ID ARRB2_HUMAN Reviewed; 409 AA. AC P32121; B4DLW0; B5B0C0; B7WPL3; D3DTK2; H0Y688; Q0Z8D3; Q2PP19; Q6ICT3; AC Q8N7Y2; Q9UEQ6; DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot. DT 05-MAR-2002, sequence version 2. DT 27-MAR-2024, entry version 220. DE RecName: Full=Beta-arrestin-2; DE AltName: Full=Arrestin beta-2; DE AltName: Full=Non-visual arrestin-3 {ECO:0000303|PubMed:23886940}; GN Name=ARRB2; Synonyms=ARB2, ARR2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Thyroid; RX PubMed=1587386; DOI=10.1016/0303-7207(92)90038-8; RA Rapoport B., Kaufman K.D., Chamenbalk G.D.; RT "Cloning of a member of the arrestin family from a human thyroid cDNA RT library."; RL Mol. Cell. Endocrinol. 84:R39-R43(1992). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Brain; RA Yu Q.M., Zhou T.H., Wu Y.L., Cheng Z.J., Ma L., Pei G.; RT "G-protein coupled receptor interaction with beta-arrestin 2 through RT specific agonist stimulation."; RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Sanchez-Laorden B.L., Jimenez-Cervantes C., Garcia-Borron J.C.; RT "A new splice-variant of beta-arrestin 2 is involved in agonist-induced RT MC1R endocytosis."; RL Submitted (MAY-2006) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Lung; RA Kaighin V.A., Martin A.L., Aronstam R.S.; RT "Isolation of cDNA coding for human arrestin, beta 2 (ARRB2), transcript RT variant 1."; RL Submitted (JUL-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4). RC TISSUE=Brain, and Testis; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Muscle, and Pancreas; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH GPCRS. RX PubMed=9346876; DOI=10.1074/jbc.272.44.27497; RA Barak L.S., Ferguson S.S.G., Zhang J., Caron M.G.; RT "A beta-arrestin/green fluorescent protein biosensor for detecting G RT protein-coupled receptor activation."; RL J. Biol. Chem. 272:27497-27500(1997). RN [12] RP FUNCTION IN INTERNALIZATION OF CXCR4, INTERACTION WITH CXCR4, AND RP MUTAGENESIS OF VAL-54. RX PubMed=10644702; DOI=10.1074/jbc.275.4.2479; RA Cheng Z.J., Zhao J., Sun Y., Hu W., Wu Y.L., Cen B., Wu G.-X., Pei G.; RT "beta-arrestin differentially regulates the chemokine receptor CXCR4- RT mediated signaling and receptor internalization, and this implicates RT multiple interaction sites between beta-arrestin and CXCR4."; RL J. Biol. Chem. 275:2479-2485(2000). RN [13] RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH ANTAGONIST-STIMULATED 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 of RT receptors."; RL J. Biol. Chem. 275:17201-17210(2000). RN [14] RP INTERACTION WITH HCK AND CXCR1. RX PubMed=10973280; DOI=10.1038/79767; RA Barlic J., Andrews J.D., Kelvin A.A., Bosinger S.E., DeVries M.E., Xu L., RA Dobransky T., Feldman R.D., Ferguson S.S., Kelvin D.J.; RT "Regulation of tyrosine kinase activation and granule release through beta- RT arrestin by CXCRI."; RL Nat. Immunol. 1:227-233(2000). RN [15] RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH ANTAGONIST-STIMULATED GPCRS. RX PubMed=11279203; DOI=10.1074/jbc.m101450200; RA Oakley R.H., Laporte S.A., Holt J.A., Barak L.S., Caron M.G.; RT "Molecular determinants underlying the formation of stable intracellular G RT protein-coupled receptor-beta-arrestin complexes after receptor RT endocytosis*."; RL J. Biol. Chem. 276:19452-19460(2001). RN [16] RP FUNCTION IN INTERNALIZATION OF ADBR2, PHOSPHORYLATION AT THR-382, RP INTERACTION WITH AP2B1; CLATHRIN AND SRC, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF THR-382. RX PubMed=11877451; DOI=10.1074/jbc.m201379200; RA Kim Y.-M., Barak L.S., Caron M.G., Benovic J.L.; RT "Regulation of arrestin-3 phosphorylation by casein kinase II."; RL J. Biol. Chem. 277:16837-16846(2002). RN [17] RP FUNCTION IN TP53-MEDIATED APOPTOSIS, AND INTERACTION WITH MDM2. RX PubMed=12488444; DOI=10.1074/jbc.m210350200; RA Wang P., Gao H., Ni Y., Wang B., Wu Y., Ji L., Qin L., Ma L., Pei G.; RT "Beta-arrestin 2 functions as a G-protein-coupled receptor-activated RT regulator of oncoprotein Mdm2."; RL J. Biol. Chem. 278:6363-6370(2003). RN [18] RP FUNCTION IN DESENSITIZATION OF ADRB2, FUNCTION IN INTERNALIZATION OF ADRB2, RP FUNCTION IN INTERNALIZATION OF AGTR1, AND FUNCTION IN AGTR1-MEDIATED ERK RP SIGNALING. RX PubMed=12582207; DOI=10.1073/pnas.262789099; RA Ahn S., Nelson C.D., Garrison T.R., Miller W.E., Lefkowitz R.J.; RT "Desensitization, internalization, and signaling functions of beta- RT arrestins demonstrated by RNA interference."; RL Proc. Natl. Acad. Sci. U.S.A. 100:1740-1744(2003). RN [19] RP FUNCTION IN AGTR1-MEDIATED ERK SIGNALING. RX PubMed=12949261; DOI=10.1073/pnas.1834556100; RA Wei H., Ahn S., Shenoy S.K., Karnik S.S., Hunyady L., Luttrell L.M., RA Lefkowitz R.J.; RT "Independent beta-arrestin 2 and G protein-mediated pathways for RT angiotensin II activation of extracellular signal-regulated kinases 1 and RT 2."; RL Proc. Natl. Acad. Sci. U.S.A. 100:10782-10787(2003). RN [20] RP FUNCTION IN ENDOCYTOSIS OF TGFBR2 AND TGFBR3, FUNCTION IN TGF-BETA RP SIGNALING, AND SUBCELLULAR LOCATION. RX PubMed=12958365; DOI=10.1126/science.1083195; RA Chen W., Kirkbride K.C., How T., Nelson C.D., Mo J., Frederick J.P., RA Wang X.