ID:ARRB2_HUMAN DESCRIPTION: RecName: Full=Beta-arrestin-2; AltName: Full=Arrestin beta-2; FUNCTION: Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G- protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta- arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and P2RY11 and ATP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 and subsequent recycling or degradation. Involved in ubiquitination of IGF1R. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for the AKT1 pathway. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin- mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Increases ERK1/2 signaling in AGTR1- and AVPR2- mediated activation (reciprocal regulation). Involved in CCR7- mediated ERK1/2 signaling involving ligand CCL19. Is involved in type-1A angiotensin II receptor/AGTR1-mediated ERK activity. Is involved in type-1A angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. Involved in AGTR1-mediated chemotaxis. Appears to function as signaling scaffold involved in regulation of MIP-1- beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. Suppresses UV-induced NF-kappa-B-dependent activation by interacting with CHUK. The function is promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. Involved in p53/TP53- mediated apoptosis by regulating MDM2 and reducing the MDM2- mediated degradation of p53/TP53. May serve as nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved in regulation of gene expression during the early processes of fertilization. Also involved in regulation of receptors others than GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down- regulates TGF-beta signaling such as NF-kappa-B activation. Involved in endocytosis of low-density lipoprotein receptor/LDLR. Involved in endocytosis of smoothened homolog/Smo, which also requires ADRBK1. Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and subsequent TGF-beta-mediated ERK activation and migration of epithelial cells. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in insulin resistance by acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in IL8-mediated granule release in neutrophils. SUBUNIT: Homooligomer; the self-association is mediated by InsP6- binding (Probable). Heterooligomer with ARRB1; the association is mediated by InsP6-binding. Interacts with ADRB2 AND CHRM2. Interacts with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. Interacts with SRC. Interacts with DUSP16; the interaction is interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts with RELA. Interacts with MDM2; the interaction is enhanced by activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6. Interacts with IGF1R. Interacts with ENG. Interacts with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with SMO (activated). Interacts with GSK3A and GSK3B. Associates with protein phosphatase 2A (PP2A) (By similarity). Interacts with DHX8; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with GAPDHS; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with H2AFX; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with KIF14; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with RCC1; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with CXCR4; the interaction is dependent on C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1 (phosphorylated). INTERACTION: P31750:Akt1 (xeno); NbExp=3; IntAct=EBI-714559, EBI-298707; P62158:CALM3; NbExp=3; IntAct=EBI-714559, EBI-397435; P06396:GSN; NbExp=3; IntAct=EBI-714559, EBI-351506; P11142:HSPA8; NbExp=4; IntAct=EBI-714559, EBI-351896; P19338:NCL; NbExp=3; IntAct=EBI-714559, EBI-346967; Q14978:NOLC1; NbExp=3; IntAct=EBI-714559, EBI-396155; Q9Q2G4:ORF (xeno); NbExp=3; IntAct=EBI-714559, EBI-6248094; P14618:PKM; NbExp=4; IntAct=EBI-714559, EBI-353408; P35813:PPM1A; NbExp=3; IntAct=EBI-714559, EBI-989143; O75688:PPM1B; NbExp=3; IntAct=EBI-714559, EBI-1047039; Q13523:PRPF4B; NbExp=3; IntAct=EBI-714559, EBI-395940; P06702:S100A9; NbExp=2; IntAct=EBI-714559, EBI-1055001; Q15208:STK38; NbExp=3; IntAct=EBI-714559, EBI-458376; Q13428:TCOF1; NbExp=3; IntAct=EBI-714559, EBI-396105; P27348:YWHAQ; NbExp=3; IntAct=EBI-714559, EBI-359854; O95218:ZRANB2; NbExp=4; IntAct=EBI-714559, EBI-1051583; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane. Membrane, clathrin-coated pit (By similarity). Cytoplasmic vesicle. Note=Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1 (By similarity). PTM: Phosphorylated at Thr-382 in the cytoplasm; probably dephosphorylated at the plasma membrane. The phosphorylation does not regulate internalization and recycling of ADRB2, interaction with clathrin or AP2B1. PTM: The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occurr GPCR-specifc. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33. Stimulation of a class B GPCR promotes a sustained ubiquitination. SIMILARITY: Belongs to the arrestin family. WEB RESOURCE: Name=Wikipedia; Note=Arrestin entry; URL="http://en.wikipedia.org/wiki/Arrestin";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P32121
