ARRB2_RAT
ID ARRB2_RAT Reviewed; 410 AA.
AC P29067;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Beta-arrestin-2;
DE AltName: Full=Arrestin beta-2;
GN Name=Arrb2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=1517224; DOI=10.1016/s0021-9258(19)37125-x;
RA Attramadal H., Arriza J.L., Aoki C., Dawson T.M., Codina J., Kwatra M.M.,
RA Snyder S.H., Caron M.G., Lefkowitz R.J.;
RT "Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene
RT family.";
RL J. Biol. Chem. 267:17882-17890(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 295-410.
RC TISSUE=Pineal gland;
RX PubMed=8308033; DOI=10.1016/s0021-9258(17)41820-5;
RA Craft C.M., Whitmore D.H., Wiechmann A.F.;
RT "Cone arrestin identified by targeting expression of a functional family.";
RL J. Biol. Chem. 269:4613-4619(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 305-386.
RC STRAIN=Sprague-Dawley; TISSUE=Retina;
RX PubMed=9767391; DOI=10.1046/j.1460-9568.1998.t01-1-00271.x;
RA Komori N., Cain S.D., Roch J.-M., Miller K.E., Matsumoto H.;
RT "Differential expression of alternative splice variants of beta-arrestin-1
RT and -2 in rat central nervous system and peripheral tissues.";
RL Eur. J. Neurosci. 10:2607-2616(1998).
RN [5]
RP INTERACTION WITH IGF1R.
RX PubMed=9822622; DOI=10.1074/jbc.273.48.31640;
RA Lin F.-T., Daaka Y., Lefkowitz R.J.;
RT "beta-arrestins regulate mitogenic signaling and clathrin-mediated
RT endocytosis of the insulin-like growth factor I receptor.";
RL J. Biol. Chem. 273:31640-31643(1998).
RN [6]
RP FUNCTION IN INTERNALIZATION OF ADRB2, INTERACTION WITH CLTC AND AP2B1,
RP MUTAGENESIS OF 374-LEU--PHE-377, AND SUBCELLULAR LOCATION.
RX PubMed=10097102; DOI=10.1073/pnas.96.7.3712;
RA Laporte S.A., Oakley R.H., Zhang J., Holt J.A., Ferguson S.S.G.,
RA Caron M.G., Barak L.S.;
RT "The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin
RT adaptor AP-2 during endocytosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:3712-3717(1999).
RN [7]
RP INTERACTION WITH SRC.
RX PubMed=10753943; DOI=10.1074/jbc.275.15.11312;
RA Miller W.E., Maudsley S., Ahn S., Khan K.D., Luttrell L.M., Lefkowitz R.J.;
RT "beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase
RT c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor
RT endocytosis.";
RL J. Biol. Chem. 275:11312-11319(2000).
RN [8]
RP FUNCTION IN INTERNALIZATION OF EDNRA AND EDNRB, AND MUTAGENESIS OF VAL-54.
RX PubMed=10747877; DOI=10.1074/jbc.m000142200;
RA Bremnes T., Paasche J.D., Mehlum A., Sandberg C., Bremnes B.,
RA Attramadal H.;
RT "Regulation and intracellular trafficking pathways of the endothelin
RT receptors.";
RL J. Biol. Chem. 275:17596-17604(2000).
RN [9]
RP SUBCELLULAR LOCATION, INTERACTION WITH AP2B1 AND CLTC, AND MUTAGENESIS OF
RP ARG-396 AND LYS-398.
RX PubMed=10770944; DOI=10.1074/jbc.m002581200;
RA Laporte S.A., Oakley R.H., Holt J.A., Barak L.S., Caron M.G.;
RT "The interaction of beta-arrestin with the AP-2 adaptor is required for the
RT clustering of beta 2-adrenergic receptor into clathrin-coated pits.";
RL J. Biol. Chem. 275:23120-23126(2000).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=10852825; DOI=10.1242/jcs.113.13.2463;
RA Santini F., Penn R.B., Gagnon A.W., Benovic J.L., Keen J.H.;
RT "Selective recruitment of arrestin-3 to clathrin coated pits upon
RT stimulation of G protein-coupled receptors.";
RL J. Cell Sci. 113:2463-2470(2000).