-F., Lefkowitz R.J., Blobe G.C.; RT "Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and RT down-regulation of its signaling."; RL Science 301:1394-1397(2003). RN [21] 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 [22] RP FUNCTION IN CCR7-MEDIATED ERK SIGNALING. RX PubMed=15054093; DOI=10.1074/jbc.m402125200; RA Kohout T.A., Nicholas S.L., Perry S.J., Reinhart G., Junger S., RA Struthers R.S.; RT "Differential desensitization, receptor phosphorylation, beta-arrestin RT recruitment, and ERK1/2 activation by the two endogenous ligands for the CC RT chemokine receptor 7."; RL J. Biol. Chem. 279:23214-23222(2004). RN [23] RP FUNCTION IN AGTR1-MEDIATED ERK SIGNALING. RX PubMed=15205453; DOI=10.1074/jbc.m405878200; RA Ahn S., Shenoy S.K., Wei H., Lefkowitz R.J.; RT "Differential kinetic and spatial patterns of beta-arrestin and G protein- RT mediated ERK activation by the angiotensin II receptor."; RL J. Biol. Chem. 279:35518-35525(2004). RN [24] RP FUNCTION IN REGULATION OF NF-KAPPA-B, SUBCELLULAR LOCATION, AND INTERACTION RP WITH CHUK AND RELA. RX PubMed=15125834; DOI=10.1016/s1097-2765(04)00216-3; RA Gao H., Sun Y., Wu Y., Luan B., Wang Y., Qu B., Pei G.; RT "Identification of beta-arrestin2 as a G protein-coupled receptor- RT stimulated regulator of NF-kappaB pathways."; RL Mol. Cell 14:303-317(2004). RN [25] RP FUNCTION IN INTERNALIZATION OF SMO. RX PubMed=15618519; DOI=10.1126/science.1104135; RA Chen W., Ren X.R., Nelson C.D., Barak L.S., Chen J.K., Beachy P.A., RA de Sauvage F., Lefkowitz R.J.; RT "Activity-dependent internalization of smoothened mediated by beta-arrestin RT 2 and GRK2."; RL Science 306:2257-2260(2004). RN [26] RP FUNCTION IN UBIQUITINATION OF IGF1R, AND INTERACTION WITH IGF1R AND 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 the RT insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 RT ligase."; RL J. Biol. Chem. 280:24412-24419(2005). RN [27] RP INTERACTION WITH DUSP16, AND SUBCELLULAR LOCATION. RX PubMed=15888437; DOI=10.1074/jbc.m501926200; RA Willoughby E.A., Collins M.K.; RT "Dynamic interaction between the dual specificity phosphatase MKP7 and the RT JNK3 scaffold protein beta-arrestin 2."; RL J. Biol. Chem. 280:25651-25658(2005). RN [28] RP FUNCTION 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-oligomers."; RL J. Biol. Chem. 280:37503-37515(2005). RN [29] RP FUNCTION IN F2LR1-MEDIATED ERK SIGNALING. RX PubMed=15475570; DOI=10.1124/mol.104.006072; RA Stalheim L., Ding Y., Gullapalli A., Paing M.M., Wolfe B.L., Morris D.R., RA Trejo J.; RT "Multiple independent functions of arrestins in the regulation of protease- RT activated receptor-2 signaling and trafficking."; RL Mol. Pharmacol. 67:78-87(2005). RN [30] RP FUNCTION IN AGTR1-MEDIATED CHEMOTAXIS. RX PubMed=15635042; DOI=10.1124/mol.104.006270; RA Hunton D.L., Barnes W.G., Kim J., Ren X.-R., Violin J.D., Reiter E., RA Milligan G., Patel D.D., Lefkowitz R.J.; RT "Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway RT of chemotaxis."; RL Mol. Pharmacol. 67:1229-1236(2005). RN [31] 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 beta- RT arrestin-mediated signaling of V2 vasopressin receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 102:1448-1453(2005). RN [32] RP FUNCTION IN ENDOCYTOSIS OF SLC9A5, AND INTERACTION WITH SLC9A5. RX PubMed=15699339; DOI=10.1073/pnas.0407444102; RA Szabo E.Z., Numata M., Lukashova V., Iannuzzi P., Orlowski J.; RT "beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ RT exchanger NHE5 isoform."; RL Proc. Natl. Acad. Sci. U.S.A. 102:2790-2795(2005). RN [33] RP INTERACTION WITH AP2B1. 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 endocytic RT cargo selection and clathrin coat assembly."; RL Dev. Cell 10:329-342(2006). RN [34] RP FUNCTION IN ADRB2-MEDIATED ERK SIGNALING. RX PubMed=16280323; DOI=10.1074/jbc.m506576200; RA Shenoy S.K., Drake M.T., Nelson C.D., Houtz D.A., Xiao K., Madabushi S., RA Reiter E., Premont R.T., Lichtarge O., Lefkowitz R.J.; RT "beta-arrestin-dependent, G protein-independent ERK1/2 activation by the RT beta2 adrenergic receptor."; RL J. Biol. Chem. 281:1261-1273(2006). RN [35] RP INTERACTION WITH HTR2C. RX PubMed=16319069; DOI=10.1074/jbc.m508074200; RA Marion S., Oakley R.H., Kim K.