ARRB2_PONAB
ID ARRB2_PONAB Reviewed; 409 AA.
AC Q5RCR4;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 25-MAY-2022, entry version 81.
DE RecName: Full=Beta-arrestin-2;
DE AltName: Full=Arrestin beta-2;
GN Name=ARRB2;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
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 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. 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 IL8-mediated
CC granule release in neutrophils. Involved in the internalization of the
CC atypical chemokine receptor ACKR3 (By similarity). Acts as an adapter
CC protein coupling FFAR4 receptor to specific downstream signaling
CC pathways, as well as mediating receptor endocytosis. During the
CC activation step of NLRP3 inflammasome, directly associates with NLRP3
CC leading to inhibition of pro-inflammatory cytokine release and
CC inhibition of inflammation. Involved in the internalization of FFAR4.
CC {ECO:0000250, ECO:0000250|UniProtKB:P32121}.
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 (By
CC similarity). Interacts with GPR61, GPR62 and GPR135 (By similarity).
CC Interacts (via NACHT and LRR domains) with NLRP3; this interaction is
CC direct and inducible by omega-3 polyunsaturated fatty acids (PUFAs) (By
CC similarity). Interacts with FFAR4 (via C-terminus); this interaction is
CC stimulated by long-chain fatty acids (LCFAs) (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:P32121, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Cell membrane {ECO:0000250}. Membrane, clathrin-coated pit
CC {ECO:0000250}. Cytoplasmic vesicle {ECO:0000250}. Note=Translocates to
CC the plasma membrane and colocalizes with antagonist-stimulated GPCRs.
CC {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 (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; CR858205; CAH90443.1; -; mRNA.
DR RefSeq; NP_001125224.1; NM_001131752.1.
DR AlphaFoldDB; Q5RCR4; -.
DR SMR; Q5RCR4; -.
DR STRING; 9601.ENSPPYP00000008826; -.
DR GeneID; 100172117; -.
DR KEGG; pon:100172117; -.
DR CTD; 409; -.
DR eggNOG; KOG3865; Eukaryota.
DR InParanoid; Q5RCR4; -.
DR OrthoDB; 783081at2759; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030139; C:endocytic vesicle; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0009968; P:negative regulation of signal transduction; IEA:UniProtKB-KW.
DR GO; GO:0002092; P:positive regulation of receptor internalization; ISS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
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 2: Evidence at transcript level;
KW Cell membrane; Coated pit; Cytoplasm; Cytoplasmic vesicle; Hydroxylation;
KW Membrane; Nucleus; Phosphoprotein; Protein transport; Reference proteome;
KW Signal transduction inhibitor; Transport; Ubl conjugation.
FT CHAIN 1..409
FT /note="Beta-arrestin-2"
FT /id="PRO_0000250485"
FT REGION 240..409
FT /note="Interaction with TRAF6"
FT /evidence="ECO:0000250"
FT REGION 363..409
FT /note="Interaction with AP2B1"
FT /evidence="ECO:0000250"
FT MOTIF 385..395
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 360
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P29067"
FT MOD_RES 382
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P29067"
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