RN [11]
RP FUNCTION IN MAPK SIGNALING, AND INTERACTION WITH MAPK10; MAP2K4 AND MAP3K5.
RX PubMed=11090355; DOI=10.1126/science.290.5496.1574;
RA McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E., Lin F.-T.,
RA Davis R.J., Lefkowitz R.J.;
RT "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of
RT JNK3.";
RL Science 290:1574-1577(2000).
RN [12]
RP INTERACTION WITH CCR5.
RX PubMed=11448957; DOI=10.1074/jbc.m102782200;
RA Kraft K., Olbrich H., Majoul I., Mack M., Proudfoot A., Oppermann M.;
RT "Characterization of sequence determinants within the carboxyl-terminal
RT domain of chemokine receptor CCR5 that regulate signaling and receptor
RT internalization.";
RL J. Biol. Chem. 276:34408-34418(2001).
RN [13]
RP FUNCTION IN MAPK SIGNALING, AND INTERACTION WITH RAF1; MAP2K1 AND MAPK1.
RX PubMed=11226259; DOI=10.1073/pnas.041604898;
RA Luttrell L.M., Roudabush F.L., Choy E.W., Miller W.E., Field M.E.,
RA Pierce K.L., Lefkowitz R.J.;
RT "Activation and targeting of extracellular signal-regulated kinases by
RT beta-arrestin scaffolds.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:2449-2454(2001).
RN [14]
RP UBIQUITINATION, AND INTERACTION WITH MDM2.
RX PubMed=11588219; DOI=10.1126/science.1063866;
RA Shenoy S.K., McDonald P.H., Kohout T.A., Lefkowitz R.J.;
RT "Regulation of receptor fate by ubiquitination of activated beta 2-
RT adrenergic receptor and beta-arrestin.";
RL Science 294:1307-1313(2001).
RN [15]
RP PHOSPHORYLATION AT SER-361 AND THR-383, INTERACTION WITH CLTC, AND
RP MUTAGENESIS OF SER-361 AND THR-383.
RX PubMed=12186555; DOI=10.1021/bi025705n;
RA Lin F.-T., Chen W., Shenoy S., Cong M., Exum S.T., Lefkowitz R.J.;
RT "Phosphorylation of beta-arrestin2 regulates its function in
RT internalization of beta(2)-adrenergic receptors.";
RL Biochemistry 41:10692-10699(2002).
RN [16]
RP INTERACTION WITH AP2B1.
RX PubMed=11777907; DOI=10.1074/jbc.m108490200;
RA Laporte S.A., Miller W.E., Kim K.-M., Caron M.G.;
RT "beta-Arrestin/AP-2 interaction in G protein-coupled receptor
RT internalization: identification of a beta-arrestin binding site in beta 2-
RT adaptin.";
RL J. Biol. Chem. 277:9247-9254(2002).
RN [17]
RP FUNCTION IN ERK SIGNALING.
RX PubMed=11777902; DOI=10.1074/jbc.m106457200;
RA Tohgo A., Pierce K.L., Choy E.W., Lefkowitz R.J., Luttrell L.M.;
RT "beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK
RT activity but inhibits ERK-mediated transcription following angiotensin AT1a
RT receptor stimulation.";
RL J. Biol. Chem. 277:9429-9436(2002).
RN [18]
RP FUNCTION IN INTERNALIZATION OF C5AR1, SUBCELLULAR LOCATION, AND INTERACTION
RP 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 internalization of
RT the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin,
RT dynamin, and clathrin-dependent pathway.";
RL J. Biol. Chem. 278:4277-4285(2003).
RN [19]
RP INTERACTION WITH LDLR.
RX PubMed=12944399; DOI=10.1074/jbc.m309450200;
RA Wu J.-H., Peppel K., Nelson C.D., Lin F.-T., Kohout T.A., Miller W.E.,
RA Exum S.T., Freedman N.J.;
RT "The adaptor protein beta-arrestin2 enhances endocytosis of the low density
RT lipoprotein receptor.";
RL J. Biol. Chem. 278:44238-44245(2003).
RN [20]
RP INTERACTION WITH PDE4D.
