal domain (Figure 2). The relative orientation of the two domains in the basal conformation of free arrestin in solution is supported by two characteristic groups of intramolecular interactions or 'clasps' (Figure 2a). Extensive mutagenesis studies indicate that both of these clasps are unfastened by receptor-attached phosphates, so that receptor binding induces a global conformational change in arrestin . This rearrangement involves the release of the arrestin carboxy-terminal tail [19, 20] and the movement of the two domains relative to each other, which is limited by the length of the inter-domain hinge . The structures of visual and non-visual arrestins from mammals and amphibians show a remarkable conservation of overall fold . Not surprisingly, the key residues that stabilize the basal conformation are conserved in all animal arrestins (Additional data file 2). Extra sequences (sometimes up to 25-30 residues) in the largest members of the family (such as Kurtz) are localized at the amino and carboxy termini or in the loops between putative β strands. Extra residues (including tags) added to these elements of vertebrate arrestins do not compromise their folding or functionality [22–24].
Each arrestin domain is an independent folding unit. Separated domains are functional: the amino-terminal domain preferentially binds active phosphoreceptors, albeit with lower affinity than the full-length protein; the carboxy-terminal domain does not [13, 22]. Both domains bind microtubules with even higher affinity than full-length arrestin . The arrestin fold was considered unique until a recent unexpected discovery of a very similar structure in Vps26 (vacuolar protein sorting-associated protein 26, a subunit of the retromer complex, which is involved in the recycling of the sorting receptor from endosomes back to the Golgi) . This 327-residue protein has two β-strand sandwich domains with an arrestin-like design and relative orientation. The inter-domain contact surface of Vps26, remarkably similar to that of arrestins, includes an analog of the polar core and an extensive set of hydrophobic interactions, even though Vps26 has no detectable sequence homology with arrestin family .
Localization and function
Arrestins are soluble, predominantly cytoplasmic proteins. Binding to phosphorylated active GPCRs and termination of G-protein-mediated signaling (receptor desensitization) was the first arrestin function described. The ability of arrestins to link GPCRs to the components of the internalization machinery - clathrin  and AP2  - was interpreted as a natural extension of their desensitizing function. Subsequent discoveries that receptor-bound arrestins interact with numerous signaling proteins, linking GPCRs to a variety of alternative signaling pathways (Table 3), put arrestins on an equal footing with G proteins as a different class of signaling adaptors recruited by active receptors [1, 17]. The interaction of arrestins and G proteins with overlapping sets of cytoplasmic receptor elements underlies their direct competition , and in most cases receptor phosphorylation gives arrestin an edge over G proteins .
Receptor-binding elements have been mapped to the concave sides of both arrestin domains and the protruding 'crest' in the middle of the molecule that includes the 'finger loop' between β-strands V and VI (Figure 2b) [20, 30]. The interaction sites of the proteins that bind the arrestin-receptor complex must be localized on the non-receptor-binding side of the molecule from this, or in the detachable arrestin carboxy-terminal tail that is released by receptor binding. The interaction sites of arrestin binding partners that are recruited to the complex have never been properly mapped, however, with the exception of clathrin and AP2, which bind to the arrestin carboxy-terminal tail . Arrestins interact with the small G proteins ADP-ribosylation factor 6 (ARF6) [32, 33] and RhoA , their regulators ARNO (ARF nucleotide binding site opener) [32, 35] and the guanine-nucleotide dissociation stimulator RalGDS , components of MAP kinase cascades [37, 38], c-Src and other non-receptor tyrosine kinases [39–41], phosphodiesterase PDE4D  and others (Table 3).
There is one common theme in the seemingly disparate functions of these multi-faceted adaptors: arrestins bring proteins together to make things happen. By interacting with several partners simultaneously, arrestins orchestrate signaling in space and time and direct enzymes to particular cellular compartments and substrates. Receptor-bound arrestins serve as scaffolds for MAP kinase cascades, bringing together apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase 3 (JNK3), as well as the kinase c-Raf-1 and extracellular signal-regulated kinase 2 (ERK2), thereby facilitating signaling in the ASK1-Map kinase kinase 4 (MKK4)-JNK3 and c-Raf-1-MAP/ERK kinase 1 (MEK1)-ERK2 pathways [37, 38]. Curiously, arrestin3 also facilitates deactivation of JNK3 by recruiting the dual-specificity phosphatase MKP7 . When ERK2 and JNK3 are activated by the arrestin-receptor complex they stay bound and therefore remain in endosomes and do not translocate to the nucleus [37, 38]. Arrestins also recruit ubiquitin ligases to the receptors: the E3 ubiquitin ligase Mdm2 mobilized by mammalian non-visual arrestins ubiquitinates GPCRs , and the E3 ligase Deltex mobilized by Kurtz ubiquitinates the Notch receptor in Drosophila . Arrestin3 binds the multi-functional anti-apoptotic protein kinase Akt (also known as protein kinase B) and its negative regulator protein phosphatase 2A (PP2A), facilitating deactivation of Akt in a manner dependent on dopamine receptor stimulation . Arrestin3 also interacts directly with IκBα, an inhibitor of NF-κB, preventing its phosphorylation and degradation and thereby modulating the activity of NF-κB . Non-visual arrestins regulate NF-κB activity in another way, by interacting with the tumor necrosis factor receptor-associated factor 6 (TRAF6) and preventing its autoubiquitination and activation of NF-κB . In addition to hundreds of GPCR subtypes, arrestins also bind several membrane proteins that do not belong to the GPCR superfamily and regulate their signaling and/or trafficking (Table 3). These include the insulin-like growth factor 1 receptor (IGF1R) , the type III transforming growth factor-β (TGFβ) receptor , the low density lipoprotein (LDL) receptor  and the Na+/H+ exchanger NHE5 .
A dramatic conformational difference between free and receptor-bound arrestin provides the structural basis for the differential interaction of various binding partners with these two functional forms of arrestin [1, 53]. However, many of the partners believed to bind selectively to the arrestin-receptor complex have been found to interact robustly with free arrestins, for example, ARF6 , JNK3 [24, 54] and Mdm2 [24, 55] (the latter even prefers arrestin 'frozen' in its basal conformation ; Table 3). Some binding partners, such as microtubules  and Ca2+-liganded calmodulin , interact with the same surface of arrestin as is engaged by the receptor; this means that they can interact only with free arrestin and thus that they compete with GPCRs. The fact that the affinity of arrestin for GPCRs is in the sub-nanomolar range  and that for microtubules  and calmodulin  is in the micromolar range suggest that the active phosphorylated receptor always wins, but other functional forms of the receptor might not. Indeed, competition between rhodopsin and microtubules has recently been shown to underlie the dramatic redistribution of rod arrestin in light- and dark-adapted photoreceptors in vivo .
The expression of rod and cone arrestins is limited to their respective photoreceptor types in the retina, although both are also present in pinealocytes. The intracellular concentration of rod arrestin in rod photoreceptors is enormous (over 100 μM) . Virtually every mammalian cell expresses both non-visual arrestins [11, 59]. Non-visual arrestins are certainly present in mouse neural precursors at embryonic day 12 , but given that arrestins have a role in the early development of zebrafish, in which functional knockdown of arrestin3 recapitulates the phenotypes of Hedgehog pathway mutants , arrestins are probably expressed much earlier in development. From C. elegans to mammals, the highest expression levels of non-visual arrestins are found in neurons [5, 15, 61]. In rat neural precursors, arrestin2 and arrestin3 are expressed at comparable levels (approximately 30 nM). During neural development the expression of arrestin2 mRNA and protein increases dramatically, so that in mature neurons arrestin2 predominates, with intracellular concentrations reaching approximately 200 nM (compared with about 10 nM of arrestin3) . There are neuronal types, however, that express arrestin3 almost exclusively, such as olfactory epithelial cells .
