ARRB2 - Beta-arrestin-2 - human protein (Function)
 
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ARRB2 »  Beta-arrestin-2
 
Protein also known as:  Arrestin beta-2.
Gene name:  ARRB2
Family name: Arrestin
Entry whose protein(s) existence is based on evidence at protein level
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1 189 5
GENE REF ISO

Function

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Overview 
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 other 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. Involved in the internalization of the atypical chemokine receptor ACKR3.  
29
  • CuratedUniProtKB
GO molecular function 
14-3-3 protein bindingdefinition[GO:0071889] silver  
  • IEAOrtholog Compara
Alpha-1A adrenergic receptor bindingdefinition[GO:0031691] silver  
  • IEAOrtholog Compara
Alpha-1B adrenergic receptor bindingdefinition[GO:0031692] silver  
  • IEAOrtholog Compara
Angiotensin receptor bindingdefinition[GO:0031701]  
1
  • IPIUniProtKB
D1 dopamine receptor bindingdefinition[GO:0031748] silver  
  • IEAOrtholog Compara
Enzyme bindingdefinition[GO:0019899]  
1
  • IPIUniProtKB
Follicle-stimulating hormone receptor bindingdefinition[GO:0031762] silver  
  • IEAOrtholog Compara
G-protein coupled receptor bindingdefinition[GO:0001664]  
1
  • IPIUniProtKB
Mitogen-activated protein kinase bindingdefinition[GO:0051019] silver  
  • IEAOrtholog Compara
Protein bindingdefinition[GO:0005515]  
15
  • IPIUniProtKB
  • IPIIntAct
  • IPIBHF-UCL
Protein complex bindingdefinition[GO:0032403] silver  
  • IEAOrtholog Compara
Protein complex scaffolddefinition[GO:0032947]  
1
  • IDABHF-UCL
Protein domain specific bindingdefinition[GO:0019904] silver  
  • IEAOrtholog Compara
Protein kinase B bindingdefinition[GO:0043422] silver  
  • IEAOrtholog Compara
Receptor bindingdefinition[GO:0005102]  
1
  • IPIUniProtKB
Type 1 angiotensin receptor bindingdefinition[GO:0031702] silver  
  • IEAOrtholog Compara
Type 2A serotonin receptor bindingdefinition[GO:0031826] silver  
  • IEAOrtholog Compara
Ubiquitin protein ligase bindingdefinition[GO:0031625]  
2
  • IPIBHF-UCL
  • IPIUniProtKB
GO biological process 
Adult walking behaviordefinition[GO:0007628] silver  
  • IEAOrtholog Compara
Apoptotic DNA fragmentationdefinition[GO:0006309] silver  
  • IEAOrtholog Compara
Brain developmentdefinition[GO:0007420] silver  
  • IEAOrtholog Compara
Cell chemotaxisdefinition[GO:0060326]  
1
  • IMPUniProtKB
Desensitization of G-protein coupled receptor protein signaling pathway by arrestindefinition[GO:0002032]  
1
  • IMPUniProtKB
Detection of temperature stimulus involved in sensory perception of paindefinition[GO:0050965] silver  
  • IEAOrtholog Compara
Follicle-stimulating hormone signaling pathwaydefinition[GO:0042699] silver  
  • IEAOrtholog Compara
G-protein coupled receptor internalizationdefinition[GO:0002031]  
2
  • IMPUniProtKB
Negative regulation of GTPase activitydefinition[GO:0034260] silver  
  • IEAOrtholog Compara
Negative regulation of interleukin-1 beta productiondefinition[GO:0032691] silver  
  • IEAOrtholog Compara
Negative regulation of interleukin-12 productiondefinition[GO:0032695] silver  
  • IEAOrtholog Compara
Negative regulation of interleukin-6 productiondefinition[GO:0032715] silver  
  • IEAOrtholog Compara
Negative regulation of natural killer cell mediated cytotoxicitydefinition[GO:0045953]  
1
  • IMPUniProtKB
Negative regulation of NF-kappaB transcription factor activitydefinition[GO:0032088]  
2
  • IDAUniProtKB
Negative regulation of protein ubiquitinationdefinition[GO:0031397]  
1
  • IDAUniProtKB
Negative regulation of smooth muscle cell apoptotic processdefinition[GO:0034392] silver  
  • IEAOrtholog Compara
Negative regulation of toll-like receptor signaling pathwaydefinition[GO:0034122] silver  
  • IEAOrtholog Compara
Negative regulation of tumor necrosis factor productiondefinition[GO:0032720] silver  
  • IEAOrtholog Compara
Positive regulation of apoptotic processdefinition[GO:0043065] silver  
  • IEAOrtholog Compara
Positive regulation of calcium ion transportdefinition[GO:0051928] silver  
  • IEAOrtholog Compara
Positive regulation of DNA biosynthetic processdefinition[GO:2000573] silver  
  • IEAOrtholog Compara
Positive regulation of ERK1 and ERK2 cascadedefinition[GO:0070374]  
2
  • IMPUniProtKB
Positive regulation of peptidyl-tyrosine phosphorylationdefinition[GO:0050731] silver  
  • IEAOrtholog Compara
Positive regulation of protein kinase B signalingdefinition[GO:0051897] silver  
  • IEAOrtholog Compara
Positive regulation of protein ubiquitinationdefinition[GO:0031398]  
1
  • IGIBHF-UCL
Positive regulation of receptor internalizationdefinition[GO:0002092]  
1
  • IMPUniProtKB
Positive regulation of release of cytochrome c from mitochondriadefinition[GO:0090200] silver  
  • IEAOrtholog Compara
Positive regulation of synaptic transmission, dopaminergicdefinition[GO:0032226] silver  
  • IEAOrtholog Compara
Proteasome-mediated ubiquitin-dependent protein catabolic processdefinition[GO:0043161]  
1
  • IMPUniProtKB
Protein transportdefinition[GO:0015031]  
  • IEAUniProtKB KW
Protein ubiquitinationdefinition[GO:0016567]  
1
  • IMPUniProtKB
Receptor internalizationdefinition[GO:0031623]  
1
  • IDABHF-UCL
Regulation of androgen receptor signaling pathwaydefinition[GO:0060765]  
1
  • IDABHF-UCL
Transcription from RNA polymerase II promoterdefinition[GO:0006366]  
1
  • IDAUniProtKB
Transforming growth factor beta receptor signaling pathwaydefinition[GO:0007179]  
1
  • IDABHF-UCL
Pathways 
According to KEGG, this protein belongs to the following pathways:
Chemokine signaling pathway  hsa04062+409  
Dopaminergic synapse  hsa04728+409  
Endocytosis  hsa04144+409  
MAPK signaling pathway  hsa04010+409  
Olfactory transduction  hsa04740+409  
Phototransduction  hsa04744+409  
According to Reactome, this protein belongs to the following pathways:
Activated NOTCH1 Transmits Signal to the Nucleus  REACT_118614  
Thrombin signalling through proteinase activated receptors (PARs)  REACT_21384  
WNT5A-dependent internalization of FZD4  REACT_172599  
 

Keywords

Biological process 
Protein transport  definition   [KW-0653]
Transport  definition   [KW-0813]
Molecular function 
Signal transduction inhibitor  definition   [KW-0734]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

GeneWiki: Arrestin_beta_2
GenomeRNAi: 409
PRO: PR:P32121