RX PubMed=14500724; DOI=10.1074/jbc.m303772200;
RA Bolger G.B., McCahill A., Huston E., Cheung Y.F., McSorley T.,
RA Baillie G.S., Houslay M.D.;
RT "The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase
RT isoform confers preferential interaction with beta-arrestins.";
RL J. Biol. Chem. 278:49230-49238(2003).
RN [21]
RP INTERACTION WITH CHUK; IKBKB AND MAP3K14.
RX PubMed=15173580; DOI=10.1073/pnas.0402851101;
RA Witherow D.S., Garrison T.R., Miller W.E., Lefkowitz R.J.;
RT "beta-Arrestin inhibits NF-kappaB activity by means of its interaction with
RT the NF-kappaB inhibitor IkappaBalpha.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:8603-8607(2004).
RN [22]
RP INTERACTION WITH 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 [23]
RP INTERACTION WITH AKT1; GSK3A AND GSK3B.
RX PubMed=16051150; DOI=10.1016/j.cell.2005.05.012;
RA Beaulieu J.-M., Sotnikova T.D., Marion S., Lefkowitz R.J.,
RA Gainetdinov R.R., Caron M.G.;
RT "An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic
RT neurotransmission and behavior.";
RL Cell 122:261-273(2005).
RN [24]
RP UBIQUITINATION, AND MUTAGENESIS OF 11-LYS-LYS-12.
RX PubMed=15699045; DOI=10.1074/jbc.m412418200;
RA Shenoy S.K., Lefkowitz R.J.;
RT "Receptor-specific ubiquitination of beta-arrestin directs assembly and
RT targeting of seven-transmembrane receptor signalosomes.";
RL J. Biol. Chem. 280:15315-15324(2005).
RN [25]
RP FUNCTION IN UBIQUITINATION OF IGF1R.
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 [26]
RP INTERACTION WITH PDE4A.
RX PubMed=15738310; DOI=10.1124/mol.104.009423;
RA Wallace D.A., Johnston L.A., Huston E., Macmaster D., Houslay T.M.,
RA Cheung Y.-F., Campbell L., Millen J.E., Smith R.A., Gall I., Knowles R.G.,
RA Sullivan M., Houslay M.D.;
RT "Identification and characterization of PDE4A11, a novel, widely expressed
RT long isoform encoded by the human PDE4A cAMP phosphodiesterase gene.";
RL Mol. Pharmacol. 67:1920-1934(2005).
RN [27]
RP UBIQUITINATION.
RX PubMed=17666399; DOI=10.1074/jbc.m700852200;
RA Shenoy S.K., Barak L.S., Xiao K., Ahn S., Berthouze M., Shukla A.K.,
RA Luttrell L.M., Lefkowitz R.J.;
RT "Ubiquitination of beta-arrestin links seven-transmembrane receptor
RT endocytosis and ERK activation.";
RL J. Biol. Chem. 282:29549-29562(2007).
RN [28]
RP FUNCTION IN DESENSITIZATION OF AGTR1, AND FUNCTION IN AGTR1-MEDIATED ERK
RP SIGNALING.
RX PubMed=18006496; DOI=10.1074/jbc.m706892200;
RA Lee M.-H., El-Shewy H.M., Luttrell D.K., Luttrell L.M.;
RT "Role of beta-arrestin-mediated desensitization and signaling in the
RT control of angiotensin AT1a receptor-stimulated transcription.";
RL J. Biol. Chem. 283:2088-2097(2008).
RN [29]
RP FUNCTION IN MAPK SIGNALING, INTERACTION WITH MAPK10 AND MAP3K5, AND
RP MUTAGENESIS OF SER-198.
RX PubMed=18408005; DOI=10.1074/jbc.m710006200;
RA Guo C., Whitmarsh A.J.;
RT "The beta-arrestin-2 scaffold protein promotes c-Jun N-terminal kinase-3
RT activation by binding to its nonconserved N terminus.";
RL J. Biol. Chem. 283:15903-15911(2008).
RN [30]
RP FUNCTION IN INTERNALIZATION OF CHRM1 AND CHRM2, AND MUTAGENESIS OF LYS-18;
RP LYS-107; LYS-108; LYS-207 AND LYS-296.