-M., Caron M.G., Barak L.S.; RT "A beta-arrestin binding determinant common to the second intracellular RT loops of rhodopsin family G protein-coupled receptors."; RL J. Biol. Chem. 281:2932-2938(2006). RN [36] 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., Lefkowitz R.J.; RT "Distinct beta-arrestin- and G protein-dependent pathways for parathyroid RT hormone receptor-stimulated ERK1/2 activation."; RL J. Biol. Chem. 281:10856-10864(2006). RN [37] RP FUNCTION IN THE NUCLEUS OF SPERMATOZOA, SUBCELLULAR LOCATION, AND RP INTERACTION WITH DHX8; GAPDHS; H2AFX; KIF14 AND RCC1. RX PubMed=16820410; DOI=10.1242/jcs.03046; RA Neuhaus E.M., Mashukova A., Barbour J., Wolters D., Hatt H.; RT "Novel function of beta-arrestin2 in the nucleus of mature spermatozoa."; RL J. Cell Sci. 119:3047-3056(2006). RN [38] 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 [39] RP INTERACTION WITH GPR143. RX PubMed=16524428; DOI=10.1111/j.1600-0749.2006.00292.x; RA Innamorati G., Piccirillo R., Bagnato P., Palmisano I., Schiaffino M.V.; RT "The melanosomal/lysosomal protein OA1 has properties of a G protein- RT coupled receptor."; RL Pigment Cell Res. 19:125-135(2006). RN [40] RP FUNCTION IN INTERNALIZATION OF ENG, FUNCTION IN TGF-BETA-MEDIATED ERK RP SIGNALING, SUBCELLULAR LOCATION, AND INTERACTION WITH ENG. RX PubMed=17540773; DOI=10.1074/jbc.m700176200; RA Lee N.Y., Blobe G.C.; RT "The interaction of endoglin with beta-arrestin2 regulates transforming RT growth factor-beta-mediated ERK activation and migration in endothelial RT cells."; RL J. Biol. Chem. 282:21507-21517(2007). RN [41] RP FUNCTION IN INTERNALIZATION OF OPRD1, AND FUNCTION IN DEGRADATION 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 isoforms."; RL J. Neurochem. 106:781-792(2008). RN [42] RP FUNCTION IN REGULATION OF INNATE IMMUNE RESPONSE, AND INTERACTION WITH RP KIR2DL1; KIR2DL3 AND KIR2DL4. RX PubMed=18604210; DOI=10.1038/ni.1635; RA Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H., Sun L., RA Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W., Pei G., Ge B.-X.; RT "An essential function for beta-arrestin 2 in the inhibitory signaling of RT natural killer cells."; RL Nat. Immunol. 9:898-907(2008). RN [43] RP FUNCTION IN TGFBR3-MEDIATED NF-KAPPA-B REGULATION. RX PubMed=19325136; DOI=10.1093/carcin/bgp071; RA You H.J., How T., Blobe G.C.; RT "The type III transforming growth factor-beta receptor negatively regulates RT nuclear factor kappa B signaling through its interaction with beta- RT arrestin2."; RL Carcinogenesis 30:1281-1287(2009). RN [44] 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 [45] RP INTERACTION WITH MAP2K4/MKK4. RX PubMed=19782076; DOI=10.1016/j.febslet.2009.09.035; RA Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C., RA Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.; RT "A scanning peptide array approach uncovers association sites within the RT JNK/beta arrestin signalling complex."; RL FEBS Lett. 583:3310-3316(2009). RN [46] 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., 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 [47] 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 the E3 RT ligase Mdm2."; RL Proc. Natl. Acad. Sci. U.S.A. 106:6650-6655(2009). RN [48] RP INTERACTION WITH CXCR4, AND FUNCTION. RX PubMed=20048153; DOI=10.1074/jbc.m109.091173; RA Busillo J.M., Armando S., Sengupta R., Meucci O., Bouvier M., Benovic J.L.; RT "Site-specific phosphorylation of CXCR4 is dynamically regulated by RT multiple kinases and results in differential modulation of CXCR4 RT signaling."; RL J. Biol. Chem. 285:7805-7817(2010). RN [49] RP HYDROXYLATION AT PRO-176 AND PRO-181. RX PubMed=21255264; DOI=10.1111/j.1582-4934.2011.01268.x; RA Yan B., Huo Z., Liu Y., Lin X., Li J., Peng L., Zhao H., Zhou Z.N., RA Liang X., Liu Y., Zhu W., Liang D., Li L., Sun Y., Cui J., Chen Y.H.; RT "Prolyl hydroxylase 2: a novel regulator of beta2 -adrenoceptor RT internalization."; RL J. Cell. Mol. Med. 15:2712-2722(2011). RN [50] RP INTERACTION WITH ACKR3. RX PubMed=22300987; DOI=10.1016/j.biocel.2012.01.007; RA Ray P., Mihalko L.A., Coggins N.L., Moudgil P., Ehrlich A., Luker K.E., RA Luker G.D.; RT "Carboxy-terminus of CXCR7 regulates receptor localization and function."; RL Int. J. Biochem. Cell Biol. 44:669-678(2012). RN [51] RP FUNCTION, AND INTERACTION WITH FFAR4. RX PubMed=22282525; DOI=10.1124/mol.111.077388; RA Watson S.J., Brown A.J., Holliday N.D.; RT "Differential signaling by splice variants of the human free fatty acid RT receptor GPR120."; RL Mol. Pharmacol. 81:631-642(2012). RN [52] RP FUNCTION, AND INTERACTION WITH ACKR3. RX PubMed=22457824; DOI=10.1371/journal.pone.0034192; RA Canals M., Scholten D.J., de Munnik S., Han M.K., Smit M.J., Leurs R.; RT "Ubiquitination of CXCR7 controls receptor trafficking."; RL PLoS ONE 7:E34192-E34192(2012). RN [53] RP FUNCTION, AND INTERACTION WITH NLRP3. RX PubMed=23809162; DOI=10.1016/j.immuni.2013.05.015; RA Yan Y., Jiang W., Spinetti T., Tardivel A., Castillo R., Bourquin C., RA Guarda G., Tian Z., Tschopp J., Zhou R.; RT "Omega-3 fatty acids prevent inflammation and metabolic disorder through RT inhibition of NLRP3 inflammasome activation."; RL Immunity 38:1154-1163(2013). RN [54] RP SUBCELLULAR LOCATION, AND INTERACTION WITH ACKR4. RX PubMed=23341447; DOI=10.1074/jbc.m112.406108; RA Watts A.O., Verkaar F., van der Lee M.M., Timmerman C.A., Kuijer M., RA van Offenbeek J., van Lith L.H., Smit M.J., Leurs R., Zaman G.J., RA Vischer H.F.; RT "Beta-arrestin recruitment and G protein signaling by the atypical human RT chemokine decoy receptor CCX-CKR."; RL J. Biol. Chem. 288:7169-7181(2013). RN [55] RP INTERACTION WITH ARRDC1. RX PubMed=23886940; DOI=10.1242/jcs.130500; RA Puca L., Chastagner P., Meas-Yedid V., Israel