ID ARRB1_HUMAN Reviewed; 418 AA. AC P49407; B6V9G8; O75625; O75630; Q2PP20; Q9BTK8; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 05-MAR-2002, sequence version 2. DT 09-FEB-2010, entry version 88. DE RecName: Full=Beta-arrestin-1; DE AltName: Full=Arrestin beta-1; GN Name=ARRB1; Synonyms=ARR1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A AND 1B). RC TISSUE=Peripheral blood; RX MEDLINE=93252853; PubMed=8486659; RA Parruti G., Peracchia F., Sallese M., Ambrosini G., Masini M., RA Rotilio D., de Blasi A.; RT "Molecular analysis of human beta-arrestin-1: cloning, tissue RT distribution, and regulation of expression. Identification of two RT isoforms generated by alternative splicing."; RL J. Biol. Chem. 268:9753-9761(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A AND 1B). RC TISSUE=Brain; RA Yu Q.M., Zhou T.H., Cheng Z.J., Ma L., Pei G.; RT "Molecular cloning of two isoforms of human beta-arrestin 1."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1B). RC TISSUE=Lung; RA Kaighin V.A., Martin A.L., Aronstam R.S.; RT "Isolation of cDNA coding for Homo sapiens arrestin, beta 1 (ARRB1), RT transcript variant 2."; RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1A). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH CCR2 AND ADRBK1. RX PubMed=9501202; DOI=10.1073/pnas.95.6.2985; RA Aragay A.M., Mellado M., Frade J.M., Martin A.M., Jimenez-Sainz M.C., RA Martinez-A C., Mayor F. Jr.; RT "Monocyte chemoattractant protein-1-induced CCR2B receptor RT desensitization mediated by the G protein-coupled receptor kinase 2."; RL Proc. Natl. Acad. Sci. U.S.A. 95:2985-2990(1998). RN [8] RP MUTAGENESIS OF ARG-169. RX PubMed=10066734; DOI=10.1074/jbc.274.11.6831; RA Kovoor A., Celver J., Abdryashitov R.I., Chavkin C., Gurevich V.V.; RT "Targeted construction of phosphorylation-independent beta-arrestin RT mutants with constitutive activity in cells."; RL J. Biol. Chem. 274:6831-6834(1999). RN [9] RP INTERACTION WITH ADRB2, AND SUBCELLULAR LOCATION. RX PubMed=9924018; DOI=10.1126/science.283.5402.655; RA Luttrell L.M., Ferguson S.S.G., Daaka Y., Miller W.E., Maudsley S., RA Della Rocca G.J., Lin F.-T., Kawakatsu H., Owada K., Luttrell D.K., RA Caron M.G., Lefkowitz R.J.; RT "Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src RT protein kinase complexes."; RL Science 283:655-661(1999). RN [10] RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH ANTAGONIST-STIMULATED RP GPCRS. RX PubMed=10748214; DOI=10.1074/jbc.M910348199; RA Oakley R.H., Laporte S.A., Holt J.A., Caron M.G., Barak L.S.; RT "Differential affinities of visual arrestin, beta arrestin1, and beta RT arrestin2 for G protein-coupled receptors delineate two major classes RT of receptors."; RL J. Biol. Chem. 275:17201-17210(2000). RN [11] RP FUNCTION IN INTERNALIZATION OF C5AR1, SUBCELLULAR LOCATION, AND RP INTERACTION WITH C5AR1. RX PubMed=12464600; DOI=10.1074/jbc.M210120200; RA Braun L., Christophe T., Boulay F.; RT "Phosphorylation of key serine residues is required for RT internalization of the complement 5a (C5a) anaphylatoxin receptor via RT a beta-arrestin, dynamin, and clathrin-dependent pathway."; RL J. Biol. Chem. 278:4277-4285(2003). RN [12] RP FUNCTION IN UBIQUITINATION OF IGF1R, AND INTERACTION WITH IGF1R AND RP MDM2. RX PubMed=15878855; DOI=10.1074/jbc.M501129200; RA Girnita L., Shenoy S.K., Sehat B., Vasilcanu R., Girnita A., RA Lefkowitz R.J., Larsson O.; RT "{beta}-Arrestin is crucial for ubiquitination and down-regulation of RT the insulin-like growth factor-1 receptor by acting as adaptor for the RT MDM2 E3 ligase."; RL J. Biol. Chem. 280:24412-24419(2005). RN [13] RP FUNCTION IN AGTR1-MEDIATED ERK SIGNALING. RX PubMed=14711824; DOI=10.1074/jbc.C300443200; RA Ahn S., Wei H., Garrison T.R., Lefkowitz R.J.; RT "Reciprocal regulation of angiotensin receptor-activated extracellular RT signal-regulated kinases by beta-arrestins 1 and 2."; RL J. Biol. Chem. 279:7807-7811(2004). RN [14] RP NUCLEAR FUNCTION IN TRANSCRIPTIONAL REGULATION, SUBCELLULAR LOCATION, RP AND INTERACTION WITH CREB1. RX PubMed=16325578; DOI=10.1016/j.cell.2005.09.011; RA Kang J., Shi Y., Xiang B., Qu B., Su W., Zhu M., Zhang M., Bao G., RA Wang F., Zhang X., Yang R., Fan F., Chen X., Pei G., Ma L.; RT "A nuclear function of beta-arrestin1 in GPCR signaling: regulation of RT histone acetylation and gene transcription."; RL Cell 123:833-847(2005). RN [15] RP FUNCTION IN CYTOSKELETAL REARRANGEMENT, AND SUBCELLULAR LOCATION. RX PubMed=15611106; DOI=10.1074/jbc.M412924200; RA Barnes W.G., Reiter E., Violin J.D., Ren X.-R., Milligan G., RA Lefkowitz R.J.; RT "beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress RT fiber formation following receptor stimulation."; RL J. Biol. Chem. 280:8041-8050(2005). RN [16] RP FUNCTION IN IN INTERNALIZATION OF CCR5, AND INTERACTION WITH CCR5. RX PubMed=16144840; DOI=10.1074/jbc.M500535200; RA Huettenrauch F., Pollok-Kopp B., Oppermann M.; RT "G protein-coupled receptor kinases promote phosphorylation and beta- RT arrestin-mediated internalization of CCR5 homo- and hetero- RT oligomers."; RL J. Biol. Chem. 280:37503-37515(2005). RN [17] RP FUNCTION IN F2LR1-MEDIATED ERK SIGNALING, AND SUBCELLULAR LOCATION. RX PubMed=15475570; DOI=10.1124/mol.104.006072; RA Stalheim L., Ding Y., Gullapalli A., Paing M.M., Wolfe B.L., RA Morris D.R., Trejo J.; RT "Multiple independent functions of arrestins in the regulation of RT protease-activated receptor-2 signaling and trafficking."; RL Mol. Pharmacol. 67:78-87(2005). RN [18] RP FUNCTION IN AVPR2-MEDIATED ERK SIGNALING. RX PubMed=15671180; DOI=10.1073/pnas.0409534102; RA Ren X.-R., Reiter E., Ahn S., Kim J., Chen W., Lefkowitz R.J.; RT "Different G protein-coupled receptor kinases govern G protein and RT beta-arrestin-mediated signaling of V2 vasopressin receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 102:1448-1453(2005). RN [19] RP INTERACTION WITH AP2B1, AND MUTAGENESIS OF PHE-388; ASP-390 AND RP ARG-393. RX PubMed=16516836; DOI=10.1016/j.devcel.2006.01.016; RA Edeling M.A., Mishra S.K., Keyel P.A., Steinhauser A.L., Collins B.M., RA Roth R., Heuser J.E., Owen D.J., Traub L.M.; RT "Molecular switches involving the AP-2 beta2 appendage regulate RT endocytic cargo selection and clathrin coat assembly."; RL Dev. Cell 10:329-342(2006). RN [20] RP FUNCTION IN ADRB2-MEDIATED ERK SIGNALING, AND SUBCELLULAR LOCATION. RX PubMed=16280323; DOI=10.1074/jbc.M506576200; RA Shenoy S.K., Drake M.T., Nelson C.D., Houtz D.A., Xiao K., RA Madabushi S., Reiter E., Premont R.T., Lichtarge O., Lefkowitz R.J.; RT "beta-arrestin-dependent, G protein-independent ERK1/2 activation by RT the beta2 adrenergic receptor."; RL J. Biol. Chem. 281:1261-1273(2006). RN [21] RP FUNCTION IN PTH1R-MEDIATED ERK SIGNALING. RX PubMed=16492667; DOI=10.1074/jbc.M513380200; RA Gesty-Palmer D., Chen M., Reiter E., Ahn S., Nelson C.D., Wang S., RA Eckhardt A.E., Cowan C.L., Spurney R.F., Luttrell L.M., RA Lefkowitz R.J.; RT "Distinct beta-arrestin- and G protein-dependent pathways for RT parathyroid hormone receptor-stimulated ERK1/2 activation."; RL J. Biol. Chem. 281:10856-10864(2006). RN [22] RP FUNCTION IN INTERNALIZATION OF PTAFR, FUNCTION IN THE P38 MAPK RP SIGNALING PATHWAY, FUNCTION IN ACTIN BUNDLE FORMATION, SUBCELLULAR RP LOCATION, AND INTERACTION WITH PTAFR AND MAP2K3. RX PubMed=16709866; RA McLaughlin N.J., Banerjee A., Kelher M.R., Gamboni-Robertson F., RA Hamiel C., Sheppard F.R., Moore E.E., Silliman C.C.; RT "Platelet-activating factor-induced clathrin-mediated endocytosis RT requires beta-arrestin-1 recruitment and activation of the p38 MAPK RT signalosome at the plasma membrane for actin bundle formation."; RL J. Immunol. 176:7039-7050(2006). RN [23] RP FUNCTION IN TLR/IL-1 RECEPTOR SIGNALING, AND INTERACTION WITH TRAF6. RX PubMed=16378096; DOI=10.1038/ni1294; RA Wang Y., Tang Y., Teng L., Wu Y., Zhao X., Pei G.; RT "Association of beta-arrestin and TRAF6 negatively regulates Toll-like RT receptor-interleukin 1 receptor signaling."; RL Nat. Immunol. 7:139-147(2006). RN [24] RP INTERACTION WITH AP2B1. RX PubMed=17456551; DOI=10.1242/jcs.03444; RA Fessart D., Simaan M., Zimmerman B., Comeau J., Hamdan F.F., RA Wiseman P.W., Bouvier M., Laporte S.A.; RT "Src-dependent phosphorylation of beta2-adaptin dissociates the beta- RT arrestin-AP-2 complex."; RL J. Cell Sci. 120:1723-1732(2007). RN [25] RP FUNCTION IN BETA-ADRENERGIC RECEPTOR REGULATION. RX PubMed=18337459; DOI=10.1096/fj.07-102459; RA Deshpande D.A., Theriot B.S., Penn R.B., Walker J.K.; RT "Beta-arrestins specifically constrain beta2-adrenergic receptor RT signaling and function in airway smooth muscle."; RL FASEB J. 22:2134-2141(2008). RN [26] RP FUNCTION IN INTERNALIZATION OF OPRD1. RX PubMed=18419762; DOI=10.1111/j.1471-4159.2008.05431.x; RA Zhang X., Wang F., Chen X., Chen Y., Ma L.; RT "Post-endocytic fates of delta-opioid receptor are regulated by GRK2- RT mediated receptor phosphorylation and distinct beta-arrestin RT isoforms."; RL J. Neurochem. 106:781-792(2008). RN [27] RP IDENTIFICATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY. RA Colinge J., Superti-Furga G., Bennett K.L.; RL Submitted (OCT-2008) to UniProtKB. RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, AND MASS RP SPECTROMETRY. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., RA Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in RT a refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [29] RP FUNCTION IN INTERNALIZATION OF CCR2. RX PubMed=19643177; DOI=10.1016/j.cellsig.2009.07.010; RA Garcia Lopez M.A., Aguado Martinez A., Lamaze C., Martinez-Alonso C., RA Fischer T.; RT "Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and RT activation of ERK1/2."; RL Cell. Signal. 