RX PubMed=19055777; DOI=10.1186/1750-2187-3-20;
RA Mosser V.A., Jones K.T., Hoffman K.M., McCarty N.A., Jackson D.A.;
RT "Differential role of beta-arrestin ubiquitination in agonist-promoted
RT down-regulation of M1 vs M2 muscarinic acetylcholine receptors.";
RL J. Mol. Signal. 3:20-20(2008).
RN [31]
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).
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 signaling scaffold for
CC MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 and
CC JNK3 activated by the beta-arrestin scaffold are largely excluded from
CC the nucleus and confined to cytoplasmic locations such as endocytic
CC vesicles, also called beta-arrestin signalosomes. Acts as signaling
CC scaffold for the AKT1 pathway. 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 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 IL8-mediated granule release in neutrophils (By
CC similarity). Involved in p53/TP53-mediated apoptosis by regulating MDM2
CC and reducing the MDM2-mediated degradation of p53/TP53. May serve as
CC nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved
CC in 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. Involved in insulin resistance by acting as insulin-
CC induced signaling scaffold for SRC, AKT1 and INSR. Involved in
CC regulation of inhibitory signaling of natural killer cells by
CC recruiting PTPN6 and PTPN11 to KIR2DL1. Involved in the internalization
CC of the atypical chemokine receptor ACKR3 (By similarity). Acts as an
CC adapter protein coupling FFAR4 receptor to specific downstream
CC signaling pathways, as well as mediating receptor endocytosis. During
CC the activation step of NLRP3 inflammasome, directly associates with
CC NLRP3 leading to inhibition of pro-inflammatory cytokine release and
CC inhibition of inflammation. {ECO:0000250, ECO:0000250|UniProtKB:P32121,
CC ECO:0000269|PubMed:10097102, ECO:0000269|PubMed:10747877,
CC ECO:0000269|PubMed:11090355, ECO:0000269|PubMed:11226259,
CC ECO:0000269|PubMed:11777902, ECO:0000269|PubMed:12464600,
CC ECO:0000269|PubMed:15878855, ECO:0000269|PubMed:18006496,
CC ECO:0000269|PubMed:18408005, ECO:0000269|PubMed:19055777}.
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 Interacts with IGF1R. Interacts with ENG. Interacts with KIR2DL1,
CC KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1.
CC Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1.
CC Interacts with MAPK1. Interacts with MAPK10; the interaction enhances
CC MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is
CC enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5.
CC Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with
CC SMO (activated). Interacts with GSK3A and GSK3B. Associates with
CC protein phosphatase 2A (PP2A). Interacts with CXCR4; the interaction is
CC dependent on C-terminal phosphorylation of CXCR4 and allows activation
CC of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1
CC (phosphorylated) (By similarity). Interacts with ACKR3 and ACKR4 (By
CC similarity). Interacts with ARRDC1; the interaction is direct
CC (PubMed:23886940). Interacts with GPR61, GPR62 and GPR135 (By
CC similarity). Interacts (via NACHT and LRR domains) with NLRP3; this
CC interaction is direct and inducible by omega-3 polyunsaturated fatty
CC acids (PUFAs) (By similarity). Interacts with FFAR4 (via C-terminus);
CC this interaction is stimulated by long-chain fatty acids (LCFAs) (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:P32121,
CC ECO:0000269|PubMed:23886940, ECO:0000305}.
CC -!- INTERACTION:
CC P29067; P29067: Arrb2; NbExp=3; IntAct=EBI-1636616, EBI-1636616;
CC P29067; P31749: AKT1; Xeno; NbExp=2; IntAct=EBI-1636616, EBI-296087;
CC P29067; P53667: LIMK1; Xeno; NbExp=2; IntAct=EBI-1636616, EBI-444403;
CC P29067; Q00987: MDM2; Xeno; NbExp=4; IntAct=EBI-1636616, EBI-389668;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000250}. Cell membrane.
CC Membrane, clathrin-coated pit. Cytoplasmic vesicle {ECO:0000250}.
CC Note=Translocates to the plasma membrane and colocalizes with
CC antagonist-stimulated GPCRs.