Both mammalian visual arrestins and arrestin3 are predominantly cytoplasmic, whereas the subcellular distribution of arrestin2 varies: for example, it is more abundant in the cytoplasm of striatal neural precursors and neurons and mostly nuclear in the pyramidal neurons [15, 24]. Although they do not have identifiable nuclear localization sequences and only arrestin3 has a recognizable nuclear export signal in its carboxy-terminal tail, all mammalian arrestins enter the nucleus and can be exported by different pathways [24, 54, 55]. In the process of export, they remove their interaction partners JNK3 and Mdm2 from the nucleus [24, 54, 55]. The subtype that is found most often in the nucleus, arrestin2, has a role in the regulation of histone acetylation and gene transcription .
Knockout of Kurtz, the only non-sensory arrestin in Drosophila, is embryonically lethal, as is the simultaneous knockout of both non-visual arrestins in mice [61, 63], whereas mice lacking either arrestin2 or arrestin3 are grossly normal . Thus, a functional non-visual arrestin is indispensable for normal development, but the two mammalian subtypes can serve as backups for one another. Probably for this reason, no human disorder associated with the loss of function of either non-visual arrestin has been described so far. The loss of rod arrestin underlies a form of congenital night blindness, Oguchi disease .
Considering the number of arrestin interaction partners that participate in life-and-death decisions in cells (such as Src, ASK1, c-Raf-1, ERK2, JNK3, Mdm2, Akt and IκBα), it is hardly surprising that arrestins have a role in cell death and survival. The effects of arrestin vary with the system, however. Stable arrestin-rhodopsin complexes in Drosophila photoreceptors induce apoptosis [65, 66], and the complex of arrestin2 and the receptor for the neuropeptide substance P induces non-apoptotic programmed cell death through activation of ERK2 and phosphorylation of the nuclear receptor Nur77 . By contrast, arrestins promote activation of phosphatidylinositol 3-kinase that is dependent on the insulin-like growth factor receptor and has an anti-apoptotic effect , and they block GPCR-mediated apoptosis . The mechanisms of arrestin-mediated cell death and survival remain to be elucidated.
As far as the origins and evolution of arrestins are concerned, several questions remain. First, did the arrestin domains, which can fold independently, emerge independently? Thus far there is no known protein that has only one of these domains; even the 'third cousins' in fungi and protists have homologs of both domains in the right order. Second, do plants have arrestins? Plants are the only large group of eukaryotes in which no arrestin-like proteins have been described. Their discovery may help to answer the first question. Third, is arrestin2 really a mammalian invention, or is it simply by chance that no close relatives have been cloned from lower vertebrates?
From a structural standpoint, the most important piece that is missing from the puzzle is the structure of 'active', receptor-bound arrestin. We have high-resolution crystal structures of three arrestins in the basal conformation, as well as three structures of the inactive prototypical GPCR, rhodopsin, but these are the functional states of these two proteins in which they do not interact. Proposed models of the arrestin-receptor complex [17, 18] are derived from a lot of indirect evidence, but they are educated guesses, not the real thing. The structure of the complex would answer biologically important questions regarding its stoichiometry. The shape of the complex would shed light on its scaffolding functions and explain why its formation facilitates signaling in so many pathways. We do not even know whether there is just one specific conformation of arrestin in the complex, or whether arrestin can assume a whole family of active conformations once the clasps holding it in the basal state are released by the receptor, as some experimental evidence suggests . Microtubule-bound arrestin assumes yet another conformation, distinct from that of the free and receptor-bound forms , but we know almost nothing about the functional capabilities of this state of arrestin.
Several laboratories using a wide variety of methods have mapped arrestin elements involved in receptor binding, so that we know exactly which side of the molecule faces the cytoplasmic tip of the receptor. The 'footprints' of microtubules  and calmodulin  on the body of the arrestin molecule, and the relatively small clathrin- and AP2-binding sites in the arrestin carboxy-terminal tail  have been identified with reasonable precision. The interaction sites for the great majority of the non-receptor binding partners have been localized very imprecisely or not at all, however. With very few exceptions, we do not know whether some signaling proteins prefer a single arrestin conformation out of the three known ones, let alone which partners bind preferentially to which functional state of arrestin. In addition, the very modest size of arrestins (40-45 kDa), along with the enormous number of known binding partners of similar or greater size, strongly suggests that arrestin in any conformation cannot interact with them all simultaneously. Thus, certain groups of arrestin partners must compete with each other for the overlapping binding sites. Which proteins can 'share' arrestin because their binding sites are far enough from each other, which partners compete, how this competition is regulated, and what factors determine the 'winners' are the key questions that need to be addressed experimentally.
