Alternative titles; symbols
HGNC Approved Gene Symbol: ARRB2
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:4,710,632-4,721,497 (from NCBI)
Using a low stringency hybridization technique to screen a rat brain cDNA library, Attramadal et al. (1992) isolated cDNA clones representing 2 distinct beta-arrestin-like genes. One of the cDNAs is the rat homolog of bovine beta-arrestin (beta-arrestin-1; ARB1; 107940). In addition, Attramadal et al. (1992) isolated a cDNA clone encoding a novel beta-arrestin-related protein, which they termed beta-arrestin-2. ARB2 exhibited 78% amino acid identity with ARB1. The primary structure of these proteins delineated a family of proteins that regulate receptor coupling to G proteins. ARB1 and ARB2 are predominantly localized in neuronal tissues and in the spleen.
Beta-arrestins were originally discovered in the context of heterotrimeric G protein-coupled receptor desensitization, but they also function in internalization and signaling of these receptors. Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3 (602897) as a binding partner of ARBB2. These results were confirmed by coimmunoprecipitation from mouse brain extracts and cotransfection in COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase-1 (ASK1; 602448) and MAP2K4 (601335) were also found in complex with ARBB2. Cellular transfection of ARBB2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor (AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2 and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000) concluded that ARBB2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a G protein-coupled receptor.
Alloway et al. (2000) demonstrated the existence of stable, persistent complexes between rhodopsin (180380) and its regulatory protein arrestin in several different retinal degeneration mutants in Drosophila. Elimination of these rhodopsin-arrestin complexes by removing either rhodopsin or arrestin rescues the degeneration phenotype. Furthermore, Alloway et al. (2000) showed that the accumulation of these complexes triggers apoptotic cell death and that the observed retinal degeneration requires the endocytic machinery. Thus, the endocytosis of rhodopsin-arrestin complexes may be a molecular mechanism for the initiation of retinal degeneration. Alloway et al. (2000) proposed that an identical mechanism may be responsible for the pathology found in a subset of human retinal degenerative disorders.
Kiselev et al. (2000) uncovered the pathway by which activation of rhodopsin in Drosophila mediates apoptosis through a G protein-independent mechanism. They found that the process involves the formation of membrane complexes of phosphorylated, activated rhodopsin and its inhibitory protein arrestin, and subsequent clathrin-dependent endocytosis of these complexes into a cytoplasmic compartment.
Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, the connection of ubiquitination with regulation of mammalian G protein-coupled receptor function was unclear. Shenoy et al. (2001) demonstrated that agonist stimulation of endogenous or transfected beta-2 adrenergic receptors (ADRB2; 109690) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin. Moreover, proteasome inhibitors reduced receptor internalization and degradation, thus implicating a role for the ubiquitination machinery in the trafficking of the beta-2 adrenergic receptor. Receptor ubiquitination required beta-arrestin, which bound the E3 ubiquitin ligase MDM2 (164785). Abrogation of beta-arrestin ubiquitination, either by expression in MDM2-null cells or by dominant-negative forms of MDM2 lacking E3 ligase activity, inhibited receptor internalization with marginal effects on receptor degradation. However, a beta-2 adrenergic receptor mutant lacking lysine residues, which was not ubiquitinated, was internalized normally but was degraded ineffectively. Shenoy et al. (2001) concluded that their results delineated an adaptor role of beta-arrestin in mediating the ubiquitination of the beta-2 adrenergic receptor and indicated that ubiquitination of the receptor and of beta-arrestin have distinct and obligatory roles in the trafficking and degradation of this prototypic G protein-coupled receptor.
Chen et al. (2003) found that beta-arrestin-2 binds to the single transmembrane-spanning type III transforming growth factor-beta receptor (TGFBR3; 600742), also known as beta-glycan. Binding of beta-arrestin-2 to TGFBR3 was also triggered by phosphorylation of the receptor on its cytoplasmic domain, likely at threonine-841. Chen et al. (2003) found that phosphorylation was mediated by the type II TGF-beta receptor (TGFBR2; 190182), which is itself a kinase, rather than by a G protein-coupled receptor kinase. Association with beta-arrestin-2 led to internalization of both receptors and downregulation of TGF-beta signaling. Chen et al. (2003) concluded that the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Chen et al. (2003) found that endocytosis of frizzled-4 (FZD4; 604579) in human embryonic kidney cells was dependent on added WNT5A (164975) protein and was accomplished by the multifunctional adaptor protein beta-arrestin-2, which was recruited to FZD4 by binding to phosphorylated dishevelled-2 (DVL2; 602151). The authors concluded that their findings provided a previously unrecognized mechanism for receptor recruitment of beta-arrestin and demonstrated that dishevelled plays an important role in the endocytosis of frizzled, as well as in promoting signaling.
Chen et al. (2004) found that 2 molecules interact with mammalian Smoothened (SMO; 601500) in an activation-dependent manner: G protein-coupled receptor kinase-2 (GRK2; 109635) leads to phosphorylation of Smo, and beta-arrestin-2 fused to green fluorescent protein interacts with Smo. These 2 processes promote endocytosis of Smo in clathrin-coated pits. Ptc (601309) inhibits association of beta-arrestin-2 with Smo, and this inhibition is relieved in cells treated with Shh (600725). A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by Grk2 and interaction of beta-arrestin-2 with Smo. Chen et al. (2004) suggested that beta-arrestin-2 and Grk2 are thus potential mediators of signaling by activated Smo.
Kovacs et al. (2008) demonstrated that beta-arrestins mediate the activity-dependent interaction of SMO and the kinesin motor protein KIF3A (604683). This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. Beta-arrestin-1 (ARRB1; 107940) or beta-arrestin-2 depletion prevented the localization of SMO to primary cilia and the SMO-dependent activation of GLI (165220). Kovacs et al. (2008) concluded that their results suggested roles for beta-arrestin in mediating the intracellular transport of a 7-transmembrane receptor to its obligate subcellular location for signaling.
Luan et al. (2009) demonstrated that in diabetic mouse models, including the db/db mouse (601007), beta-arrestin-2 is severely downregulated. Knockdown of beta-arrestin-2 exacerbated insulin resistance, whereas administration of beta-arrestin-2 restored insulin sensitivity in mice. Further investigation revealed that insulin stimulates the formation of a beta-arrestin-2 signal complex in which beta-arrestin-2 scaffolds Akt (164730) and Src (190090) to insulin receptor (147670). Loss or dysfunction of beta-arrestin-2 resulted in deficiency of this signal complex and disturbance of insulin signaling in vivo, thereby contributing to the development of insulin resistance and progression of type 2 diabetes.
Using immunofluorescence microscopy, Coureuil et al. (2010) demonstrated that Neisseria meningitidis (Nm) colonies at the cell surface of human brain endothelial cells promoted translocation of ARRB1 and ARRB2 to the inner surface of the plasma membrane, facing the bacteria. ARRBs translocated under the colonies served as a scaffolding platform for signaling events elicited by Nm. ADRB2 was the only G protein-coupled receptor expressed in the cell line that played a permissive role in the formation of cortical plaques under colonies and in bacterial crossing of cell monolayers. Coureuil et al. (2010) concluded that the ADRB2/ARRB signaling pathway is required for Nm to promote stable adhesion to brain endothelial cells and subsequent crossing of the blood-brain barrier.
Using immunoprecipitation analysis, Puca et al. (2013) showed that human ARRDC1 (619768) interacted directly with ITCH (606409) and that the interaction was mediated by the PPxY motifs of ARRDC1. Simultaneously, ARRDC1 interacted directly with beta-arrestin-1 and beta-arrestin-2 to form a complex that recruited ITCH to NOTCH (NOTCH1; 190198). Through these interactions, ARRDC1 was involved in ITCH-mediated NOTCH ubiquitylation and lysosomal degradation at the same step, but not redundantly, with the beta-arrestins. Moreover, ARRDC1 and the beta-arrestins acted as negative regulators of NOTCH signaling as members of the same complex.
By fluorescence in situ hybridization, Calabrese et al. (1994) mapped the ARRB2 gene to 17p13.
Bohn et al. (1999) generated beta-arrestin-2 knockout mice by inactivation of the gene by homologous recombination. Homozygous mutant mice were viable and had no gross phenotypic abnormalities. However, after administration of morphine, obvious differences became apparent between the genotypes. Beta-arrestin-2 knockout mice had remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that mu-opioid receptor (600018) desensitization was impaired. Even at doses of morphine that were subanalgesic in wildtype mice, homozygous mutant animals displayed a significant increase in their nociceptive thresholds. The number and affinity of mu-opioid receptors did not significantly differ between the 2 genotypes in any of the brain regions examined. Differences in response to other G protein-coupled receptor-directed drugs were not observed. Bohn et al. (1999) suggested that their results provided evidence in vivo for the physiologic importance of beta-arrestin-2 in regulating the function of a specific G protein-coupled receptor, the mu-opioid receptor. Moreover, they suggested that inhibition of beta-arrestin-2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.
Bohn et al. (2000) showed that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent a chronic morphine-induced upregulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.
Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived factor 1 (SDF1; 600835) acting via G protein-coupled receptors. Because members of this receptor family are regulated (desensitized) by G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and beta-arrestin binding, Fong et al. (2002) examined signaling and chemotactic responses in splenocytes derived from knockout mice deficient in various beta-arrestins and GRKs, with the expectation that these responses might be enhanced. Knockouts of beta-arrestin-2, GPRK5 (600870), and GPRK6 (600869) were examined because all 3 proteins are expressed at high levels in purified mouse CD3(+) T and B220(+) B splenocytes. SDF1 stimulation of membrane GTPase activity was unaffected in splenocytes derived from Grk5-deficient mice but was increased in splenocytes from the beta-arrestin-2- and Grk6-deficient animals. Surprisingly, however, both T and B cells from beta-arrestin-2-deficient animals and T cells from Grk6-deficient animals were strikingly impaired in their ability to respond to SDF1 both in transwell migration assays and in transendothelial migration assays. Chemotactic responses of lymphocytes from Grk5-deficient mice were unaffected. Thus, these results indicated that beta-arrestin-2 and GPRK6 actually play positive regulatory roles in mediating the chemotactic responses of T and B lymphocytes to SDF1.
Wilbanks et al. (2004) showed that the functional knockdown of beta-arrestin-2 in zebrafish embryos recapitulates the many phenotypes of Hedgehog pathway mutants. Expression of wildtype beta-arrestin-2, or constitutive activation of the Hedgehog pathway downstream of Smoothened (SMO; 601500), rescues the phenotypes caused by beta-arrestin-2 deficiency. These results suggested to Wilbanks et al. (2004) that a functional interaction between beta-arrestin-2 and Smo may be critical to regulate Hedgehog signaling in zebrafish development.
BARR2 is crucial in transducing CXCR2 (146928)-mediated signals associated with chemotaxis. Su et al. (2005) examined peritoneal neutrophils from Barr2-deficient mice to assess Cxcr2 signaling activity and observed increased Ca(2+) mobilization, superoxide anion production, and GTPase activity, but decreased receptor internalization, compared with wildtype mice. Both dorsal air pouch and excisional wound healing models in Barr2 -/- mice showed increased neutrophil recruitment in response to Cxcl1 (155730). Wound reepithelialization was also significantly faster in mice lacking Barr2. Su et al. (2005) concluded that BARR2 is a negative regulator of CXCR2 signaling.
Lithium, a pharmacologic agent used to treat psychiatric disorders, acts by regulating GSK3 (see 606784)/AKT1 (164730) signaling. Beaulieu et al. (2008) found that wildtype mice treated with lithium showed increased phosphorylation/activation of Akt, resulting in phosphorylation/inhibition of Gsk3b (605004) in the striatum. In contrast, Barr2-null treated with lithium mice showed a minor reduction in striatal phospho-Akt and no change in phospho-Gsk3b levels. Lithium administration inhibited activity and decreased immobility in the tail suspension test in wildtype mice, but had no behavioral effects on Barr2-null mice. Further studies showed that Barr2 and PP2CA phosphatase (PPP2CA; 176915) formed a complex, which inhibits AKT1 activation. Beaulieu et al. (2008) postulated that lithium acts by destabilizing the AKT1/PP2CA/BARR2 signaling complex, thereby enhancing the activation of AKT1 and inhibition of GSK3B, which ultimately mediates behavioral changes. Barr2-null mice that are unable to form this signaling complex have a loss of indirect inhibition of Gsk3B and thus do not exhibit behavioral responses to lithium. The findings suggested that BARR2 is an important determinant of the regulation of behavior by lithium via G protein-coupled receptors.
Alloway, P. G., Howard, L., Dolph, P. J. The formation of stable rhodopsin-arrestin complexes induces apoptosis and photoreceptor cell degeneration. Neuron 28: 129-138, 2000. [PubMed: 11086989] [Full Text: https://doi.org/10.1016/s0896-6273(00)00091-x]
Attramadal, H., Arriza, J. L., Aoki, C., Dawson, T. M., Codina, J., Kwatra, M. M., Snyder, S. H., Caron, M. G., Lefkowitz, R. J. Beta-arrestin-2, a novel member of the arrestin/beta-arrestin gene family. J. Biol. Chem. 267: 17882-17890, 1992. [PubMed: 1517224]