CC -!- TISSUE SPECIFICITY: Predominantly localized in neuronal tissues and in
CC the spleen.
CC -!- PTM: Phosphorylated at Thr-383 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 (By similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
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. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the arrestin family. {ECO:0000305}.
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DR EMBL; M91590; AAA74460.1; -; mRNA.
DR EMBL; BC087578; AAH87578.1; -; mRNA.
DR EMBL; U03627; AAA17551.1; -; mRNA.
DR EMBL; AF051457; AAC28617.1; -; Genomic_DNA.
DR PIR; A59279; A59279.
DR RefSeq; NP_037043.1; NM_012911.1.
DR PDB; 6K3F; X-ray; 2.30 A; A/B/C/D/E/F=1-356.
DR PDBsum; 6K3F; -.
DR AlphaFoldDB; P29067; -.
DR SMR; P29067; -.
DR BioGRID; 247426; 12.
DR CORUM; P29067; -.
DR DIP; DIP-40507N; -.
DR IntAct; P29067; 21.
DR MINT; P29067; -.
DR STRING; 10116.ENSRNOP00000026207; -.
DR iPTMnet; P29067; -.
DR PhosphoSitePlus; P29067; -.
DR PaxDb; P29067; -.
DR PRIDE; P29067; -.
DR GeneID; 25388; -.
DR KEGG; rno:25388; -.
DR UCSC; RGD:2157; rat.
DR CTD; 409; -.
DR RGD; 2157; Arrb2.
DR VEuPathDB; HostDB:ENSRNOG00000019308; -.
DR eggNOG; KOG3865; Eukaryota.
DR HOGENOM; CLU_033484_1_1_1; -.
DR InParanoid; P29067; -.
DR OMA; PHDHIIT; -.
DR OrthoDB; 783081at2759; -.
DR PhylomeDB; P29067; -.
DR Reactome; R-RNO-418555; G alpha (s) signalling events.
DR Reactome; R-RNO-456926; Thrombin signalling through proteinase activated receptors (PARs).
DR Reactome; R-RNO-5099900; WNT5A-dependent internalization of FZD4.
DR Reactome; R-RNO-5635838; Activation of SMO.
DR Reactome; R-RNO-5674135; MAP2K and MAPK activation.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR Reactome; R-RNO-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-RNO-8856828; Clathrin-mediated endocytosis.
DR PRO; PR:P29067; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Bgee; ENSRNOG00000019308; Expressed in thymus and 19 other tissues.
DR Genevisible; P29067; RN.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:RGD.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:ARUK-UCL.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0043197; C:dendritic spine; IDA:RGD.
DR GO; GO:0030139; C:endocytic vesicle; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:ARUK-UCL.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; ISO:RGD.
DR GO; GO:0014069; C:postsynaptic density; IDA:RGD.
DR GO; GO:0045211; C:postsynaptic membrane; IDA:RGD.
DR GO; GO:0071889; F:14-3-3 protein binding; IDA:RGD.
DR GO; GO:0031691; F:alpha-1A adrenergic receptor binding; IPI:RGD.
DR GO; GO:0031692; F:alpha-1B adrenergic receptor binding; IDA:RGD.
DR GO; GO:0031701; F:angiotensin receptor binding; ISO:RGD.
DR GO; GO:1990763; F:arrestin family protein binding; IPI:UniProtKB.
DR GO; GO:0031748; F:D1 dopamine receptor binding; IPI:RGD.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0031762; F:follicle-stimulating hormone receptor binding; IPI:RGD.
DR GO; GO:0001664; F:G protein-coupled receptor binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0051019; F:mitogen-activated protein kinase binding; IPI:RGD.
DR GO; GO:0031859; F:platelet activating factor receptor binding; IPI:RGD.
DR GO; GO:0019904; F:protein domain specific binding; IPI:RGD.
DR GO; GO:0043422; F:protein kinase B binding; ISO:RGD.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:RGD.
DR GO; GO:0005102; F:signaling receptor binding; ISO:RGD.
DR GO; GO:0031702; F:type 1 angiotensin receptor binding; IPI:RGD.
