Sequence 202 (b-arrestin(ineffective), barrestin(ineffective) )

From Wikisequences
Jump to: navigation, search
Sequence b-arrestin(ineffective), barrestin(ineffective)
Target ARRB2 ( Homo sapiens )
Description Arrestin, beta 2

Ensembl: ENSG00000141480 UniGene: Hs.435811 EntrezGene: 409 Ensembl Chr17: 4560538 - 4571543 Strand: 1 GO terms: 0001932 0005515 0005622 0005634 0005737 0005886 0007165 0007600 0008277 0050896

Design siRNA
Chemistry RNA
Sequence siRNA sense (21b) GTGGACCCTGTAGATGGCGTT / siRNA antisense (21b) CGCCATCTACAGGGTCCACTT
Application gene silencing
Name b-arrestin(ineffective), barrestin(ineffective)

References

Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference.Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ.Proc Natl Acad Sci U S A. 2003 Feb 18;100(4) :1740-4. Epub 2003 Feb 11.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Comments

Background

Gene Function. 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.

Animal Model. 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.

Support Doctors Without Borders