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 membra (updated: April 1, 2015)

Protein identification was indicated in the following studies:

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

Publication	Identification ¹	Uniprot mapping ²	Not mapped / Obsolete	TrEMBL	Swiss-Prot
Goodman (2013)	2289 (gene list)	2278	53	20599	2269
Lange (2014)	1234	1234	7	28	1224
Hegedus (2015)	2638	2622	0	235	2387
Wilson (2016)	1658	1528	170	291	1068
d'Alessandro (2017)	1826	1817	2	0	1815
Bryk (2017)	2090	2060	10	108	1942
Chu (2018)	1853	1804	55	362	1387

¹ as available in the article and/or in supplementary material
² uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Protein sequence (FASTA)

Protein coevolution profile (FreeContact)

Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.

Total structural coverage: 98%

Model score: 0

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Biological Process

Adult walking behavior

Blood coagulation

Brain development

Cell chemotaxis

Chemical synaptic transmission, postsynaptic

Desensitization of G protein-coupled receptor signaling pathway by arrestin

Detection of temperature stimulus involved in sensory perception of pain

Dopamine receptor signaling pathway

Excitatory postsynaptic potential

Follicle-stimulating hormone signaling pathway

G protein-coupled receptor internalization

G protein-coupled receptor signaling pathway

Membrane organization

Negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

Negative regulation of GTPase activity

Negative regulation of interleukin-1 beta production

Negative regulation of interleukin-12 production

Negative regulation of interleukin-6 production

Negative regulation of natural killer cell mediated cytotoxicity

Negative regulation of neuron apoptotic process

Negative regulation of NF-kappaB transcription factor activity

Negative regulation of protein kinase B signaling

Negative regulation of protein phosphorylation

Negative regulation of protein ubiquitination

Negative regulation of release of cytochrome c from mitochondria

Negative regulation of smooth muscle cell apoptotic process

Negative regulation of toll-like receptor signaling pathway

Negative regulation of tumor necrosis factor production

Notch signaling pathway

Platelet activation

Positive regulation of calcium ion transport

Positive regulation of cardiac muscle cell differentiation

Positive regulation of collagen biosynthetic process

Positive regulation of DNA biosynthetic process

Positive regulation of epithelial cell apoptotic process

Positive regulation of ERK1 and ERK2 cascade

Positive regulation of gene expression

Positive regulation of peptidyl-serine phosphorylation

Positive regulation of peptidyl-tyrosine phosphorylation

Positive regulation of protein kinase B signaling

Positive regulation of protein ubiquitination

Positive regulation of receptor internalization

Positive regulation of synaptic transmission, dopaminergic

Proteasome-mediated ubiquitin-dependent protein catabolic process

Protein deubiquitination

Protein transport

Protein ubiquitination

Receptor internalization

Regulation of androgen receptor signaling pathway

Transcription by RNA polymerase II

Transforming growth factor beta receptor signaling pathway

Wnt signaling pathway, planar cell polarity pathway

Cellular Component

Basolateral plasma membrane

Clathrin-coated pit

Cytoplasm

Cytoplasmic vesicle

Cytosol

Dendritic spine

Endocytic vesicle

Endosome

Intracellular membrane-bounded organelle

Nucleoplasm

Nucleus

Plasma membrane

Postsynaptic density

Postsynaptic membrane

Molecular Function

14-3-3 protein binding

Alpha-1A adrenergic receptor binding

Alpha-1B adrenergic receptor binding

Angiotensin receptor binding

Arrestin family protein binding

D1 dopamine receptor binding

Enzyme binding

Follicle-stimulating hormone receptor binding

G protein-coupled receptor binding

Identical protein binding

Mitogen-activated protein kinase binding

Molecular adaptor activity

Platelet activating factor receptor binding

Protein complex binding

Protein domain specific binding

Protein kinase B binding

Protein-containing complex binding

Protein-containing complex scaffold activity

Signaling receptor binding

Type 1 angiotensin receptor binding

Type 2A serotonin receptor binding

Ubiquitin protein ligase binding

The reference OMIM entry for this protein is 107941

Arrestin, beta, 2; arrb2
Beta-arrestin 2; arb2
Barr2

CLONING

Using a low stringency hybridization technique to screen a rat brain cDNA library, Attramadal et al. (1992) isolated cDNA clones representing 2 distinct beta-arrestin-like genes. One of the cDNAs is the rat homolog of bovine beta-arrestin (beta-arrestin-1; ARB1; 107940). In addition, Attramadal et al. (1992) isolated a cDNA clone encoding a novel beta-arrestin-related protein, which they termed beta-arrestin-2. ARB2 exhibited 78% amino acid identity with ARB1. The primary structure of these proteins delineated a family of proteins that regulate receptor coupling to G proteins. ARB1 and ARB2 are predominantly localized in neuronal tissues and in the spleen.

GENE FUNCTION

Beta-arrestins were originally discovered in the context of heterotrimeric G protein-coupled receptor desensitization, but they also function in internalization and signaling of these receptors. Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3 (602897) as a binding partner of ARBB2. These results were confirmed by coimmunoprecipitation from mouse brain extracts and cotransfection in COS-7 cells. The upstream JNK activators apoptosis signal-regulating kinase-1 (ASK1; 602448) and MAP2K4 (601335) were also found in complex with ARBB2. Cellular transfection of ARBB2 caused cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor (AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2 and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000) concluded that ARBB2 acts as a scaffold protein, which brings the spatial distribution and activity of this MAPK module under the control of a G protein-coupled receptor. Alloway et al. (2000) demonstrated the existence of stable, persistent complexes between rhodopsin (180380) and its regulatory protein arrestin in several different retinal degeneration mutants in Drosophila. Elimination of these rhodopsin-arrestin complexes by removing either rhodopsin or arrestin rescues the degeneration phenotype. Furthermore, Alloway et al. (2000) showed that the accumulation of these complexes triggers apoptotic cell death and that the observed retinal degeneration requires the endocytic machinery. Thus, the endocytosis of rhodopsin-arrestin complexes may be a molecular mechanism for the initiation of retinal degeneration. Alloway et al. (2000) proposed that an identical mechanism may be responsible for the pathology found in a subset of human retinal degenerative disorders. Kiselev et al. (2000) uncovered the pathway by which activation of rhodopsin in Drosophila mediates apoptosis through a G protein-independent mechanism. They found that the process involves the formation of membrane complexes of phosphorylated, activated rhodopsin and its inhibitory protein arrestin, and subsequent clathrin-dependent endocytosis of these complexes into a cytoplasmic compartment. Although trafficking and degradation of several membrane proteins are regulated by ubiquitination catalyzed by E3 ubiquitin ligases, the connection of ubiquitination with regulation of mammalian G protein-coupled receptor function was unclear. Shenoy et al. (2001) demonstrated that agonist stimulation of endogenous or transfected beta-2 adrenergic receptors (ADRB2; 109690) led to rapid ubiquitination of both the receptors and the receptor regulatory protein, beta-arrestin. Moreover, proteasome inhibitors reduced receptor i ... More on the omim web site

Subscribe to this protein entry history

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 25, 2017: Additional information
No protein expression data in P. Mayeux work for ARRB2

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 107941 was added.

Beta-arrestin-2 (ARRB2)