21:1748-1757(2009). RN [30] RP FUNCTION IN MIP-1-BETA-STIMULATED CHEMOTAXIS. RX PubMed=19620252; DOI=10.1189/jlb.0908551; RA Cheung R., Malik M., Ravyn V., Tomkowicz B., Ptasznik A., RA Collman R.G.; RT "An arrestin-dependent multi-kinase signaling complex mediates MIP- RT 1beta/CCL4 signaling and chemotaxis of primary human macrophages."; RL J. Leukoc. Biol. 86:833-845(2009). RN [31] RP UBIQUITINATION, DEUBIQUITINATION BY USP33, AND INTERACTION WITH USP33. RX PubMed=19363159; DOI=10.1073/pnas.0901083106; RA Shenoy S.K., Modi A.S., Shukla A.K., Xiao K., Berthouze M., Ahn S., RA Wilkinson K.D., Miller W.E., Lefkowitz R.J.; RT "Beta-arrestin-dependent signaling and trafficking of 7-transmembrane RT receptors is reciprocally regulated by the deubiquitinase USP33 and RT the E3 ligase Mdm2."; RL Proc. Natl. Acad. Sci. U.S.A. 106:6650-6655(2009). RN [32] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 383-402 IN COMPLEX WITH RP AP2B1. RX PubMed=16903783; DOI=10.1371/journal.pbio.0040262; RA Schmid E.M., Ford M.G.J., Burtey A., Praefcke G.J.K., Peak-Chew S.-Y., RA Mills I.G., Benmerah A., McMahon H.T.; RT "Role of the AP2 beta-appendage hub in recruiting partners for RT clathrin-coated vesicle assembly."; RL PLoS Biol. 4:E262-E262(2006). CC -!- FUNCTION: Functions in regulating agonist-mediated G-protein CC coupled receptor (GPCR) signaling by mediating both receptor CC desensitization and resensitization processes. During homologous CC desensitization, beta-arrestins bind to the GPRK-phosphorylated CC receptor and sterically preclude its coupling to the cognate G- CC protein; the binding appears to require additional receptor CC determinants exposed only in the active receptor conformation. The CC beta-arrestins target many receptors for internalization by acting CC as endocytic adapters (CLASPs, clathrin-associated sorting CC proteins) and recruiting the GPRCs to the adaptor protein 2 CC complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the CC extent of beta-arrestin involvement appears to vary significantly CC depending on the receptor, agonist and cell type. Internalized CC arrestin-receptor complexes traffic to intracellular endosomes, CC where they remain uncoupled from G-proteins. Two different modes CC of arrestin-mediated internalization occur. Class A receptors, CC like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta- CC arrestin at or near the plasma membrane and undergo rapid CC recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and CC TACR1 internalize as a complex with arrestin and traffic with it CC to endosomal vesicles, presumably as desensitized receptors, for CC extended periods of time. Receptor resensitization then requires CC that receptor-bound arrestin is removed so that the receptor can CC be dephosphorylated and returned to the plasma membrane. Involved CC in internalization of P2RY4 and UTP-stimulated internalization of CC P2RY2. Involved in phopshorylation-dependent internalization of CC OPRD1 ands subsequent recycling. Involved in the degradation of CC cAMP by recruiting cAMP phosphodiesterases to ligand-activated CC receptors. Beta-arrestins function as multivalent adapter proteins CC that can switch the GPCR from a G-protein signaling mode that CC transmits short-lived signals from the plasma