In summary, we know that arrestins do a lot more than simply block binding of G proteins to active receptors. Arrestins are multi-functional regulators at the crossroads of multiple signaling pathways. The next challenge is to understand the fine molecular mechanisms of their functional interactions with an incredible variety of signaling proteins. These studies have clear therapeutic potential as they will provide a firm foundation for the targeted manipulation of arrestin function.
Gurevich VV, Gurevich EV: The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol Ther. 2006, 110: 465-502. 10.1016/j.pharmthera.2005.09.008.
Sakuma H, Murakami A, Fujimaki T, Inana G: Isolation and characterization of the human X-arrestin gene. Gene. 1998, 224: 87-95. 10.1016/S0378-1119(98)00510-1.
Yamaki K, Tsuda M, Kikuchi T, Chen KH, Huang KP, Shinohara T: Structural organization of the human S-antigen gene. cDNA, amino acid, intron, exon, promoter, in vitro transcription, retina, and pineal gland. J Biol Chem. 1990, 265: 20757-20762.
Nakagawa M, Orii H, Yoshida N, Jojima E, Horie T, Yoshida R, Haga T, Tsuda M: Ascidian arrestin (Ci-arr), the origin of the visual and nonvisual arrestins of vertebrate. Eur J Biochem. 2002, 269: 5112-5118. 10.1046/j.1432-1033.2002.03240.x.
Palmitessa A, Hess HA, Bany IA, Kim YM, Koelle MR, Benovic JL: Caenorhabditis elegans arrestin regulates neural G protein signaling and olfactory adaptation and recovery. J Biol Chem. 2005, 280: 24649-24662. 10.1074/jbc.M502637200.
Smith DP, Shieh BH, Zuker CS: Isolation and structure of an arrestin gene from Drosophila. Proc Natl Acad Sci USA. 1990, 87: 1003-1007. 10.1073/pnas.87.3.1003.
Han M, Gurevich VV, Vishnivetskiy SA, Sigler PB, Schubert C: Crystal structure of beta-arrestin at 1.9 A: possible mechanism of receptor binding and membrane translocation. Structure. 2001, 9: 869-880. 10.1016/S0969-2126(01)00644-X.
Hirsch JA, Schubert C, Gurevich VV, Sigler PB: The 2.8 Å crystal structure of visual arrestin: a model for arrestin's regulation. Cell. 1999, 97: 257-269. 10.1016/S0092-8674(00)80735-7.
Sutton RB, Vishnivetskiy SA, Robert J, Hanson SM, Raman D, Knox BE, Kono M, Navarro J, Gurevich VV: Crystal structure of cone arrestin at 2.3Å: evolution of receptor specificity. J Mol Biol. 2005, 354: 1069-1080. 10.1016/j.jmb.2005.10.023.
Mushegian AR, Vishnivetskiy SA, Gurevich VV: Conserved phosphoprotein interaction motif is functionally interchangeable between ataxin-7 and arrestins. Biochemistry. 2000, 39: 6809-6813. 10.1021/bi992694y.
Sterne-Marr R, Gurevich VV, Goldsmith P, Bodine RC, Sanders C, Donoso LA, Benovic JL: Polypeptide variants of beta-arrestin and arrestin3. J Biol Chem. 1993, 268: 15640-15648.
Pulvermuller A, Maretzki D, Rudnicka-Nawrot M, Smith WC, Palczewski K, Hofmann KP: Functional differences in the interaction of arrestin and its splice variant, p44, with rhodopsin. Biochemistry. 1997, 36: 9253-9260. 10.1021/bi970772g.
Gurevich VV, Dion SB, Onorato JJ, Ptasienski J, Kim CM, Sterne-Marr R, Hosey MM, Benovic JL: Arrestin interaction with G protein-coupled receptors. Direct binding studies of wild type and mutant arrestins with rhodopsin, beta2-adrenergic, and m2 muscarinic cholinergic receptors. J Biol Chem. 1995, 270: 720-731. 10.1074/jbc.270.2.720.