Beaulieu, J.-M., Marion, S., Rodriguiz, R. M., Medvedev, I. O., Sotnikova, T. D., Ghisi, V., Wetsel, W. C., Lefkowitz, R. J., Gainetdinov, R. R., Caron, M. G. A beta-arrestin 2 signaling complex mediates lithium action on behavior. Cell 132: 125-136, 2008. [PubMed: 18191226] [Full Text: https://doi.org/10.1016/j.cell.2007.11.041]
Bohn, L. M., Gainetdinov, R. R., Lin, F.-T., Lefkowitz, R. J., Caron, M. G. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408: 720-723, 2000. [PubMed: 11130073] [Full Text: https://doi.org/10.1038/35047086]
Bohn, L. M., Lefkowitz, R. J., Gainetdinov, R. R., Peppel, K., Caron, M. G., Lin, F.-T. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286: 2495-2498, 1999. [PubMed: 10617462] [Full Text: https://doi.org/10.1126/science.286.5449.2495]
Calabrese, G., Sallese, M., Stornaiuolo, A., Stuppia, L., Palka, G., De Blasi, A. Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes. Genomics 23: 286-288, 1994. [PubMed: 7695743] [Full Text: https://doi.org/10.1006/geno.1994.1497]
Chen, W., Kirkbride, K. C., How, T., Nelson, C. D., Mo, J., Frederick, J. P., Wang, X.-F., Lefkowitz, R. J., Blobe, G. C. Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science 301: 1394-1397, 2003. [PubMed: 12958365] [Full Text: https://doi.org/10.1126/science.1083195]
Chen, W., Ren, X.-R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., Lefkowitz, R. J. Activity-dependent internalization of Smoothened mediated by beta-arrestin 2 and GRK2. Science 306: 2257-2260, 2004. [PubMed: 15618519] [Full Text: https://doi.org/10.1126/science.1104135]
Chen, W., ten Berge, D., Brown, J., Ahn, S., Hu, L. A., Miller, W. E., Caron, M. G., Barak, L. S., Nusse, R., Lefkowitz, R. J. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of frizzled 4. Science 301: 1391-1394, 2003. [PubMed: 12958364] [Full Text: https://doi.org/10.1126/science.1082808]
Coureuil, M., Lecuyer, H., Scott, M. G. H., Boularan, C., Enslen, H., Soyer, M., Mikaty, G., Bourdoulous, S., Nassif, X., Marullo, S. Meningococcus hijacks a beta-2-adrenoceptor/beta-arrestin pathway to cross brain microvasculature endothelium. Cell 143: 1149-1160, 2010. [PubMed: 21183077] [Full Text: https://doi.org/10.1016/j.cell.2010.11.035]
Fong, F. M., Premont, R. T., Richardson, R. M., Yu, Y.-R. A., Lefkowitz, R. J., Patel, D. D. Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc. Nat. Acad. Sci. 99: 7478-7483, 2002. [PubMed: 12032308] [Full Text: https://doi.org/10.1073/pnas.112198299]
Kiselev, A., Socolich, M., Vinos, J., Hardy, R. W., Zuker, C. S., Ranganathan, R. A molecular pathway for light-dependent photoreceptor apoptosis in Drosophila. Neuron 28: 139-152, 2000. [PubMed: 11086990] [Full Text: https://doi.org/10.1016/s0896-6273(00)00092-1]
Kovacs, J. J., Whalen, E. J., Liu, R., Xiao, K., Kim, J., Chen, M., Wang, J., Chen, W., Lefkowitz, R. J. Beta-arrestin-mediated localization of Smoothened to the primary cilium. Science 320: 1777-1781, 2008. [PubMed: 18497258] [Full Text: https://doi.org/10.1126/science.1157983]
Luan, B., Zhao, J., Wu, H., Duan, B., Shu, G., Wang, X., Li, D., Jia, W., Kang, J., Pei, G. Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 457: 1146-1149, 2009. [PubMed: 19122674] [Full Text: https://doi.org/10.1038/nature07617]
McDonald, P. H., Chow, C.-W., Miller, W. E., Laporte, S. A., Field, M. E., Lin, F.-T., Davis, R. J., Lefkowitz, R. J. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290: 1574-1577, 2000. [PubMed: 11090355] [Full Text: https://doi.org/10.1126/science.290.5496.1574]
Puca, L., Chastagner, P., Meas-Yedid, V., Israel, A., Brou, C. Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals. J. Cell Sci. 126: 4457-4468, 2013. [PubMed: 23886940] [Full Text: https://doi.org/10.1242/jcs.130500]
Shenoy, S. K., McDonald, P. H., Kohout, T. A., Lefkowitz, R. J. Regulation of receptor fate by ubiquitination of activated beta-2-adrenergic receptor and beta-arrestin. Science 294: 1307-1313, 2001. [PubMed: 11588219] [Full Text: https://doi.org/10.1126/science.1063866]
Su, Y., Raghuwanshi, S. K., Yu, Y., Nanney, L. B., Richardson, R. M., Richmond, A. Altered CXCR2 signaling in beta-arrestin-2-deficient mouse models. J. Immun. 175: 5396-5402, 2005. [PubMed: 16210646] [Full Text: https://doi.org/10.4049/jimmunol.175.8.5396]
Wilbanks, A. M., Fralish, G. B., Kirby, M. L., Barak, L. S., Li, Y.-X., Caron, M. G. Beta-arrestin 2 regulates zebrafish development through the Hedgehog signaling pathway. Science 306: 2264-2267, 2004. [PubMed: 15618520] [Full Text: https://doi.org/10.1126/science.1104193]