DR GO; GO:0031826; F:type 2A serotonin receptor binding; IPI:RGD.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0007628; P:adult walking behavior; ISO:RGD.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:0060326; P:cell chemotaxis; ISO:RGD.
DR GO; GO:0002032; P:desensitization of G protein-coupled receptor signaling pathway by arrestin; IMP:RGD.
DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; IMP:RGD.
DR GO; GO:0006897; P:endocytosis; IDA:RGD.
DR GO; GO:0042699; P:follicle-stimulating hormone signaling pathway; IDA:RGD.
DR GO; GO:0002031; P:G protein-coupled receptor internalization; ISO:RGD.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:RGD.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:RGD.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:RGD.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; ISO:RGD.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; ISO:RGD.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; ISO:RGD.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:RGD.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISO:RGD.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IMP:RGD.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IMP:RGD.
DR GO; GO:0034392; P:negative regulation of smooth muscle cell apoptotic process; IMP:RGD.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; ISO:RGD.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISO:RGD.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; IMP:RGD.
DR GO; GO:2000727; P:positive regulation of cardiac muscle cell differentiation; ISO:RGD.
DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IMP:RGD.
DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IMP:RGD.
DR GO; GO:1904037; P:positive regulation of epithelial cell apoptotic process; IMP:RGD.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IMP:RGD.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IMP:RGD.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:RGD.
DR GO; GO:0002092; P:positive regulation of receptor internalization; IMP:RGD.
DR GO; GO:0032226; P:positive regulation of synaptic transmission, dopaminergic; ISO:RGD.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISO:RGD.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0016567; P:protein ubiquitination; ISO:RGD.
DR GO; GO:0031623; P:receptor internalization; ISO:RGD.
DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; IDA:RGD.
DR GO; GO:0001932; P:regulation of protein phosphorylation; ISO:RGD.
DR GO; GO:0006366; P:transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISO:RGD.
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; PTHR11792; 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; SSF81296; 2.
DR PROSITE; PS00295; ARRESTINS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Coated pit; Cytoplasm; Cytoplasmic vesicle;
KW Hydroxylation; Membrane; Nucleus; Phosphoprotein; Protein transport;
KW Reference proteome; Signal transduction inhibitor; Transport;
KW Ubl conjugation.
FT CHAIN 1..410
FT /note="Beta-arrestin-2"
FT /id="PRO_0000205201"
FT REGION 241..410
FT /note="Interaction with TRAF6"
FT /evidence="ECO:0000250"
FT REGION 378..410
FT /note="Interaction with AP2B1"
FT MOTIF 386..396
FT /note="[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif"
FT /evidence="ECO:0000250"
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:0000250"
FT MOD_RES 181
FT /note="Hydroxyproline; by PHD2"
FT /evidence="ECO:0000250"
FT MOD_RES 361
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:12186555"
FT MOD_RES 383
FT /note="Phosphothreonine; by CaMK2"
FT /evidence="ECO:0000305|PubMed:12186555"
FT MUTAGEN 11..12
FT /note="KK->RR: Transient ubiquitination; no stable
FT endocytic complexes with AGTR1; impaired in scaffolding-
FT activated ERK1/2."
FT /evidence="ECO:0000269|PubMed:15699045"
FT MUTAGEN 18
FT /note="K->R: Promotes agonist-stimulated down-regulation of
FT CHRM2 and CHRM1; no effect on internalization of CHRM2;
FT when associated with R-107, R-108, R-207 and R-296."
FT /evidence="ECO:0000269|PubMed:19055777"
FT MUTAGEN 54
FT /note="V->A: Inhibits internalization of EDNRA and EDNRB."
FT /evidence="ECO:0000269|PubMed:10747877"
FT MUTAGEN 107
FT /note="K->R: Promotes agonist-stimulated down-regulation of
FT CHRM2 and CHRM1; no effect on internalization of CHRM2;
FT when associated with R-18, R-108, R-207 and R-296."
FT /evidence="ECO:0000269|PubMed:19055777"
FT MUTAGEN 108
FT /note="K->R: Promotes agonist-stimulated down-regulation of
FT CHRM2 and CHRM1; no effect on internalization of CHRM2;
FT when associated with R-18, R-107, R-207 and R-296."
FT /evidence="ECO:0000269|PubMed:19055777"
FT MUTAGEN 198
FT /note="S->P: Greatly reduces interaction with MAPK10."
FT /evidence="ECO:0000269|PubMed:18408005"
FT MUTAGEN 207
FT /note="K->R: Promotes agonist-stimulated down-regulation of
FT CHRM2 and CHRM1; no effect on internalization of CHRM2;
FT when associated with R-18, R-107, R-108 and R-296."
FT /evidence="ECO:0000269|PubMed:19055777"
FT MUTAGEN 296
FT /note="K->R: Promotes agonist-stimulated down-regulation of
FT CHRM2 and CHRM1; no effect on internalization of CHRM2;
FT when associated with R-18, R-107, R-108 and R-207."
FT /evidence="ECO:0000269|PubMed:19055777"
FT MUTAGEN 361
FT /note="S->D: Almost abolishes phosphorylation; inhibits
FT internalization of ADRB2; when associated with D-383."
FT /evidence="ECO:0000269|PubMed:12186555"
FT MUTAGEN 361
FT /note="S->D: Reduces interaction with CLTC."
FT /evidence="ECO:0000269|PubMed:12186555"
FT MUTAGEN 374..377
FT /note="LIEF->AAEA: Abolishes interaction with CLTC; reduces
FT interaction with AP2B1."
FT /evidence="ECO:0000269|PubMed:10097102"
FT MUTAGEN 383
FT /note="T->D: Almost abolishes phosphorylation; inhibits
FT internalization of ADRB2; when associated with D-361."
FT /evidence="ECO:0000269|PubMed:12186555"
FT MUTAGEN 383
FT /note="T->D: Reduces interaction with CLTC."
FT /evidence="ECO:0000269|PubMed:12186555"
FT MUTAGEN 394
FT /note="R->A: Abolishes interaction with AP2B1; no effect on
FT interaction with clathrin."
FT MUTAGEN 396
FT /note="R->A: Abolishes interaction with AP2B1."
FT /evidence="ECO:0000269|PubMed:10770944"
FT MUTAGEN 398
FT /note="K->A: No effect on interaction with AP2B1."
FT /evidence="ECO:0000269|PubMed:10770944"
FT STRAND 10..13
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 17..24
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 26..30
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 32..34
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 41..44
FT /evidence="ECO:0007829|PDB:6K3F"
FT TURN 46..48
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 55..63
FT /evidence="ECO:0007829|PDB:6K3F"
FT TURN 67..71
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 72..74
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 80..85
FT /evidence="ECO:0007829|PDB:6K3F"
FT HELIX 100..108
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 142..150
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 161..163
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 168..173
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 185..187
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 208..210
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 216..223
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 226..228
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 230..240
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 243..251
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 253..260
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 266..269
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 272..276
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 325..331
FT /evidence="ECO:0007829|PDB:6K3F"
FT TURN 332..334
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 335..339
FT /evidence="ECO:0007829|PDB:6K3F"
FT STRAND 343..345
FT /evidence="ECO:0007829|PDB:6K3F"
SQ SEQUENCE 410 AA; 46340 MW; 0DFA6A897C2B86BA CRC64;
MGEKPGTRVF KKSSPNCKLT VYLGKRDFVD HLDKVDPVDG VVLVDPDYLK DRKVFVTLTC
AFRYGREDLD VLGLSFRKDL FIATYQAFPP MPNPPRPPTR LQDRLLKKLG QHAHPFFFTI
PQNLPCSVTL QPGPEDTGKA CGVDFEIRAF CAKSIEEKSH KRNSVRLIIR KVQFAPETPG
PQPSAETTRH FLMSDRRSLH LEASLDKELY YHGEPLNVNV HVTNNSAKTV KKIRVSVRQY
ADICLFSTAQ YKCPVAQLEQ DDQVSPSSTF CKVYTITPLL SDNREKRGLA LDGQLKHEDT
NLASSTIVKE GANKEVLGIL VSYRVKVKLV VSRGGDVSVE LPFVLMHPKP HDHITLPRPQ
SAPREIDIPV DTNLIEFDTN YATDDDIVFE DFARLRLKGM KDDDCDDQFC