A., Brou C.; RT "Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch RT degradation in mammals."; RL J. Cell Sci. 126:4457-4468(2013). RN [56] RP FUNCTION, AND DEUBIQUITINATION BY USP20 AND TRAF6. RX PubMed=26839314; DOI=10.1074/jbc.m115.687129; RA Jean-Charles P.Y., Zhang L., Wu J.H., Han S.O., Brian L., Freedman N.J., RA Shenoy S.K.; RT "Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of beta- RT Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor kappaB (NFkappaB) RT Activation."; RL J. Biol. Chem. 291:7450-7464(2016). RN [57] RP INTERACTION WITH GPR61; GPR62 AND GPR135. RX PubMed=28827538; DOI=10.1038/s41598-017-08996-7; RA Oishi A., Karamitri A., Gerbier R., Lahuna O., Ahmad R., Jockers R.; RT "Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor RT reciprocally modulate their signaling functions."; RL Sci. Rep. 7:8990-8990(2017). RN [58] RP INTERACTION WITH GPR84. RX PubMed=35427647; DOI=10.1016/j.jbc.2022.101932; RA Marsango S., Ward R.J., Jenkins L., Butcher A.J., Al Mahmud Z., Dwomoh L., RA Nagel F., Schulz S., Tikhonova I.G., Tobin A.B., Milligan G.; RT "Selective phosphorylation of threonine residues defines GPR84-arrestin RT interactions of biased ligands."; RL J. Biol. Chem. 298:101932-101932(2022). RN [59] RP INTERACTION WITH GPR35. RX PubMed=37660910; DOI=10.1016/j.jbc.2023.105218; RA Ganguly A., Quon T., Jenkins L., Joseph B., Al-Awar R., Chevigne A., RA Tobin A.B., Uehling D.E., Hoffmann C., Drube J., Milligan G.; RT "G protein-receptor kinases 5/6 are the key regulators of G protein-coupled RT receptor 35-arrestin interactions."; RL J. Biol. Chem. 0:0-0(2023). CC -!- FUNCTION: Functions in regulating agonist-mediated G-protein coupled CC receptor (GPCR) signaling by mediating both receptor desensitization CC and resensitization processes. During homologous desensitization, beta- CC arrestins bind to the GPRK-phosphorylated receptor and sterically CC preclude its coupling to the cognate G-protein; the binding appears to CC require additional receptor determinants exposed only in the active CC receptor conformation. The beta-arrestins target many receptors for CC internalization by acting as endocytic adapters (CLASPs, clathrin- CC associated sorting proteins) and recruiting the GPRCs to the adapter CC protein 2 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, where CC they remain uncoupled from G-proteins. Two different modes of arrestin- CC mediated internalization occur. Class A receptors, like ADRB2, OPRM1, CC ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the CC plasma membrane and undergo rapid recycling. Class B receptors, like CC AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with CC arrestin and traffic with it to endosomal vesicles, presumably as CC desensitized receptors, for extended periods of time. Receptor CC resensitization then requires that receptor-bound arrestin is removed CC so that the receptor can be dephosphorylated and returned to the plasma CC membrane. Mediates endocytosis of CCR7 following ligation of CCL19 but CC not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and CC P2RY11 and ATP-stimulated internalization of P2RY2. Involved in CC phosphorylation-dependent internalization of OPRD1 and subsequent CC recycling or degradation. Involved in ubiquitination of IGF1R. Beta- CC arrestins function as multivalent adapter proteins that can switch the CC GPCR from a G-protein signaling mode that transmits short-lived signals CC from the plasma membrane via small molecule second messengers and ion CC channels to a beta-arrestin signaling mode that transmits a distinct CC set of signals that are initiated as the receptor internalizes and CC transits the intracellular compartment. Acts as a signaling scaffold CC for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 CC and JNK3 activated by the beta-arrestin scaffold are largely excluded CC from the nucleus and confined to cytoplasmic locations such as CC endocytic vesicles, also called beta-arrestin signalosomes. Acts as a CC signaling scaffold for the AKT1 pathway. GPCRs for which the beta- CC arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent CC regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta- CC arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is CC inhibited by the other respective beta-arrestin form (reciprocal CC regulation). Increases ERK1/2 signaling in AGTR1- and AVPR2-mediated CC activation (reciprocal regulation). Involved in CCR7-mediated ERK1/2 CC signaling involving ligand CCL19. Is involved in type-1A angiotensin II CC receptor/AGTR1-mediated ERK activity. Is involved in type-1A CC angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in CC dopamine-stimulated AKT1 activity in the striatum by disrupting the CC association of AKT1 with its negative regulator PP2A. Involved in CC AGTR1-mediated chemotaxis. Appears to function as signaling scaffold CC involved in regulation of MIP-1-beta-stimulated CCR5-dependent CC chemotaxis. Involved in attenuation of NF-kappa-B-dependent CC transcription in response