membrane via small CC molecule second messengers and ion channels to a beta-arrestin CC signaling mode that transmits a distinct set of signals that are CC initiated as the receptor internalizes and transits the CC intracellular compartment. Acts as signaling scaffold for MAPK CC pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta- CC arrestin scaffold is largely excluded from the nucleus and CC confined to cytoplasmic locations such as endocytic vesicles, also CC called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 CC resulting in ERK activation. GPCRs for which the beta-arrestin- CC mediated signaling relies on both ARRB1 and ARRB2 (codependent CC regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the CC beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 CC and is inhibited by the other respective beta-arrestin form CC (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and CC AVPR2-mediated activation (reciprocal regulation). Is required for CC SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to CC internalized NK1R resulting in ERK1/2 activation, which is CC required for the antiapoptotic effects of SP. Is involved in CC proteinase-activated F2RL1-mediated ERK activity. Acts as CC signaling scaffold for the AKT1 pathway. Is involved in alpha- CC thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated CC AKT1 signaling leading to increased protection from apoptosis. CC Involved in activation of the p38 MAPK signaling pathway and in CC actin bundle formation. Involved in F2RL1-mediated cytoskeletal CC rearrangement and chemotaxis. Involved in AGTR1-mediated stress CC fiber formation by acting together with GNAQ to activate RHOA. CC Appears to function as signaling scaffold involved in regulation CC of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in CC attenuation of NF-kappa-B-dependent transcription in response to CC GPCR or cytokine stimulation by interacting with and stabilizing CC CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1- CC stimulated transcriptional regulation by translocating to CDKN1B CC and FOS promoter regions and recruiting EP300 resulting in CC acetylation of histone H4. Involved in regulation of LEF1 CC transcriptional activity via interaction with DVL1 and/or DVL2 CC Also involved in regulation of receptors others than GPCRs. CC Involved in Toll-like receptor and IL-1 receptor signaling through CC the interaction with TRAF6 which prevents TRAF6 autoubiquitination CC and oligomerization required for activation of NF-kappa-B and JUN. CC Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) CC (By similarity). CC -!- SUBUNIT: Monomer. Homodimer. Homooligomer; the self-association is CC mediated by InsP6-binding. Heterooligomer with ARRB2; the CC association is mediated by InsP6-binding. Interacts with ADRB2 CC (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts CC with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 CC (dephosphorylated at 'Tyr-737'); phosphorylation of AP2B1 at 'Tyr- CC 737' disrupts the interaction. Interacts (dephosphorylated at Ser- CC 412) with CLTC. Interacts with CCR2 and ADRBK1. Interacts with CC CRR5. Interacts with PTAFR (phosphorylated on serine residues). CC Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts CC with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. CC Interacts with PDE4D. Interacts with SRC (via the SH3 domain and CC the protein kinase domain); the interaction is independent of the CC phosphorylation state of SRC C-terminus. Interacts with TACR1. CC Interacts with RAF1. Interacts with CHUK, IKBKB and MAP3K14. CC Interacts with DVL1; the interaction is enhanced by CC phosphorylation of DVL1. Interacts with DVL2; the interaction is CC enhanced by phosphorylation of DVL2. Interacts with IGF1R. CC Associates with MAP kinase p38. Part of a MAPK signaling complex CC consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 CC (activated). Part of a MAPK signaling complex consisting of F2RL1, CC ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated) (By CC similarity). CC -!- INTERACTION: CC O00203:AP3B1; NbExp=1; IntAct=EBI-743313, EBI-1044383; CC P36575:ARR3; NbExp=1; IntAct=EBI-743313, EBI-718116; CC P32121:ARRB2; NbExp=1; IntAct=EBI-743313, EBI-714559; CC Q14137:BOP1; NbExp=1; IntAct=EBI-743313, EBI-1050828; CC P62158:CALM1; NbExp=1; IntAct=EBI-743313, EBI-397435; CC Q16627:CCL14; NbExp=1; IntAct=EBI-743313, EBI-1046947; CC Q96DG6:CMBL; NbExp=1; IntAct=EBI-743313, EBI-1044268; CC P68400:CSNK2A1; NbExp=1; IntAct=EBI-743313, EBI-347804; CC Q96GQ7:DDX27; NbExp=1; IntAct=EBI-743313, EBI-722051; CC P06396:GSN; NbExp=1; IntAct=EBI-743313, EBI-351506; CC Q7Z4V5:HDGFRP2; NbExp=1; IntAct=EBI-743313, EBI-1049136; CC P11142:HSPA8; NbExp=1; IntAct=EBI-743313, EBI-351896; CC P50053:KHK; NbExp=1; IntAct=EBI-743313, EBI-1053974; CC O00505:KPNA3; NbExp=1; IntAct=EBI-743313, EBI-358297; CC P53779:MAPK10; NbExp=1; IntAct=EBI-743313, EBI-713543; CC Q00987:MDM2; NbExp=1; IntAct=EBI-743313, EBI-389668; CC P19338:NCL; NbExp=1; IntAct=EBI-743313, EBI-352553; CC P25963:NFKBIA; NbExp=1; IntAct=EBI-743313, EBI-307386; CC Q14978:NOLC1; NbExp=2; IntAct=EBI-743313, EBI-396155; CC O00541:PES1; NbExp=1; IntAct=EBI-743313, EBI-1053271; CC P14618:PKM2; NbExp=1; IntAct=EBI-743313, EBI-353408; CC P35813:PPM1A; NbExp=1; IntAct=EBI-743313, EBI-989143; CC O75688:PPM1B; NbExp=1; IntAct=EBI-743313, EBI-1047039; CC Q13523:PRPF4B; NbExp=1; IntAct=EBI-743313, EBI-395940; CC Q6DKI1:RPL7L1; NbExp=1; IntAct=EBI-743313, EBI-1052408; CC Q92541:RTF1; NbExp=1; IntAct=EBI-743313, EBI-1055239; CC P06702:S100A9; NbExp=1; IntAct=EBI-743313, EBI-1055001; CC Q15208:STK38; NbExp=1; IntAct=EBI-743313, EBI-458376; CC Q13428:TCOF1; NbExp=2; IntAct=EBI-743313, EBI-396105; CC Q9Y4K3:TRAF6; NbExp=1; IntAct=EBI-743313, EBI-359276; CC P27348:YWHAQ; NbExp=1; IntAct=EBI-743313, EBI-359854; CC P25490:YY1; NbExp=2; IntAct=EBI-743313, EBI-765538; CC O95218:ZRANB2; NbExp=2; IntAct=EBI-743313, EBI-1051583; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane. Membrane, CC clathrin-coated pit (Probable). Cell projection, pseudopodium (By CC similarity). Cytoplasmic vesicle. Note=Translocates to the plasma CC membrane and colocalizes with antagonist-stimulated GPCRs. The CC monomeric form is predominantly located in the nucleus. The CC oligomeric form is located in the cytoplasm. Translocates to the CC nucleus upon stimulation of OPRD1 (By similarity). CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1A; CC IsoId=P49407-1; Sequence=Displayed; CC Name=1B; CC IsoId=P49407-2; Sequence=VSP_000322; CC -!- DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates CC interaction the AP-2 complex subunit AP2B1 (By similarity). CC Binding to phosphorylated GPCRs induces a conformationanl change CC that exposes the motif to the surface. CC -!- DOMAIN: The N-terminus binds InsP6 with low affinity (By CC similarity). CC -!- DOMAIN: The C-terminus binds InsP6 with high affinity (By CC similarity). CC -!- PTM: Constitutively phosphorylated at Ser-412 in the cytoplasm. At CC the plasma membrane, is rapidly dephosphorylated, a process that CC is required for clathrin binding and ADRB2 endocytosis but not for CC ADRB2 binding and desensitization. Once internalized, is CC rephosphorylated. CC -!- PTM: The ubiquitination status appears to regulate the formation CC and trafficking of beta-arrestin-GPCR complexes and signaling. CC Ubiquitination appears to occur GPCR-specific. Ubiquitinated by CC MDM2; the ubiquitination is required for rapid internalization of CC ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a CC dissociation of the beta-arrestin-GPCR complex. Stimulation of a CC class A GPCR, such as ADRB2, induces transient ubiquitination and CC subsequently promotes association with USP33. CC -!- SIMILARITY: Belongs to the arrestin family. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Arrestin entry; CC URL="http://en.wikipedia.org/wiki/Arrestin"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L04685; AAA35559.1; -; mRNA. DR EMBL; L04685; AAA35558.1; -; mRNA. DR EMBL; AF084040; AAC33295.1; -; mRNA. DR EMBL; AF084940; AAC34123.1; -; mRNA. DR EMBL; DQ314865; ABC40724.1; -; Genomic_DNA. DR EMBL; FJ348262; ACI96306.1; -; mRNA. DR EMBL; CH471076; EAW74962.1; -; Genomic_DNA. DR EMBL; BC003636; AAH03636.1; -; mRNA. DR IPI; IPI00293857; -. DR IPI; IPI00336017; -. DR PIR; B46682; B46682. DR RefSeq; NP_004032.2; -. DR RefSeq; NP_064647.1; -. DR UniGene; Hs.503284; -. DR UniGene; Hs.625320; -. DR PDB; 2IV8; X-ray; 2.80 A; P/Q=383-402. DR PDBsum; 2IV8; -. DR SMR; P49407; 5-393. DR DIP; DIP-29979N; -. DR IntAct; P49407; 193. DR STRING; P49407; -. DR PhosphoSite; P49407; -. DR OGP; P49407; -. DR PRIDE; P49407; -. DR Ensembl; ENST00000393505; ENSP00000377141; ENSG00000137486; Homo sapiens. DR GeneID; 408; -. DR KEGG; hsa:408; -. DR UCSC; uc001owe.1; human. DR UCSC; uc001owf.1; human. DR CTD; 408; -. DR GeneCards; GC11M074654; -. DR H-InvDB; HIX0009944; -. DR HGNC; HGNC:711; ARRB1. DR HPA; CAB003763; -. DR MIM; 107940; gene. DR PharmGKB; PA59; -. DR eggNOG; prNOG15451; -. DR HOGENOM; HBG315972; -. DR HOVERGEN; P49407; -. DR InParanoid; P49407; -. DR OMA; FVDHIDL; -. DR OrthoDB; EOG92NMJT; -. DR Pathway_Interaction_DB; arf6cyclingpathway; Arf6 signaling events. DR Reactome; REACT_11123; Membrane Trafficking. DR NextBio; 1713; -. DR ArrayExpress; P49407; -. DR Bgee; P49407; -. DR CleanEx; HS_ARRB1; -. DR Genevestigator; P49407; -. DR GermOnline; ENSG00000137486; Homo sapiens. DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell. DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell. DR GO; GO:0005624; C:membrane fraction; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0031143; C:pseudopodium; IEA:UniProtKB-SubCell. DR GO; GO:0005625; C:soluble fraction; TAS:UniProtKB. DR GO; GO:0004857; F:enzyme inhibitor activity; TAS:ProtInc. DR GO; GO:0005515; F:protein binding; IPI:UniProtKB. DR GO; GO:0016044; P:membrane organization; EXP:Reactome. DR GO; GO:0009968; P:negative regulation of signal transduction; IEA:UniProtKB-KW. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; EXP:Reactome. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0045449; P:regulation of transcription; IEA:UniProtKB-KW. DR GO; GO:0007600; P:sensory perception; IEA:InterPro. DR GO; GO:0006350; P:transcription; IEA:UniProtKB-KW. DR InterPro; IPR000698; Arrestin. DR InterPro; IPR011022; Arrestin-like_C. DR InterPro; IPR011021; Arrestin-like_N. DR InterPro; IPR014752; Arrestin_C. DR InterPro; IPR017864; Arrestin_CS. DR InterPro; IPR014753; Arrestin_N. DR InterPro; IPR014756; Ig_E-set. DR Gene3D; G3DSA:2.60.40.640; Arrestin_C; 1. DR Gene3D; G3DSA:2.60.40.840; Arrestin_N; 1. DR PANTHER; PTHR11792; Arrestin; 1. DR Pfam; PF02752; Arrestin_C; 1. DR Pfam; PF00339; Arrestin_N; 1. DR PRINTS; PR00309; ARRESTIN. DR PROSITE; PS00295; ARRESTINS; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle; KW Membrane; Nucleus; Phosphoprotein; Protein transport; KW Signal transduction inhibitor; Transcription; KW Transcription regulation; Transport; Ubl conjugation. FT CHAIN 1 418 Beta-arrestin-1. FT /FTId=PRO_0000205194. FT REGION 1 163 Interaction with SRC (By similarity). FT REGION 45 86 Interaction with CHRM2 (By similarity). FT REGION 318 418 Interaction with TRAF6. FT MOTIF 385 395 [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif. FT BINDING 250 250 Inositol hexakisphosphate (By FT similarity). FT BINDING 255 255 Inositol hexakisphosphate (By FT similarity). FT BINDING 324 324 Inositol hexakisphosphate (By FT similarity). FT BINDING 326 326 Inositol hexakisphosphate (By FT similarity). FT MOD_RES 47 47 Phosphotyrosine (By similarity). FT MOD_RES 410 410 Phosphothreonine (By similarity). FT MOD_RES 412 412 Phosphoserine. FT VAR_SEQ 334 341 Missing (in isoform 1B). FT /FTId=VSP_000322. FT MUTAGEN 169 169 R->E: Constitutive active; enables FT phosphorylation-independent binding to FT GPCRs. FT MUTAGEN 388 388 F->A: Abolishes interaction with AP2B1. FT MUTAGEN 390 390 D->P: Abolishes interaction with AP2B1. FT MUTAGEN 393 393 R->A: Abolishes interaction with AP2B1. FT CONFLICT 146 146 V -> A (in Ref. 1; AAA35559/AAA35558). FT CONFLICT 165 165 R -> G (in Ref. 1; AAA35559/AAA35558). FT CONFLICT 229 229 K -> E (in Ref. 1; AAA35559/AAA35558). FT CONFLICT 329 329 V -> E (in Ref. 2; AAC33295/AAC34123). FT CONFLICT 400 400 K -> E (in Ref. 1; AAA35559/AAA35558). FT CONFLICT 414 414 Q -> R (in Ref. 1; AAA35559/AAA35558). FT CONFLICT 417 417 N -> D (in Ref. 1; AAA35559/AAA35558). FT HELIX 384 394 SQ SEQUENCE 418 AA; 47066 MW; 0A3C135092338D10 CRC64; MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPPA PEDKKPLTRL QERLIKKLGE HAYPFTFEIP PNLPCSVTLQ PGPEDTGKAC GVDYEVKAFC AENLEEKIHK RNSVRLVIRK VQYAPERPGP QPTAETTRQF LMSDKPLHLE ASLDKEIYYH GEPISVNVHV TNNTNKTVKK IKISVRQYAD ICLFNTAQYK CPVAMEEADD TVAPSSTFCK VYTLTPFLAN NREKRGLALD GKLKHEDTNL ASSTLLREGA NREILGIIVS YKVKVKLVVS RGGLLGDLAS SDVAVELPFT LMHPKPKEEP PHREVPENET PVDTNLIELD TNDDDIVFED FARQRLKGMK DDKEEEEDGT GSPQLNNR //