Disease relevance of ARRB1

• Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2 [1].
• Conversely, in the two studied human melanoma cell lines both beta-arrestin isoforms seemed to be involved in IGF-1R ubiquitination [2].
• Role of beta-arrestin 1 in the metastatic progression of colorectal cancer [3].
• Furthermore, our data implicate a functional role for beta-arrestin 1 as a mediator of cellular migration and metastasis [3].
• In order to investigate this interaction, we generated a recombinant baculovirus for the expression of beta-arrestin in Sf9 insect cells [4].

Psychiatry related information on ARRB1

• The findings in human subjects support the implication of beta-arrestin-1 in the pathophysiology of mood disorders [5].
• The reduction in beta-arrestin-1 levels was significantly correlated with the severity of depressive symptoms [5].
• The identification of the ubiquitin-proteasome pathway and beta-arrestin as molecular targets of neurotoxicity is expected to provide novel therapeutic strategies both for the treatment of drug addiction and the treatment of neurodegenerative disorders [6].

High impact information on ARRB1

• (2005) provide evidence that beta-arrestin 1 moves to the nucleus in response to GPCR stimulation, where it regulates gene expression by facilitating histone acetylation at specific gene promoters [7].
• Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin [8].
• 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 [8].
• These data suggest that beta-arrestin binding, which terminates receptor-G protein coupling, also initiates a second wave of signal transduction in which the "desensitized" receptor functions as a critical structural component of a mitogenic signaling complex [9].
• Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes [9].

Biological context of ARRB1

• Assignment of the beta-arrestin 1 gene (ARRB1) to human chromosome 11q13 [10].
• Here we report the chromosome mapping of the human gene for beta-arrestin 1 (ARRB1) to chromosome 11q13 by fluorescence in situ hybridization (FISH) [10].
• In this report, we find that beta-arrestin function and Src-mediated phosphorylation of GRK2 are critically involved in GRK2 proteolysis [11].
• Angiotensin II-stimulated receptor phosphorylation, beta-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3 [12].
• Conversely, suppression of beta-arrestin 1, but not beta-arrestin 2, expression by using RNA interference led to a 3-fold increase in tumor necrosis factor-stimulated NF-kappaB activity as measured by NF-kappaB mobility-shift analysis [13].

Anatomical context of ARRB1

• In contrast, this activation was inhibited by a dominant negative mutant of beta-arrestin and was abolished in mouse embryonic fibroblasts lacking beta-arrestin 1 and 2 [14].
• beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation [15].
• A beta-arrestin-dependent scaffold is associated with prolonged MAPK activation in pseudopodia during protease-activated receptor-2-induced chemotaxis [16].
• By confocal microscopy, we observed beta-arrestin 1 and 2, translocated to the plasma membrane and colocalized with D2L and D2S receptors upon stimulation with dopamine, and this was followed by the translocation of receptors into endocytic vesicles [17].
• Interferon beta-1a counteracts effects of activation on the expression of G-protein-coupled receptor kinases 2 and 3, beta-arrestin-1, and regulators of G-protein signalling 2 and 16 in human mononuclear leukocytes [18].

Associations of ARRB1 with chemical compounds

• Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling [12].
• This phenomenon is not unique to beta2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited beta-arrestin and stimulated ERK1/2 [14].
• ICI118551 and propranolol also promoted beta-arrestin recruitment to the receptor [14].
• Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway [19].
• Isoprenaline-stimulated membrane recruitment of PDE4D is ablated upon beta arrestin knockdown [20].
• The NADPH oxidase complex is a downstream target of beta-arrestin-1, as evidenced by the fact that isoproterenol-induced Rac1 activation was also suppressed by beta-arrestin-1 knockdown [21].

Physical interactions of ARRB1

• The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B [22].
• Both beta-arrestin 1 and 2 interact with IkappaBalpha in transfected cells as assessed by immunoprecipitation experiments [13].
• Endogenous beta-arrestin is found in complex with ARNO [23].
• Immunoprecipitation experiments demonstrated that beta-arrestin 1 physically interacts with delta opioid receptor (DOR) co-expressed in human embryonic kidney 293 cells in an agonist-enhanced manner and truncation of the carboxyl terminus of DOR partially impairs the interaction [24].
• Overlay studies with PDE4D5 scanning peptide array libraries showed that RACK1 and beta-arrestin interact at overlapping sites within the unique N-terminal region of PDE4D5 and at distinct sites within the conserved PDE4 catalytic domain [25].

Enzymatic interactions of ARRB1

• In vitro studies demonstrated that beta-arrestin-V53D bound better to clathrin than beta-arrestin but was significantly impaired in its interaction with phosphorylated G protein-coupled receptors [26].

Co-localisations of ARRB1

• We show that, using transient transfection of either beta-arrestin-1 or its dominant negative Delta-arrestin-1 in CHO cells stably transfected with the sst2A, beta-arrestin-1 is colocalized with the receptor in endosomal vesicles after somatostatin-induced sequestration [27].

Regulatory relationships of ARRB1

• Consistent with a GRK mechanism, receptor-specific desensitization of the beta 1AR was enhanced by overexpression of beta-arrestin-1 and -2 in transfected 293 cells [28].
• c-Src regulates clathrin adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1 receptor during clathrin- mediated internalization [29].
• beta-Arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha [13].
• In addition, we identify a beta-arrestin mutant with enhanced affinity for the agonist-activated beta2-adrenergic receptor that traffics into endocytic vesicles with receptors that lack serine/threonine clusters and normally dissociate from wild-type beta-arrestin at the plasma membrane [30].
• Internalization determinants of the parathyroid hormone receptor differentially regulate beta-arrestin/receptor association [31].

Other interactions of ARRB1

• We also demonstrate that GRK2 and the uncoupling protein beta-arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding [32].
• In HEK293 cells expressing dominant suppressor mutants of beta-arrestin or dynamin, beta2-adrenergic receptor-mediated activation of MAP kinase is inhibited [33].
• We now show that PAR-2 activation promotes ERK1/2- and beta-arrestin-dependent reorganization of the actin cytoskeleton, polarized pseudopodia extension, and chemotaxis [16].
• Here we investigate the role of PAR-2 in the constitutive migration of a metastatic breast cancer cell line, MDA MB-231, and use small interfering RNA to determine the contribution of each beta-arrestin to this process [1].
• Thus, the results suggest that the C5aR is internalized via a pathway dependent on beta-arrestin, clathrin, and dynamin [19].

Analytical, diagnostic and therapeutic context of ARRB1

• At the protein level, beta-arrestin-1 was readily detected by Western blotting in human heart [34].
• Both cell types also express beta ARK1 and the associated inhibitory proteins beta-arrestin-1 and beta-arrestin-2, as assessed by immunoblotting [28].
• Inhibition of phosphorylation of either Ser(239) or Ser(357), through site directed mutagenesis, impaired desensitization while mutation of both Ser(239) and Ser(357) almost completely abolished desensitization of signalling, GRK phosphorylation and beta-arrestin association, thereby blocking TPbeta internalization [35].
• Surface plasmon resonance determination further revealed that binding of CT and I3L of DOR to beta-arrestin is additive, suggesting these two domains bind at distinctly different sites on beta-arrestin without considerable spatial hindrance [24].
• GRK2 and beta-arrestin-1 messenger RNAs were identified by Northern blot analysis to be expressed endogenously in betaTC3 and L293 cells [36].

References