Herranz S, Rodriguez JM, Bussink HJ, Sanchez-Ferrero JC, Arst HN, Penalva MA, Vincent O: Arrestin-related proteins mediate pH signaling in fungi. Proc Natl Acad Sci USA. 2005, 102: 12141-12146. 10.1073/pnas.0504776102.
Gurevich EV, Benovic JL, Gurevich VV: Arrestin2 expression selectively increases during neural differentiation. J Neurochem. 2004, 91: 1404-1416. 10.1111/j.1471-4159.2004.02830.x.
Merrill CE, Sherertz TM, Walker WB, Zwiebel LJ: Odorant-specific requirements for arrestin function in Drosophila olfaction. J Neurobiol. 2005, 63: 15-28. 10.1002/neu.20113.
Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by beta-arrestins. Science. 2005, 308: 512-517. 10.1126/science.1109237.
Gurevich VV, Gurevich EV: The molecular acrobatics of arrestin activation. Trends Pharmacol Sci. 2004, 25: 105-111. 10.1016/j.tips.2003.12.008.
Palczewski K, Pulvermuller A, Buczylko J, Hofmann KP: Phosphorylated rhodopsin and heparin induce similar conformational changes in arrestin. J Biol Chem. 1991, 266: 18649-18654.
Hanson SM, Francis DJ, Vishnivetskiy SA, Kolobova EA, Hubbell WL, Klug CS, Gurevich VV: Differential interaction of spin-labeled arrestin with inactive and active phosphorhodopsin. Proc Natl Acad Sci USA. 2006, 103: 4900-4905. 10.1073/pnas.0600733103.
Vishnivetskiy SA, Hirsch JA, Velez M-G, Gurevich YV, Gurevich VV: Transition of arrestin in the active receptor-binding state requires an extended interdomain hinge. J Biol Chem. 2002, 277: 43961-43967. 10.1074/jbc.M206951200.
Gurevich VV, Benovic JL: Visual arrestin interaction with rhodopsin. Sequential multisite binding ensures strict selectivity towards light-activated phosphorylated rhodopsin. J Biol Chem. 1993, 268: 11628-11638.
Barak LS, Ferguson SS, Zhang J, Caron MG: A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J Biol Chem. 1997, 272: 27497-27500. 10.1074/jbc.272.44.27497.
Song X, Raman D, Gurevich EV, Vishnivetskiy SA, Gurevich VV: Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J Biol Chem. 2006, 281: 21491-21499. 10.1074/jbc.M603659200.
Hanson SM, Francis DJ, Vishnivetskiy SA, Klug CS, Gurevich VV: Visual arrestin binding to microtubules involves a distinct conformational change. J Biol Chem. 2006, 281: 9765-9772. 10.1074/jbc.M510738200.
Shi H, Rojas R, Bonifacino JS, Hurley JH: The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol. 2006, 13: 540-548. 10.1038/nsmb1103.
Goodman OB, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL: Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature. 1996, 383: 447-450. 10.1038/383447a0.
Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SS, Caron MG, Barak LS: The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci USA. 1999, 96: 3712-3717. 10.1073/pnas.96.7.3712.
Krupnick JG, Gurevich VV, Benovic JL: Mechanism of quenching of phototransduction. Binding competition between arrestin and transducin for phosphorhodopsin. J Biol Chem. 1997, 272: 18125-18131. 10.1074/jbc.272.29.18125.
Vishnivetskiy SA, Hosey MM, Benovic JL, Gurevich VV: Mapping the arrestin-receptor interface. Structural elements responsible for receptor specificity of arrestin proteins. J Biol Chem. 2004, 279: 1262-1268. 10.1074/jbc.M308834200.
Kim YM, Benovic JL: Differential roles of arrestin-2 interaction with clathrin and adaptor protein 2 in G protein-coupled receptor trafficking. J Biol Chem. 2002, 277: 30760-30768. 10.1074/jbc.M204528200.
