Tbio ARRB2 Beta-arrestin-2

Protein Classes

PANTHER Classes

Protein / Enzyme Modulator / Beta-arrestin-2

DTO Classes

Protein / Enzyme Modulator / Beta-arrestin-2

Protein Summary

Description

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. Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G-protein-coupled receptors and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. Arrestin beta 2, like arrestin beta 1, was shown to inhibit beta-adrenergic receptor function in vitro. It is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. Besides the brain, a cDNA for arrestin beta 2 was isolated from thyroid gland, and thus it may also be involved in hormone-specific desensitization of TSH receptors. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

Uniprot Accession IDs

• P32121
• B4DLW0
• B5B0C0
• B7WPL3
• D3DTK2
• H0Y688
• Q0Z8D3
• Q2PP19
• Q6ICT3
• Q8N7Y2
• Q9UEQ6

Gene Name

• ARRB2

Ensembl ID

• ENST00000269260
• ENSP00000269260
• ENSG00000141480
• ENST00000346341
• ENSP00000341895
• ENST00000381488
• ENSP00000370898
• ENST00000412477
• ENSP00000403701

Symbol

• ARB2
• ARR2
• ARB2
• ARR2
• BARR2

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	1
hub protein	1
protein domain	0.92
molecular function	0.9
cellular component	0.87

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Target Illumination GWAS Analytics (TIGA)

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GENEVA

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GlyGen

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 678.15   (req: < 5)

Gene RIFs: 198   (req: <= 3)

Antibodies: 338   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 678.15   (req: >= 5)

Gene RIFs: 198   (req: > 3)

Antibodies: 338   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 69

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

GWAS Traits (5)

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 5

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
lymphocyte count	EFO_0004587	2	2	2		83.1
C-X-C motif chemokine 16 measurement	EFO_0010911	1	1	1		29.8
leukocyte count	EFO_0004308	1	1	1		16.4
blood protein measurement	EFO_0007937	1	1	1		16
lymphocyte percentage of leukocytes	EFO_0007993	1	1	1		4.9

• Explore on Target Illumination GWAS Analytics (TIGA)

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
lymphocyte count	EFO_0004587	2		83.1
C-X-C motif chemokine 16 measurement	EFO_0010911	1		29.8
leukocyte count	EFO_0004308	1		16.4
blood protein measurement	EFO_0007937	1		16
lymphocyte percentage of leukocytes	EFO_0007993	1		4.9

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Orthologs (11)

1 – 5 of 11

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	arrestin beta 2	VGNC:9221	454450
Macaque	arrestin beta 2		709399
Mouse	arrestin, beta 2	MGI:99474	216869
Rat	arrestin, beta 2	RGD:2157	25388
Dog	arrestin beta 2	VGNC:38137	607262

Species	Name	OMA	EggNOG	Inparanoid
Chimp	arrestin beta 2
Macaque	arrestin beta 2
Mouse	arrestin, beta 2
Rat	arrestin, beta 2
Dog	arrestin beta 2

Protein Structure (0 Structures, 1 AlphaFold Model)

Representation

  axes   backbone   ball+stick   cartoon   rocket   rope   spacefill

Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

AF-P32121-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

Pathways (81)

Reactome (42)

KEGG (10)

PathwayCommons (20)

WikiPathways (9)

Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Reactome	Activation of SMO	18 targets	R-HSA-5635838
Reactome	Beta-catenin independent WNT signaling	146 targets	R-HSA-3858494
Reactome	Cargo recognition for clathrin-mediated endocytosis	105 targets	R-HSA-8856825
Reactome	Clathrin-mediated endocytosis	143 targets	R-HSA-8856828

Name	Explore in Pharos	Explore in Source
Activated NOTCH1 Transmits Signal to the Nucleus	31 targets	R-HSA-2122948
Activation of SMO	18 targets	R-HSA-5635838
Beta-catenin independent WNT signaling	146 targets	R-HSA-3858494
Cargo recognition for clathrin-mediated endocytosis	105 targets	R-HSA-8856825
Clathrin-mediated endocytosis	143 targets	R-HSA-8856828

Gene Ontology Terms (82)

Functions (20)

Components (13)

Processes (49)

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Items per page:

10

1 – 10 of 20

GO Term	Evidence	Assigned by
protein-containing complex scaffold activity	Inferred from Direct Assay (IDA)	BHF-UCL
angiotensin receptor binding	Inferred from Physical Interaction (IPI)	UniProtKB
enzyme binding	Inferred from Physical Interaction (IPI)	UniProtKB
G protein-coupled receptor binding	Inferred from Physical Interaction (IPI)	UniProtKB
signaling receptor binding	Inferred from Physical Interaction (IPI)	UniProtKB
ubiquitin protein ligase binding	Inferred from Physical Interaction (IPI)	UniProtKB
14-3-3 protein binding	Inferred from Electronic Annotation (IEA)	Ensembl
alpha-1A adrenergic receptor binding	Inferred from Electronic Annotation (IEA)	Ensembl
alpha-1B adrenergic receptor binding	Inferred from Electronic Annotation (IEA)	Ensembl
arrestin family protein binding	Inferred from Electronic Annotation (IEA)	Ensembl

Protein-Protein Interactions (783)

Explore Interacting Targets

1 – 10 of 783

• See Interactions on String-DB

ARRB1

Tbio

Novelty: 0.00262758

p_int: 1

Score: 0.968

Data Source: BioPlex,STRINGDB

ARR3

Tbio

Novelty: 0.00575939

p_int: 0.999999919

p_wrong: 8.1e-8

Score: 0.375

Data Source: BioPlex,STRINGDB

KANK1

Tbio

Novelty: 0.02077359

p_int: 0.999999642

p_ni: 3.58e-7

Score: 0.213

Data Source: BioPlex,STRINGDB

BRPF1

Tchem

Family: Epigenetic

Novelty: 0.02524021

p_int: 0.999998135

p_ni: 0.000001863

p_wrong: 2e-9

Score: 0.65

Data Source: BioPlex,STRINGDB

SLC9A3R2

Tbio

Family: Transporter

Novelty: 0.01401705

p_int: 0.999990192

p_ni: 0.000009808

Data Source: BioPlex

DIEXF

Tbio

Novelty: 0.05892659

p_int: 0.999961745

p_ni: 0.000036846

p_wrong: 0.000001408

Data Source: BioPlex

NAA15

Tbio

Family: Enzyme

Novelty: 0.00513055

p_int: 0.999933599

p_ni: 0.000066401

Data Source: BioPlex

RTF1

Tbio

Family: Enzyme

Novelty: 0.02255644

p_int: 0.99990018

p_ni: 0.00009982

Score: 0.659

Data Source: BioPlex,STRINGDB

RFX1

Tbio

Family: TF

Novelty: 0.00225236

p_int: 0.999398822

p_ni: 0.000601178

Data Source: BioPlex

WDR70

Tdark

Novelty: 0.37521871

p_int: 0.998989784

p_ni: 0.000328176

p_wrong: 0.00068204

Score: 0.177

Data Source: BioPlex,STRINGDB

Publication Statistics

PubMed Score  678.15

PubMed score by year

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PubTator Score  306.06

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

Alternative splicing
Cell membrane
Coated pit
Complete proteome
Cytoplasm
Cytoplasmic vesicle
Hydroxylation
Membrane
Nucleus
Phosphoprotein

GWAS Trait Find Similar Targets

blood protein measurement
C-X-C motif chemokine 16 measurement
leukocyte count
lymphocyte count
lymphocyte percentage of leukocytes

MGI Phenotype Find Similar Targets

adipose tissue phenotype
behavior/neurological phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype