UniProt Accession

 ARRB2_HUMAN; P32121; B4DLW0; B5B0C0; B7WPL3; D3DTK2; H0Y688; Q0Z8D3; Q2PP19; Q6ICT3; Q8N7Y2; Q9UEQ6 

Genbank Protein ID

 Z11501; AF106941; DQ664180; EU883572; AK097542; AK297181; CR450310; DQ314866; AC091153; CH471108; CH471108; BC007427; BC067368 

Genbank Nucleotide ID

 CAA77577.1; AAC99468.1; ABG47460.1; ACG60646.1; BAC05094.1; BAG59672.1; CAG29306.1; ABC40725.1; EAW90421.1; EAW90422.1; AAH07427.1; AAH67368.1 

Protein Name

 Beta-arrestin-2 

Protein Synonyms/Alias

 Arrestin beta-2 

Gene Name

 ARRB2 

Gene Synonyms/Alias

 ARB2; ARR2 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
78	VLGLSFRKDLFIATY	ubiquitination	[1, 2]
178	KVQFAPEKPGPQPSA	ubiquitination	[3]
230	NNSTKTVKKIKVSVR	acetylation	[4]
231	NSTKTVKKIKVSVRQ	acetylation	[4]
233	TKTVKKIKVSVRQYA	acetylation	[4]
293	RGLALDGKLKHEDTN	sumoylation	[5]
293	RGLALDGKLKHEDTN	ubiquitination	[6]
295	LALDGKLKHEDTNLA	sumoylation	[5]
308	LASSTIVKEGANKEV	ubiquitination	[3]
397	DFARLRLKGMKDDDY	sumoylation	[5]
397	DFARLRLKGMKDDDY	ubiquitination	[6]
400	RLRLKGMKDDDYDDQ	sumoylation	[5]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [3] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [4] Regulation of cellular metabolism by protein lysine acetylation.
 Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL.
 Science. 2010 Feb 19;327(5968):1000-4. [PMID: 20167786]
 [5] Small ubiquitin-like modifier modification of arrestin-3 regulates receptor trafficking.
 Wyatt D, Malik R, Vesecky AC, Marchese A.
 J Biol Chem. 2011 Feb 4;286(5):3884-93. [PMID: 21118812]
 [6] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961] 

Functional 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 others 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. 

Sequence Annotation

 REGION 240 409 Interaction with TRAF6.
 REGION 363 409 Interaction with AP2B1.
 MOTIF 385 395 [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif.
 MOD_RES 48 48 Phosphotyrosine (By similarity).
 MOD_RES 176 176 Hydroxyproline; by PHD2.
 MOD_RES 181 181 Hydroxyproline; by PHD2.
 MOD_RES 360 360 Phosphoserine (By similarity).
 MOD_RES 382 382 Phosphothreonine.  

Keyword

 Alternative splicing; Cell membrane; Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle; Hydroxylation; Membrane; Nucleus; Phosphoprotein; Protein transport; Reference proteome; Signal transduction inhibitor; Transport; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 409 AA 

Protein Sequence

Gene Ontology

 GO:0016323; C:basolateral plasma membrane; IEA:Compara.
 GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
 GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
 GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0005886; C:plasma membrane; IDA:UniProtKB.
 GO:0014069; C:postsynaptic density; IEA:Compara.
 GO:0045211; C:postsynaptic membrane; IEA:Compara.
 GO:0032947; F:protein complex scaffold; IDA:BHF-UCL.
 GO:0007628; P:adult walking behavior; IEA:Compara.
 GO:0007420; P:brain development; IEA:Compara.
 GO:0060326; P:cell chemotaxis; IMP:UniProtKB.
 GO:0002032; P:desensitization of G-protein coupled receptor protein signaling pathway by arrestin; IMP:UniProtKB.
 GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; IEA:Compara.
 GO:0042699; P:follicle-stimulating hormone signaling pathway; IEA:Compara.
 GO:0002031; P:G-protein coupled receptor internalization; IDA:UniProtKB.
 GO:0034260; P:negative regulation of GTPase activity; IEA:Compara.
 GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Compara.
 GO:0032695; P:negative regulation of interleukin-12 production; IEA:Compara.
 GO:0032715; P:negative regulation of interleukin-6 production; IEA:Compara.
 GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; IMP:UniProtKB.
 GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
 GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB.
 GO:0034392; P:negative regulation of smooth muscle cell apoptotic process; IEA:Compara.
 GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IEA:Compara.
 GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Compara.
 GO:0007219; P:Notch signaling pathway; TAS:Reactome.
 GO:0030168; P:platelet activation; TAS:Reactome.
 GO:0051928; P:positive regulation of calcium ion transport; IEA:Compara.
 GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
 GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Compara.
 GO:0051897; P:positive regulation of protein kinase B signaling cascade; IEA:Compara.
 GO:0031398; P:positive regulation of protein ubiquitination; IGI:BHF-UCL.
 GO:0002092; P:positive regulation of receptor internalization; IEA:Compara.
 GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; IEA:Compara.
 GO:0043161; P:proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
 GO:0015031; P:protein transport; IEA:UniProtKB-KW.
 GO:0016567; P:protein ubiquitination; IMP:UniProtKB.
 GO:0060765; P:regulation of androgen receptor signaling pathway; IDA:BHF-UCL.
 GO:0006366; P:transcription from RNA polymerase II promoter; IDA:UniProtKB.
 GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL. 

Interpro

 IPR000698; Arrestin.
 IPR011021; Arrestin-like_N.
 IPR014752; Arrestin_C.
 IPR011022; Arrestin_C-like.
 IPR017864; Arrestin_CS.
 IPR014753; Arrestin_N.
 IPR014756; Ig_E-set. 

Pfam

 PF02752; Arrestin_C
 PF00339; Arrestin_N 

SMART

 SM01017; Arrestin_C 

PROSITE

 PS00295; ARRESTINS 

PRINTS

 PR00309; ARRESTIN.