Claing A, Chen W, Miller WE, Vitale N, Moss J, Premont RT, Lefkowitz RJ: beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis. J Biol Chem. 2001, 276: 42509-42513. 10.1074/jbc.M108399200.
Hunzicker-Dunn M, Gurevich VV, Casanova JE, Mukherjee S: ARF6: a newly appreciated player in G protein-coupled receptor desensitization. FEBS Lett. 2002, 521: 3-8. 10.1016/S0014-5793(02)02822-3.
Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, Lefkowitz RJ: beta-arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem. 2005, 280: 8041-8050. 10.1074/jbc.M412924200.
Mukherjee S, Gurevich VV, Jones JCR, Casanova JE, Frank SR, Maizels ET, Bader MF, Kahn RA, Palczewski K, Aktories K, Hunzicker-Dunn M: The ADP ribosylation factor nucleotide exchange factor ARNO promotes beta-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization. Proc Natl Acad Sci USA. 2000, 97: 5901-5906. 10.1073/pnas.100127097.
Bhattacharya M, Anborgh PH, Babwah AV, Dale LB, Dobransky T, Benovic JL, Feldman RD, Verdi JM, Rylett RJ, Ferguson SS: Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. Nat Cell Biol. 2002, 4: 547-555.
Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ: Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci USA. 2001, 98: 2449-2454. 10.1073/pnas.041604898.
McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ: Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000, 290: 1574-1577. 10.1126/science.290.5496.1574.
Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin F, Kawakatsu H, Owada K, Luttrell DK, et al: Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science. 1999, 283: 655-661. 10.1126/science.283.5402.655.
Barlic J, Andrews JD, Kelvin AA, Bosinger SE, DeVries ME, Xu L, Dobransky T, Feldman RD, Ferguson SS, Kelvin DJ: Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI. Nat Immunol. 2000, 1: 227-233. 10.1038/79767.
Imamura T, Huang J, Dalle S, Ugi S, Usui I, Luttrell LM, Miller WE, Lefkowitz RJ, Olefsky JM: beta-Arrestin-mediated recruitment of the Src family kinase Yes mediates endothelin-1-stimulated glucose transport. J Biol Chem. 2001, 276: 43663-43667. 10.1074/jbc.M105364200.
Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, Miller WE, McLean AJ, Conti M, Houslay MD, Lefkowitz RJ: Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002, 298: 834-836. 10.1126/science.1074683.
Willoughby EA, Collins MK: Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. J Biol Chem. 2005, 280: 25651-25658. 10.1074/jbc.M501926200.
Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ: Regulation of receptor fate by ubiquitination of activated beta2-adrenergic receptor and beta-arrestin. Science. 2001, 294: 1307-1313. 10.1126/science.1063866.
Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S: Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol. 2005, 7: 1191-1201. 10.1038/ncb1327.
Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG: An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005, 122: 261-273. 10.1016/j.cell.2005.05.012.
Gao H, Sun Y, Wu Y, Luan B, Wang Y, Qu B, Pei G: Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-κB pathways. Mol Cell. 2004, 14: 303-317. 10.1016/S1097-2765(04)00216-3.
Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G: Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2006, 7: 139-147. 10.1038/ni1294.
Lin FT, Daaka Y, Lefkowitz RJ: beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor. J Biol Chem. 1998, 273: 31640-31643. 10.1074/jbc.273.48.31640.
Chen W, Kirkbride KC, How T, Nelson CD, Mo J, Frederick JP, Wang XF, Lefkowitz RJ, Blobe GC: Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 2003, 301: 1394-1397. 10.1126/science.1083195.
Wu JH, Peppel K, Nelson CD, Lin FT, Kohout TA, Miller WE, Exum ST, Freedman NJ: The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. J Biol Chem. 2003, 278: 44238-44245. 10.1074/jbc.M309450200.
Szabo EZ, Numata M, Lukashova V, Iannuzzi P, Orlowski J: beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform. Proc Natl Acad Sci USA. 2005, 102: 2790-2795. 10.1073/pnas.0407444102.