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0001664 G-protein coupled receptor binding GO:0005102 receptor binding GO:0005515 protein binding GO:0019899 enzyme binding GO:0019904 protein domain specific binding GO:0031625 ubiquitin protein ligase binding GO:0031691 alpha-1A adrenergic receptor binding GO:0031692 alpha-1B adrenergic receptor binding GO:0031701 angiotensin receptor binding GO:0031702 type 1 angiotensin receptor binding GO:0031748 D1 dopamine receptor binding GO:0031762 follicle-stimulating hormone receptor binding GO:0031826 type 2A serotonin receptor binding GO:0031859 platelet activating factor receptor binding GO:0032947 protein complex scaffold GO:0042802 identical protein binding GO:0043422 protein kinase B binding GO:0044877 macromolecular complex binding GO:0051019 mitogen-activated protein kinase binding GO:0071889 14-3-3 protein binding GO:1990763 arrestin family protein binding
Biological Process: GO:0001932 regulation of protein phosphorylation GO:0001933 negative regulation of protein phosphorylation GO:0001934 positive regulation of protein phosphorylation GO:0002031 G-protein coupled receptor internalization GO:0002032 desensitization of G-protein coupled receptor protein signaling pathway by arrestin GO:0002092 positive regulation of receptor internalization GO:0006366 transcription from RNA polymerase II promoter GO:0006897 endocytosis GO:0007165 signal transduction GO:0007179 transforming growth factor beta receptor signaling pathway GO:0007186 G-protein coupled receptor signaling pathway GO:0007212 dopamine receptor signaling pathway GO:0007420 brain development GO:0007628 adult walking behavior GO:0008277 regulation of G-protein coupled receptor protein signaling pathway GO:0009968 negative regulation of signal transduction GO:0010628 positive regulation of gene expression GO:0015031 protein transport GO:0016567 protein ubiquitination GO:0016579 protein deubiquitination GO:0030168 platelet activation GO:0031397 negative regulation of protein ubiquitination GO:0031398 positive regulation of protein ubiquitination GO:0031623 receptor internalization GO:0032088 negative regulation of NF-kappaB transcription factor activity GO:0032226 positive regulation of synaptic transmission, dopaminergic GO:0032691 negative regulation of interleukin-1 beta production GO:0032695 negative regulation of interleukin-12 production GO:0032715 negative regulation of interleukin-6 production GO:0032720 negative regulation of tumor necrosis factor production GO:0032967 positive regulation of collagen biosynthetic process GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0034122 negative regulation of toll-like receptor signaling pathway GO:0034260 negative regulation of GTPase activity GO:0034392 negative regulation of smooth muscle cell apoptotic process GO:0042699 follicle-stimulating hormone signaling pathway GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043524 negative regulation of neuron apoptotic process GO:0045953 negative regulation of natural killer cell mediated cytotoxicity GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050965 detection of temperature stimulus involved in sensory perception of pain GO:0051897 positive regulation of protein kinase B signaling GO:0051898 negative regulation of protein kinase B signaling GO:0051928 positive regulation of calcium ion transport GO:0060071 Wnt signaling pathway, planar cell polarity pathway GO:0060079 excitatory postsynaptic potential GO:0060326 cell chemotaxis GO:0060765 regulation of androgen receptor signaling pathway GO:0061024 membrane organization GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0090201 negative regulation of release of cytochrome c from mitochondria GO:1904037 positive regulation of epithelial cell apoptotic process GO:2000573 positive regulation of DNA biosynthetic process GO:2000727 positive regulation of cardiac muscle cell differentiation
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Common Gene Haplotype Alleles 