to GPCR or cytokine stimulation by CC interacting with and stabilizing CHUK. Suppresses UV-induced NF-kappa- CC B-dependent activation by interacting with CHUK. The function is CC promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. CC Involved in p53/TP53-mediated apoptosis by regulating MDM2 and reducing CC the MDM2-mediated degradation of p53/TP53. May serve as nuclear CC messenger for GPCRs. Upon stimulation of OR1D2, may be involved in CC regulation of gene expression during the early processes of CC fertilization. Also involved in regulation of receptors other than CC GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates CC TGF-beta signaling such as NF-kappa-B activation. Involved in CC endocytosis of low-density lipoprotein receptor/LDLR. Involved in CC endocytosis of smoothened homolog/Smo, which also requires GRK2. CC Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and CC subsequent TGF-beta-mediated ERK activation and migration of epithelial CC cells. Involved in Toll-like receptor and IL-1 receptor signaling CC through the interaction with TRAF6 which prevents TRAF6 CC autoubiquitination and oligomerization required for activation of NF- CC kappa-B and JUN (PubMed:26839314). Involved in insulin resistance by CC acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. CC Involved in regulation of inhibitory signaling of natural killer cells CC by recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in IL8-mediated CC granule release in neutrophils. Involved in the internalization of the CC atypical chemokine receptor ACKR3. Acts as an adapter protein coupling CC FFAR4 receptor to specific downstream signaling pathways, as well as CC mediating receptor endocytosis (PubMed:22282525, PubMed:23809162). CC During the activation step of NLRP3 inflammasome, directly associates CC with NLRP3 leading to inhibition of pro-inflammatory cytokine release CC and inhibition of inflammation (PubMed:23809162). CC {ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:11877451, CC ECO:0000269|PubMed:12488444, ECO:0000269|PubMed:12582207, CC ECO:0000269|PubMed:12949261, ECO:0000269|PubMed:12958365, CC ECO:0000269|PubMed:14711824, ECO:0000269|PubMed:15054093, CC ECO:0000269|PubMed:15125834, ECO:0000269|PubMed:15205453, CC ECO:0000269|PubMed:15475570, ECO:0000269|PubMed:15618519, CC ECO:0000269|PubMed:15635042, ECO:0000269|PubMed:15671180, CC ECO:0000269|PubMed:15699339, ECO:0000269|PubMed:15878855, CC ECO:0000269|PubMed:16144840, ECO:0000269|PubMed:16280323, CC ECO:0000269|PubMed:16378096, ECO:0000269|PubMed:16492667, CC ECO:0000269|PubMed:16820410, ECO:0000269|PubMed:17540773, CC ECO:0000269|PubMed:18419762, ECO:0000269|PubMed:18604210, CC ECO:0000269|PubMed:19325136, ECO:0000269|PubMed:19620252, CC ECO:0000269|PubMed:19643177, ECO:0000269|PubMed:20048153, CC ECO:0000269|PubMed:22282525, ECO:0000269|PubMed:22457824, CC ECO:0000269|PubMed:23809162, ECO:0000269|PubMed:26839314}. CC -!- SUBUNIT: Homooligomer; the self-association is mediated by InsP6- CC binding (Probable). Heterooligomer with ARRB1; the association is CC mediated by InsP6-binding. Interacts with ADRB2 and CHRM2. Interacts CC with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and CC MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. CC Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. CC Interacts with SRC. Interacts with DUSP16; the interaction is CC interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts CC with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts CC with RELA. Interacts with MDM2; the interaction is enhanced by CC activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6 CC (PubMed:26839314). Interacts with IGF1R. Interacts with ENG. Interacts CC with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with CC AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with CC MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction CC enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the CC interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts CC with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. CC Interacts with SMO (activated). Interacts with GSK3A and GSK3B. CC Associates with protein phosphatase 2A (PP2A) (By similarity). CC Interacts with DHX8; the interaction is detected in the nucleus upon CC OR1D2 stimulation. Interacts with GAPDHS; the interaction is detected CC in the nucleus upon OR1D2 stimulation. Interacts with H2AFX; the CC interaction is detected in the nucleus upon OR1D2 stimulation. CC Interacts with KIF14; the interaction is detected in the nucleus upon CC OR1D2 stimulation. Interacts with RCC1; the interaction is detected in CC the nucleus upon OR1D2 stimulation. Interacts with CXCR4; the CC interaction is dependent on C-terminal phosphorylation of CXCR4 and CC allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts CC with HCK and CXCR1 (phosphorylated). Interacts with ACKR3 and ACKR4. CC Interacts with ARRDC1; the interaction is direct (PubMed:23886940). CC Interacts with GPR61, GPR62 and GPR135 (PubMed:28827538). Interacts CC (via NACHT and LRR domains) with NLRP3; this interaction is direct and CC inducible by omega-3 polyunsaturated fatty acids (PUFAs) CC (PubMed:23809162). Interacts with FFAR4 (via C-terminus); this CC interaction is stimulated by long-chain fatty acids (LCFAs) CC (PubMed:22282525). Interacts with GPR35 (PubMed:37660910). Interacts CC with GPR84 (PubMed:35427647). {ECO:0000250, CC ECO:0000269|PubMed:10644702, ECO:0000269|PubMed:10973280, CC ECO:0000269|PubMed:11877451, ECO:0000269|PubMed:12488444, CC ECO:0000269|PubMed:15125834, ECO:0000269|PubMed:15699339, CC ECO:0000269|PubMed:15878855, ECO:0000269|PubMed:15888437, CC ECO:0000269|PubMed:16144840, ECO:0000269|PubMed:16319069, CC ECO:0000269|PubMed:16378096, ECO:0000269|PubMed:16516836, CC ECO:0000269|PubMed:16524428, ECO:0000269|PubMed:16820410, CC ECO:0000269|PubMed:17540773, ECO:0000269|PubMed:18604210, CC ECO:0000269|PubMed:19363159, ECO:0000269|PubMed:19782076, CC ECO:0000269|PubMed:20048153, ECO:0000269|PubMed:22282525, CC ECO:0000269|PubMed:22300987, ECO:0000269|PubMed:22457824, CC ECO:0000269|PubMed:23341447, ECO:0000269|PubMed:23809162, CC ECO:0000269|PubMed:23886940, ECO:0000269|PubMed:26839314, CC ECO:0000269|PubMed:28827538, ECO:0000269|PubMed:35427647, CC ECO:0000269|PubMed:37660910, ECO:0000305}. CC -!- INTERACTION: CC P32121; P07550: ADRB2; NbExp=3; IntAct=EBI-714559, EBI-491169; CC P32121; P62158: CALM3; NbExp=3; IntAct=EBI-714559, EBI-397435; CC P32121; Q00610: CLTC; NbExp=6; IntAct=EBI-714559, EBI-354967; CC P32121; P25101: EDNRA; NbExp=2; IntAct=EBI-714559, EBI-6624559; CC P32121; P06396: GSN; NbExp=3; IntAct=EBI-714559, EBI-351506; CC P32121; P11142: HSPA8; NbExp=4; IntAct=EBI-714559, EBI-351896; CC P32121; P06213-1: INSR; NbExp=2; IntAct=EBI-714559, EBI-15558981; CC P32121; Q99683: MAP3K5; NbExp=2; IntAct=EBI-714559, EBI-476263; CC P32121; P45984: MAPK9; NbExp=9; IntAct=EBI-714559, EBI-713568; CC P32121; P19338: NCL; NbExp=3; IntAct=EBI-714559, EBI-346967; CC P32121; Q14978: NOLC1; NbExp=3; IntAct=EBI-714559, EBI-396155; CC P32121; Q08499: PDE4D; NbExp=2; IntAct=EBI-714559, EBI-1642831; CC P32121; Q08499-2: PDE4D; NbExp=2; IntAct=EBI-714559, EBI-8095525; CC P32121; P14618: PKM; NbExp=4; IntAct=EBI-714559, EBI-353408; CC P32121; P35813: PPM1A; NbExp=3; IntAct=EBI-714559, EBI-989143; CC P32121; O75688: PPM1B; NbExp=4; IntAct=EBI-714559, EBI-1047039; CC P32121; Q13523: PRPF4B; NbExp=3; IntAct=EBI-714559, EBI-395940; CC P32121; P06702: S100A9; NbExp=2; IntAct=EBI-714559, EBI-1055001; CC P32121; P12931: SRC; NbExp=2; IntAct=EBI-714559, EBI-621482; CC P32121; Q15208: STK38; NbExp=3; IntAct=EBI-714559, EBI-458376; CC P32121; Q13428: TCOF1; NbExp=3; IntAct=EBI-714559, EBI-396105; CC P32121; P27348: YWHAQ; NbExp=3; IntAct=EBI-714559, EBI-359854; CC P32121; O95218: ZRANB2; NbExp=4; IntAct=EBI-714559, EBI-1051583; CC P32121; P31750: Akt1; Xeno; NbExp=3; IntAct=EBI-714559, EBI-298707; CC P32121; Q9Q2G4: ORF; Xeno; NbExp=3; IntAct=EBI-714559, EBI-6248094; CC P32121; P40417: rl; Xeno; NbExp=4; IntAct=EBI-714559, EBI-867790; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane. Membrane, CC clathrin-coated pit {ECO:0000250}. Cytoplasmic vesicle. CC Note=Translocates to the plasma membrane and colocalizes with CC antagonist-stimulated GPCRs. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=P32121-1; Sequence=Displayed; CC Name=2; CC IsoId=P32121-3; Sequence=VSP_008195; CC Name=3; CC IsoId=P32121-2; Sequence=VSP_008194, VSP_008195; CC Name=4; CC IsoId=P32121-4; Sequence=VSP_044697; CC Name=5; CC IsoId=P32121-5; Sequence=VSP_008194; CC -!- DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction CC the AP-2 complex subunit AP2B1. {ECO:0000250}. CC -!- PTM: Phosphorylated at Thr-382 in the cytoplasm; probably CC dephosphorylated at the plasma membrane. The phosphorylation does not CC regulate internalization and recycling of ADRB2, interaction with CC clathrin or AP2B1. {ECO:0000269|PubMed:11877451}. CC -!- PTM: The ubiquitination status appears to regulate the formation and CC trafficking of beta-arrestin-GPCR complexes and signaling. CC Ubiquitination appears to occur GPCR-specific. Ubiquitinated by MDM2; CC the ubiquitination is required for rapid internalization of ADRB2. CC Deubiquitinated by USP33; the deubiquitination leads to a dissociation CC of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such CC as ADRB2, induces transient ubiquitination and subsequently promotes CC association with USP33. Stimulation of a class B GPCR promotes a CC sustained ubiquitination. Deubiquitinated by USP20; allowing USP20 to CC deubiquitinate TRAF6 leading to inhibition of NF-kappa-B signaling CC (PubMed:26839314). {ECO:0000269|PubMed:19363159, CC ECO:0000269|PubMed:26839314}. CC -!- PTM: Hydroxylation by PHD2 modulates the rate of internalization by CC slowing down recruitment to the plasma membrane and inhibiting CC subsequent co-internalization with class A receptors. CC {ECO:0000269|PubMed:21255264}. CC -!