Gurevich VV, Gurevich EV: The new face of active receptor bound arrestin attracts new partners. Structure. 2003, 11: 1037-1042. 10.1016/S0969-2126(03)00184-9.
Scott MG, Le Rouzic E, Perianin A, Pierotti V, Enslen H, Benichou S, Marullo S, Benmerah A: Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2. J Biol Chem. 2002, 277: 37693-37701. 10.1074/jbc.M207552200.
Wang P, Wu Y, Ge X, Ma L, Pei G: Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J Biol Chem. 2003, 278: 11648-11653. 10.1074/jbc.M208109200.
Wu N, Hanson SM, Francis DJ, Vishnivetskiy SA, Thibonnier M, Klug CS, Shoham M, Gurevich VV: Arrestin binding to calmodulin: a direct interaction between two ubiquitous signaling proteins. J Mol Biol. 2006.
Nair KS, Hanson SM, Mendez A, Gurevich EV, Kennedy MJ, Shestopalov VI, Vishnivetskiy SA, Chen J, Hurley JB, Gurevich VV, et al: Light-dependent redistribution of arrestin in vertebrate rods is an energy-independent process governed by protein-protein interactions. Neuron. 2005, 46: 555-567. 10.1016/j.neuron.2005.03.023.
Strissel KJ, Sokolov M, Trieu LH, Arshavsky VY: Arrestin translocation is induced at a critical threshold of visual signaling and is superstoichiometric to bleached rhodopsin. J Neurosci. 2006, 26: 1146-1153. 10.1523/JNEUROSCI.4289-05.2006.
Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, Snyder SH, Caron MG, Lefkowitz RJ: Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem. 1992, 267: 17882-17890.
Wilbanks AM, Fralish GB, Kirby ML, Barak LS, Li YX, Caron MG: Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science. 2004, 306: 2264-2267. 10.1126/science.1104193.
Roman G, He J, Davis RL: kurtz, a novel nonvisual arrestin, is an essential neural gene in Drosophila. Genetics. 2000, 155: 1281-1295.
Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, Zhang M, Bao G, Wang F, Zhang X, et al: A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell. 2005, 123: 833-847. 10.1016/j.cell.2005.09.011.
Kohout TA, Lin FS, Perry SJ, Conner DA, Lefkowitz RJ: beta-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc Natl Acad Sci USA. 2001, 98: 1601-1606. 10.1073/pnas.041608198.
Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet. 1995, 10: 360-362. 10.1038/ng0795-360.
Kiselev A, Socolich M, Vinos J, Hardy RW, Zuker CS, Ranganathan R: A molecular pathway for light-dependent photoreceptor apoptosis in Drosophila. Neuron. 2000, 28: 139-152. 10.1016/S0896-6273(00)00092-1.
Alloway PG, Howard L, Dolph PJ: The formation of stable rhodopsin-arrestin complexes induces apoptosis and photoreceptor cell degeneration. Neuron. 2000, 28: 129-138. 10.1016/S0896-6273(00)00091-X.
Castro-Obregon S, Rao RV, del Rio G, Chen SF, Poksay KS, Rabizadeh S, Vesce S, Zhang XK, Swanson RA, Bredesen DE: Alternative, nonapoptotic programmed cell death: mediation by arrestin 2, ERK2, and Nur77. J Biol Chem. 2004, 279: 17543-17553. 10.1074/jbc.M312363200.
Povsic TJ, Kohout TA, Lefkowitz RJ: Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. J Biol Chem. 2003, 278: 51334-51339. 10.1074/jbc.M309968200.
Revankar CM, Vines CM, Cimino DF, Prossnitz ER: Arrestins block G protein-coupled receptor-mediated apoptosis. J Biol Chem. 2004, 279: 24578-24584. 10.1074/jbc.M402121200.
Hanson SM, Gurevich VV: The differential engagement of arrestin surface charges by the various functional forms of the receptor. J Biol Chem. 2006, 281: 3458-3462. 10.1074/jbc.M512148200.
Gurevich VV, Benovic JL: Mechanism of phosphorylation-recognition by visual arrestin and the transition of arrestin into a high affinity binding state. Mol Pharmacol. 1997, 51: 161-169.
