Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0003800
UniProt IDP32121
Primary gene name(s)ARRB2
Synonym gene name(s)ARB2, ARR2
Protein nameBeta-arrestin-2
Protein functionFunctions 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. {ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:11877451, ECO:0000269|PubMed:12488444, ECO:0000269|PubMed:12582207, ECO:0000269|PubMed:12949261, ECO:0000269|PubMed:12958365, ECO:0000269|PubMed:14711824, ECO:0000269|PubMed:15054093, ECO:0000269|PubMed:15125834, ECO:0000269|PubMed:15205453, ECO:0000269|PubMed:15475570, ECO:0000269|PubMed:15618519, ECO:0000269|PubMed:15635042, ECO:0000269|PubMed:15671180, ECO:0000269|PubMed:15699339, ECO:0000269|PubMed:15878855, ECO:0000269|PubMed:16144840, ECO:0000269|PubMed:16280323, ECO:0000269|PubMed:16378096, ECO:0000269|PubMed:16492667, ECO:0000269|PubMed:16820410, ECO:0000269|PubMed:17540773, ECO:0000269|PubMed:18419762, ECO:0000269|PubMed:18604210, ECO:0000269|PubMed:19325136, ECO:0000269|PubMed:19620252, ECO:0000269|PubMed:19643177, ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:22457824}.
Subcellular locationCytoplasm. Nucleus. Cell membrane. Membrane, clathrin-coated pit {ECO:0000250}. Cytoplasmic vesicle. Note=Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P32121
Gene Ontology
(Biological Process)
Complete annatation
adult walking behavior [GO:0007628];
brain development [GO:0007420];
cell chemotaxis [GO:0060326];
chemical synaptic transmission, postsynaptic [GO:0099565];
desensitization of G-protein coupled receptor protein signaling pathway by arrestin [GO:0002032];
detection of temperature stimulus involved in sensory perception of pain [GO:0050965];
dopamine receptor signaling pathway [GO:0007212];
follicle-stimulating hormone signaling pathway [GO:0042699];
G-protein coupled receptor internalization [GO:0002031];
negative regulation of cysteine-type endopeptidase activity involved in apoptotic process [GO:0043154];
negative regulation of GTPase activity [GO:0034260];
negative regulation of interleukin-12 production [GO:0032695];
negative regulation of interleukin-1 beta production [GO:0032691];
negative regulation of interleukin-6 production [GO:0032715];
negative regulation of natural killer cell mediated cytotoxicity [GO:0045953];
negative regulation of NF-kappaB transcription factor activity [GO:0032088];
negative regulation of protein kinase B signaling [GO:0051898];
negative regulation of protein phosphorylation [GO:0001933];
negative regulation of protein ubiquitination [GO:0031397];
negative regulation of release of cytochrome c from mitochondria [GO:0090201];
negative regulation of smooth muscle cell apoptotic process [GO:0034392];
negative regulation of toll-like receptor signaling pathway [GO:0034122];
negative regulation of tumor necrosis factor production [GO:0032720];
platelet activation [GO:0030168];
positive regulation of calcium ion transport [GO:0051928];
positive regulation of cardiac muscle cell differentiation [GO:2000727];
positive regulation of DNA biosynthetic process [GO:2000573];
positive regulation of ERK1 and ERK2 cascade [GO:0070374];
positive regulation of gene expression [GO:0010628];
positive regulation of peptidyl-serine phosphorylation [GO:0033138];
positive regulation of peptidyl-tyrosine phosphorylation [GO:0050731];
positive regulation of protein kinase B signaling [GO:0051897];
positive regulation of protein ubiquitination [GO:0031398];
positive regulation of receptor internalization [GO:0002092];
positive regulation of synaptic transmission, dopaminergic [GO:0032226];
proteasome-mediated ubiquitin-dependent protein catabolic process [GO:0043161];
protein transport [GO:0015031];
protein ubiquitination [GO:0016567];
receptor internalization [GO:0031623];
regulation of androgen receptor signaling pathway [GO:0060765];
transcription from RNA polymerase II promoter [GO:0006366];
transforming growth factor beta receptor signaling pathway [GO:0007179];
Wnt signaling pathway, planar cell polarity pathway [GO:0060071]
Gene Ontology
(Molecular Function)
Complete annatation
angiotensin receptor binding [GO:0031701];
enzyme binding [GO:0019899];
G-protein coupled receptor binding [GO:0001664];
protein complex scaffold [GO:0032947];
receptor binding [GO:0005102];
ubiquitin protein ligase binding [GO:0031625]
Gene Ontology
(Cellular Component)
Complete annatation
basolateral plasma membrane [GO:0016323];
coated pit [GO:0005905];
cytoplasm [GO:0005737];
cytoplasmic vesicle [GO:0031410];
cytosol [GO:0005829];
dendritic spine [GO:0043197];
endocytic vesicle [GO:0030139];
nucleus [GO:0005634];
plasma membrane [GO:0005886];
postsynaptic density [GO:0014069];
postsynaptic membrane [GO:0045211]
Protein-protein interaction106902
Phylogenetic treeP32121
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD3-1.97643867927718.69216720822408e-091.03563908428738e-07
AZA vs. DISU-0.2263922906988720.3703476017897220.896735609264834
AZA vs. IL7-0.1476998615861980.4414857130617650.999311006273513
AZA vs. SAHA-0.6778535782538320.005688757050848810.067521514790941
DISU vs. CD31.737704715604224.56440598806118e-063.69219222197304e-05
DISU vs. IL70.06932519580176790.7830386257869270.950465331549835
DISU vs. SAHA-0.4494074117551530.1248131698085970.454362145455402
DMSO vs. AZA-0.04979262450815660.7656700095171691
DMSO vs. CD31.915913885659331.03070278978379e-081.10280806307477e-07
DMSO vs. DISU0.1749361256846330.4729277435752730.897519127204587
DMSO vs. IL7-0.09069317810158320.6132547654564550.915237658574009
DMSO vs. SAHA-0.634274918535380.007375454955815040.0731286063415056
HIV vs. Mock in Activation0.2396074738454970.7004215648596370.999983755607037
HIV vs. Mock in Latency0.09237964866368480.6133437107189120.999834320637052
IL7 vs. CD31.835278267800984.08509401861323e-085.45874309774444e-07
SAHA vs. CD31.274787059570460.0004102459088691780.0016499615283316
SAHA vs. IL7-0.5331147325054090.02892098283151230.127397690006492
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.0618165 0.726733
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
0.953 0.9 0.86 0.956 0.909
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

not found

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
Pol interacts with 22190034
Tat upregulates 17855543
retropepsin interacts with 22190034

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04010 MAPK signaling pathway - Homo sapiens (human)
hsa04062 Chemokine signaling pathway - Homo sapiens (human)
hsa04144 Endocytosis - Homo sapiens (human)
hsa04340 Hedgehog signaling pathway - Homo sapiens (human)
hsa04728 Dopaminergic synapse - Homo sapiens (human)
hsa04740 Olfactory transduction - Homo sapiens (human)
hsa05032 Morphine addiction - Homo sapiens (human)