- SIMILARITY: Belongs to the arrestin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Arrestin entry; CC URL="https://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; Z11501; CAA77577.1; -; mRNA. DR EMBL; AF106941; AAC99468.1; -; mRNA. DR EMBL; DQ664180; ABG47460.1; -; mRNA. DR EMBL; EU883572; ACG60646.1; -; mRNA. DR EMBL; AK097542; BAC05094.1; -; mRNA. DR EMBL; AK297181; BAG59672.1; -; mRNA. DR EMBL; CR450310; CAG29306.1; -; mRNA. DR EMBL; DQ314866; ABC40725.1; -; Genomic_DNA. DR EMBL; AC091153; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471108; EAW90421.1; -; Genomic_DNA. DR EMBL; CH471108; EAW90422.1; -; Genomic_DNA. DR EMBL; BC007427; AAH07427.1; -; mRNA. DR EMBL; BC067368; AAH67368.1; -; mRNA. DR CCDS; CCDS11050.1; -. [P32121-1] DR CCDS; CCDS11051.1; -. [P32121-5] DR CCDS; CCDS58504.1; -. [P32121-4] DR CCDS; CCDS58505.1; -. [P32121-2] DR PIR; S18984; S18984. DR RefSeq; NP_001244257.1; NM_001257328.1. [P32121-4] DR RefSeq; NP_001244258.1; NM_001257329.1. DR RefSeq; NP_001244259.1; NM_001257330.1. [P32121-3] DR RefSeq; NP_001244260.1; NM_001257331.1. [P32121-2] DR RefSeq; NP_001316993.1; NM_001330064.1. DR RefSeq; NP_004304.1; NM_004313.3. [P32121-1] DR RefSeq; NP_945355.1; NM_199004.1. [P32121-5] DR AlphaFoldDB; P32121; -. DR SMR; P32121; -. DR BioGRID; 106902; 440. DR CORUM; P32121; -. DR DIP; DIP-40089N; -. DR IntAct; P32121; 346. DR MINT; P32121; -. DR STRING; 9606.ENSP00000403701; -. DR MoonDB; P32121; Curated. DR MoonProt; P32121; -. DR TCDB; 8.A.136.1.2; the alpha/beta-arrestin (arrb) family. DR GlyGen; P32121; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P32121; -. DR PhosphoSitePlus; P32121; -. DR BioMuta; ARRB2; -. DR DMDM; 20141230; -. DR EPD; P32121; -. DR jPOST; P32121; -. DR MassIVE; P32121; -. DR MaxQB; P32121; -. DR PaxDb; 9606-ENSP00000403701; -. DR PeptideAtlas; P32121; -. DR ProteomicsDB; 35156; -. DR ProteomicsDB; 54838; -. [P32121-1] DR ProteomicsDB; 54839; -. [P32121-2] DR ProteomicsDB; 54840; -. [P32121-3] DR Pumba; P32121; -. DR Antibodypedia; 23372; 422 antibodies from 37 providers. DR DNASU; 409; -. DR Ensembl; ENST00000269260.7; ENSP00000269260.2; ENSG00000141480.18. [P32121-1] DR Ensembl; ENST00000346341.6; ENSP00000341895.2; ENSG00000141480.18. [P32121-2] DR Ensembl; ENST00000381488.10; ENSP00000370898.6; ENSG00000141480.18. [P32121-5] DR Ensembl; ENST00000412477.7; ENSP00000403701.3; ENSG00000141480.18. [P32121-4] DR GeneID; 409; -. DR KEGG; hsa:409; -. DR MANE-Select; ENST00000269260.7; ENSP00000269260.2; NM_004313.4; NP_004304.1. DR UCSC; uc002fyj.4; human. [P32121-1] DR AGR; HGNC:712; -. DR CTD; 409; -. DR DisGeNET; 409; -. DR GeneCards; ARRB2; -. DR HGNC; HGNC:712; ARRB2. DR HPA; ENSG00000141480; Tissue enhanced (bone marrow, lymphoid tissue). DR MIM; 107941; gene. DR neXtProt; NX_P32121; -. DR OpenTargets; ENSG00000141480; -. DR PharmGKB; PA60; -. DR VEuPathDB; HostDB:ENSG00000141480; -. DR eggNOG; KOG3865; Eukaryota. DR GeneTree; ENSGT00950000182887; -. DR HOGENOM; CLU_033484_1_1_1; -. DR InParanoid; P32121; -. DR OMA; TSRHFLM; -. DR OrthoDB; 3059077at2759; -. DR PhylomeDB; P32121; -. DR TreeFam; TF314260; -. DR PathwayCommons; P32121; -. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR Reactome; R-HSA-456926; Thrombin signalling through proteinase activated receptors (PARs). DR Reactome; R-HSA-5099900; WNT5A-dependent internalization of FZD4. DR Reactome; R-HSA-5635838; Activation of SMO. DR Reactome; R-HSA-5674135; MAP2K and MAPK activation. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants. DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants. DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions. DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF. DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis. DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis. DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants. DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants. DR SignaLink; P32121; -. DR SIGNOR; P32121; -. DR BioGRID-ORCS; 409; 11 hits in 1157 CRISPR screens. DR ChiTaRS; ARRB2; human. DR GeneWiki; Arrestin_beta_2; -. DR GenomeRNAi; 409; -. DR Pharos; P32121; Tbio. DR PRO; PR:P32121; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P32121; Protein. DR Bgee; ENSG00000141480; Expressed in granulocyte and 168 other cell types or tissues. DR ExpressionAtlas; P32121; baseline and differential. DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0030139; C:endocytic vesicle; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0031701; F:angiotensin receptor binding; IPI:UniProtKB. DR GO; GO:0031748; F:D1 dopamine receptor binding; IPI:ARUK-UCL. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0001664; F:G protein-coupled receptor binding; IPI:UniProtKB. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt. DR GO; GO:0043422; F:protein kinase B binding; IEA:Ensembl. DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0060326; P:cell chemotaxis; IMP:UniProtKB. DR GO; GO:0002032; P:desensitization of G protein-coupled receptor signaling pathway by arrestin; IMP:UniProtKB. DR GO; GO:0007212; P:dopamine receptor signaling pathway; NAS:ParkinsonsUK-UCL. DR GO; GO:0060079; P:excitatory postsynaptic potential; NAS:ParkinsonsUK-UCL. DR GO; GO:0002031; P:G protein-coupled receptor internalization; IDA:UniProtKB. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; IDA:UniProt. DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IEA:Ensembl. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl. DR GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; IMP:UniProtKB. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; NAS:ParkinsonsUK-UCL. DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IEA:Ensembl. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IEA:Ensembl. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:2000727; P:positive regulation of cardiac muscle cell differentiation; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IEA:Ensembl. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl. DR GO; GO:0002092; P:positive regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; IEA:Ensembl. DR GO; GO:0098926; P:postsynaptic signal transduction; IEA:Ensembl. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB. DR GO; GO:0031623; P:receptor internalization; IDA:BHF-UCL. DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL. DR Gene3D; 2.60.40.640; -; 1. DR Gene3D; 2.60.40.840; -; 1. DR InterPro; IPR000698; Arrestin. DR InterPro; IPR014752; Arrestin-like_C. DR InterPro; IPR011021; Arrestin-like_N. DR InterPro; IPR011022; Arrestin_C-like. DR InterPro; IPR017864; Arrestin_CS. DR InterPro; IPR014753; Arrestin_N. DR InterPro; IPR014756; Ig_E-set. DR PANTHER; PTHR11792; ARRESTIN; 1. DR PANTHER; PTHR11792:SF20; BETA-ARRESTIN-2; 1. DR Pfam; PF02752; Arrestin_C; 1. DR Pfam; PF00339; Arrestin_N; 1. DR PRINTS; PR00309; ARRESTIN. DR SMART; SM01017; Arrestin_C; 1. DR SUPFAM; SSF81296; E set domains; 2. DR PROSITE; PS00295; ARRESTINS; 1. DR Genevisible; P32121; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Coated pit; Cytoplasm; KW Cytoplasmic vesicle; Hydroxylation; Membrane; Nucleus; Phosphoprotein; KW Protein transport; Reference proteome; Signal transduction inhibitor; KW Transport; Ubl conjugation. FT CHAIN 1..409 FT /note="Beta-arrestin-2" FT /id="PRO_0000205199" FT REGION 240..409 FT /note="Interaction with TRAF6" FT /evidence="ECO:0000269|PubMed:16378096" FT REGION 363..409 FT /note="Interaction with AP2B1" FT MOTIF 385..395 FT /note="[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif" FT MOD_RES 48 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q91YI4" FT MOD_RES 176 FT /note="Hydroxyproline; by PHD2" FT /evidence="ECO:0000269|PubMed:21255264" FT MOD_RES 181 FT /note="Hydroxyproline; by PHD2" FT /evidence="ECO:0000269|PubMed:21255264" FT MOD_RES 360 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P29067" FT MOD_RES 382 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:11877451" FT VAR_SEQ 39..53 FT /note="Missing (in isoform 3 and isoform 5)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_008194" FT VAR_SEQ 119 FT /note="T -> TVRMPLPSEGQGAGAGTVSGVG (in isoform 4)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044697" FT VAR_SEQ 360 FT /note="S -> SAPTPTPPLPVPP (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.3" FT /id="VSP_008195" FT MUTAGEN 11 FT /note="K->A: Abolishes interaction with CHUK; when FT associated with A-12; A-230 and A-231." FT MUTAGEN 12 FT /note="K->A: Abolishes interaction with CHUK; when FT associated with A-11; A-230 and A-231." FT MUTAGEN 54 FT /note="V->A: Inhibits internalization of CXCR4; no effect FT on interaction with CXCR4." FT /evidence="ECO:0000269|PubMed:10644702" FT MUTAGEN 230 FT /note="K->A: Abolishes interaction with CHUK; when FT associated with A-11; A-12 and A-231." FT MUTAGEN 231 FT /note="K->A: Abolishes interaction with CHUK; when FT associated with A-11; A-12 and A-230." FT MUTAGEN 360 FT /note="S->A,D: Reduces interaction with CHUK; when FT associated with A-382." FT MUTAGEN 382 FT /note="T->A,D: Reduces interaction with CHUK; when FT associated with A-360." FT /evidence="ECO:0000269|PubMed:11877451" FT MUTAGEN 382 FT /note="T->A: Loss of phosphorylation." FT /evidence="ECO:0000269|PubMed:11877451" FT CONFLICT 13 FT /note="S -> P (in Ref. 5; BAG59672)" FT /evidence="ECO:0000305" FT CONFLICT 189 FT /note="R -> P (in Ref. 1; CAA77577)" FT /evidence="ECO:0000305" FT CONFLICT 190 FT /note="H -> R (in Ref. 3; ABG47460)" FT /evidence="ECO:0000305" FT CONFLICT 192 FT /note="L -> P (in Ref. 6; CAG29306)" FT /evidence="ECO:0000305" FT CONFLICT 366 FT /note="D -> G (in Ref. 5; BAG59672)" FT /evidence="ECO:0000305" SQ SEQUENCE 409 AA; 46106 MW; DEEC507D4A7B84FF CRC64; MGEKPGTRVF KKSSPNCKLT VYLGKRDFVD HLDKVDPVDG VVLVDPDYLK DRKVFVTLTC AFRYGREDLD VLGLSFRKDL FIATYQAFPP VPNPPRPPTR LQDRLLRKLG QHAHPFFFTI PQNLPCSVTL QPGPEDTGKA CGVDFEIRAF CAKSLEEKSH KRNSVRLVIR KVQFAPEKPG PQPSAETTRH FLMSDRSLHL EASLDKELYY HGEPLNVNVH VTNNSTKTVK KIKVSVRQYA DICLFSTAQY KCPVAQLEQD DQVSPSSTFC KVYTITPLLS DNREKRGLAL DGKLKHEDTN LASSTIVKEG ANKEVLGILV SYRVKVKLVV SRGGDVSVEL PFVLMHPKPH DHIPLPRPQS AAPETDVPVD TNLIEFDTNY ATDDDIVFED FARLRLKGMK DDDYDDQLC //