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HMDB Protein ID HMDBP14520
Secondary Accession Numbers None
Name Beta-arrestin-2
  1. Arrestin beta-2
  2. Non-visual arrestin-3
Gene Name ARRB2
Protein Type Unknown
Biological Properties
General Function Not Available
Specific 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 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 GRK2. 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. Acts as an adapter protein coupling FFAR4 receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis (PubMed:22282525, PubMed:23809162). During the activation step of NLRP3 inflammasome, directly associates with NLRP3 leading to inhibition of proinflammatory cytokine release and inhibition of inflammation (PubMed:23809162).
  • Chemical carcinogenesis - receptor activation
  • Chemokine signaling pathway
  • Dopaminergic synapse
  • Endocytosis
  • GnRH secretion
  • Hedgehog signaling pathway
  • MAPK signaling pathway
  • Morphine addiction
  • Olfactory transduction
  • Parathyroid hormone synthesis, secretion and action
  • Relaxin signaling pathway
Reactions Not Available
GO Classification
Biological Process
dopamine receptor signaling pathway
protein deubiquitination
transcription from RNA polymerase II promoter
platelet activation
negative regulation of release of cytochrome c from mitochondria
negative regulation of protein ubiquitination
negative regulation of neuron apoptotic process
cell chemotaxis
membrane organization
protein transport
negative regulation of protein kinase B signaling cascade
regulation of excitatory postsynaptic membrane potential
G-protein coupled receptor signaling pathway
negative regulation of interleukin-1 beta production
receptor internalization
negative regulation of tumor necrosis factor production
positive regulation of DNA biosynthetic process
positive regulation of collagen biosynthetic process
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
positive regulation of ERK1 and ERK2 cascade
G-protein coupled receptor internalization
negative regulation of GTPase activity
negative regulation of protein phosphorylation
positive regulation of peptidyl-tyrosine phosphorylation
adult walking behavior
negative regulation of NF-kappaB transcription factor activity
positive regulation of protein kinase B signaling cascade
brain development
positive regulation of calcium ion transport
desensitization of G protein-coupled receptor signaling pathway by arrestin
follicle-stimulating hormone signaling pathway
negative regulation of natural killer cell mediated cytotoxicity
negative regulation of toll-like receptor signaling pathway
positive regulation of cardiac muscle cell differentiation
negative regulation of smooth muscle cell apoptotic process
positive regulation of epithelial cell apoptotic process
Wnt signaling pathway, planar cell polarity pathway
positive regulation of synaptic transmission, dopaminergic
positive regulation of receptor internalization
negative regulation of interleukin-6 production
transforming growth factor beta receptor signaling pathway
detection of temperature stimulus involved in sensory perception of pain
positive regulation of gene expression
proteasomal ubiquitin-dependent protein catabolic process
positive regulation of peptidyl-serine phosphorylation
negative regulation of interleukin-12 production
protein ubiquitination
Cellular Component
plasma membrane
endocytic vesicle
postsynaptic membrane
coated pit
basolateral plasma membrane
dendritic spine
cytoplasmic vesicle
postsynaptic density
Molecular Function
protein-containing complex binding
G protein-coupled receptor binding
ubiquitin protein ligase binding
receptor binding
alpha-1A adrenergic receptor binding
alpha-1B adrenergic receptor binding
14-3-3 protein binding
angiotensin receptor binding
D1 dopamine receptor binding
follicle-stimulating hormone receptor binding
mitogen-activated protein kinase binding
platelet activating factor receptor binding
type 2A serotonin receptor binding
protein domain specific binding
enzyme binding
arrestin family protein binding
protein kinase B binding
identical protein binding
type 1 angiotensin receptor binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 409
Molecular Weight 46105.36
Theoretical pI 7.69
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID P32121
UniProtKB/Swiss-Prot Entry Name ARRB2_HUMAN
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
General References
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