McDonald PH, Cote NL, Lin FT, Premont RT, Pitcher JA, Lefkowitz RJ: Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation. J Biol Chem. 1999, 274: 10677-10680. 10.1074/jbc.274.16.10677.
Rakhit S, Pyne S, Pyne NJ: Nerve growth factor stimulation of p42/p44 mitogen-activated protein kinase in PC12 cells: role of G(i/o), G protein-coupled receptor kinase 2, beta-arrestin I, and endocytic processing. Mol Pharmacol. 2001, 60: 63-70.
Witherow DS, Garrison TR, Miller WE, Lefkowitz RJ: beta-arrestin inhibits NF-κB activity by means of its interaction with the NF-κB inhibitor IκBα. Proc Natl Acad Sci USA. 2004, 101: 8603-8607. 10.1073/pnas.0402851101.
Hanson SM, Francis DJ, Vishnivetskiy SA, Raman D, Van Eps N, Hubbell WL, Klug CS, Gurevich VV: Arrestin binding to microtubules involves a distinct conformational change [abstract]. FASEB J. 2006, 20: A110-
Chen W, ten Berge D, Brown J, Ahn S, Hu LA, Miller WE, Caron MG, Barak LS, Nusse R, Lefkowitz RJ: Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science. 2003, 301: 1391-1394. 10.1126/science.1082808.
Chen W, Hu LA, Semenov MV, Yanagawa S, Kikuchi A, Lefkowitz RJ, Miller WE: beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci USA. 2001, 98: 14889-14894. 10.1073/pnas.211572798.
Gaidarov I, Krupnick JG, Falck JR, Benovic JL, Keen JH: Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO J. 1999, 18: 871-881. 10.1093/emboj/18.4.871.
Lee SJ, Xu H, Kang LW, Amzel LM, Montell C: Light adaptation through phosphoinositide-regulated translocation of Drosophila visual arrestin. Neuron. 2003, 39: 121-132. 10.1016/S0896-6273(03)00390-8.
Gurevich VV, Chen CY, Kim CM, Benovic JL: Visual arrestin binding to rhodopsin. Intramolecular interaction between the basic N-terminus and acidic C-terminus of arrestin may regulate binding selectivity. J Biol Chem. 1994, 269: 8721-8727.
Milano SK, Kim YM, Stefano FP, Benovic JL, Brenner C: Nonvisual arrestin oligomerization and cellular localization are regulated by inositol hexakisphosphate binding. J Biol Chem. 2006, 281: 9812-9823. 10.1074/jbc.M512703200.
Vishnivetskiy SA, Paz CL, Schubert C, Hirsch JA, Sigler PB, Gurevich VV: How does arrestin respond to the phosphorylated state of rhodopsin?. J Biol Chem. 1999, 274: 11451-11454. 10.1074/jbc.274.17.11451.
Vishnivetskiy SA, Schubert C, Climaco GC, Gurevich YV, Velez M-G, Gurevich VV: An additional phosphate-binding element in arrestin molecule. Implications for the mechanism of arrestin activation. J Biol Chem. 2000, 275: 41049-41057. 10.1074/jbc.M007159200.
Merrill CE, Pitts RJ, Zwiebel LJ: Molecular characterization of arrestin family members in the malaria vector mosquito, Anopheles gambiae. Insect Mol Biol. 2003, 12: 641-650. 10.1046/j.1365-2583.2003.00450.x.
Gurevich VV: The selectivity of visual arrestin for light-activated phosphorhodopsin is controlled by multiple nonredundant mechanisms. J Biol Chem. 1998, 273: 15501-15506. 10.1074/jbc.273.25.15501.
We thank Susan M Hanson for critical reading of the manuscript. This work was supported by NIH grants EY11500 (to V.V.G.) and NS45117 (to E.V.G.).
About this article
Cite this article
Gurevich, E.V., Gurevich, V.V. Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol 7, 236 (2006) doi:10.1186/gb-2006-7-9-236
- Additional Data File
- Olivopontocerebellar Atrophy
- Olfactory Epithelial Cell
- Oguchi Disease
- Basal Conformation