Q91YI4 (ARRB2_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 99. History...
Names and origin
|Protein names||Recommended name:|
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||410 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. Involved in internalization of P2RY1, P2RY4, P2RY6 and P2RY11 and ATP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 and subsequent recycling or degradation. Involved in ubiquitination of IGF1R. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2) and MAPK10 (JNK3). ERK1/2 and JNK3 activated by the beta-arrestin scaffold are largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for the AKT1 pathway. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Increases ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Involved in CCR7-mediated ERK1/2 signaling involving ligand CCL19. Is involved in type-1A angiotensin II receptor/AGTR1-mediated ERK activity. Is involved in type-1A angiotensin II receptor/AGTR1-mediated MAPK10 activity. Is involved in dopamine-stimulated AKT1 activity in the striatum by disrupting the association of AKT1 with its negative regulator PP2A. Involved in AGTR1-mediated chemotaxis. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. Suppresses UV-induced NF-kappa-B-dependent activation by interacting with CHUK. The function is promoted by stimulation of ADRB2 and dephosphorylation of ARRB2. Involved in IL8-mediated granule release in neutrophils By similarity. Involved in p53/TP53-mediated apoptosis by regulating MDM2 and reducing the MDM2-mediated degradation of p53/TP53. May serve as nuclear messenger for GPCRs. Upon stimulation of OR1D2, may be involved in regulation of gene expression during the early processes of fertilization. Also involved in regulation of receptors others than GPCRs. Involved in endocytosis of TGFBR2 and TGFBR3 and down-regulates TGF-beta signaling such as NF-kappa-B activation. Involved in endocytosis of low-density lipoprotein receptor/LDLR. Involved in endocytosis of smoothened homolog/Smo, which also requires ADRBK1. Involved in endocytosis of SLC9A5. Involved in endocytosis of ENG and subsequent TGF-beta-mediated ERK activation and migration of epithelial cells. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Involved in insulin resistance by acting as insulin-induced signaling scaffold for SRC, AKT1 and INSR. Involved in regulation of inhibitory signaling of natural killer cells by recruiting PTPN6 and PTPN11 to KIR2DL1. Ref.6 Ref.7 Ref.8 Ref.9 Ref.12 Ref.13
Homooligomer; the self-association is mediated by InsP6-binding Probable. Heterooligomer with ARRB1; the association is mediated by InsP6-binding. Interacts with ADRB2 AND CHRM2. Interacts with PDE4A. Interacts with PDE4D. Interacts with MAPK10, MAPK1 and MAPK3. Interacts with DRD2. Interacts with FSHR. Interacts with CLTC. Interacts with HTR2C. Interacts with CCR5. Interacts with CXCR4. Interacts with SRC. Interacts with DUSP16; the interaction is interrupted by stimulation of AGTR1 and activation of MAPK10. Interacts with CHUK; the interaction is enhanced stimulation of ADRB2. Interacts with RELA. Interacts with MDM2; the interaction is enhanced by activation of GPCRs. Interacts with SLC9A5. Interacts with TRAF6. Interacts with IGF1R. Interacts with ENG. Interacts with ARRB2. Interacts with KIR2DL1, KIR2DL3 and KIR2DL4. Interacts with LDLR. Interacts with AP2B1. Interacts with C5AR1. Interacts with RAF1. Interacts with MAP2K1. Interacts with MAPK1. Interacts with MAPK10; the interaction enhances MAPK10 activation by MAP3K5. Interacts with MAP2K4; the interaction is enhanced by presence of MAP3K5 and MAPK10. Interacts with MAP3K5. Interacts with AKT1. Interacts with IKBKB and MAP3K14. Interacts with SMO (activated). Interacts with GSK3A and GSK3B. Interacts with CXCR4; the interaction is dependent on C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with GPR143. Interacts with HCK and CXCR1 (phosphorylated) By similarity. Associates with protein phosphatase 2A (PP2A). Ref.7 Ref.10 Ref.13
Cytoplasm. Nucleus. Cell membrane. Membrane › clathrin-coated pit By similarity. Cytoplasmic vesicle By similarity. Note: Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. Ref.5
Predominantly localized in neuronal tissues and in the spleen.
Phosphorylated at Thr-383 in the cytoplasm; probably dephosphorylated at the plasma membrane. The phosphorylation does not regulate internalization and recycling of ADRB2, interaction with clathrin or AP2B1 By similarity.
The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occurr GPCR-specifc. Ubiquitinated by MDM2; the ubiquitination is required for rapid internalization of ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a dissociation of the beta-arrestin-GPCR complex. Stimulation of a class A GPCR, such as ADRB2, induces transient ubiquitination and subsequently promotes association with USP33. Stimulation of a class B GPCR promotes a sustained ubiquitination By similarity.
Hydroxylation by PHD2 modulates the rate of internalization by slowing down recruitment to the plasma membrane and inhibiting subsequent co-internalization with class A receptors By similarity.
Loss of beta-2 adrenergic receptor/ADRB2 ubiquitination. Reduction of dopamine-dependent behaviors, loss of Akt1 regulation by dopamine in the striatum and disruption of the dopamine-dependent interaction of Akt1 with its negative regulator, protein phosphatase 2A. Increased serum LDL-cholesterol levels upon high fat diet. Exacerbates insulin resistance. Elevated cytotoxicity of natural killer cells and lowered susceptibility to mouse cytomegalovirus infection. Ref.4 Ref.6 Ref.7 Ref.12 Ref.13
Belongs to the arrestin family.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: Q91YI4-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: Q91YI4-2) |
The sequence of this isoform differs from the canonical sequence as follows:
360-360: Q → QSAPIHPPLLCP
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 410||410||Beta-arrestin-2||PRO_0000205200|
|Region||241 – 410||170||Interaction with TRAF6 By similarity|
|Region||364 – 410||47||Interaction with AP2B1 By similarity|
|Motif||386 – 396||11||[DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif By similarity|
Amino acid modifications
|Modified residue||48||1||Phosphotyrosine Ref.11|
|Modified residue||176||1||Hydroxyproline; by PHD2 By similarity|
|Modified residue||181||1||Hydroxyproline; by PHD2 By similarity|
|Modified residue||361||1||Phosphoserine By similarity|
|Modified residue||383||1||Phosphothreonine By similarity|
|Alternative sequence||360||1||Q → QSAPIHPPLLCP in isoform 2.||VSP_020652|
|Mutagenesis||395||1||L → A: Nuclear localization. Causes nuclear relocalization of MAPK10. Ref.5|
|Sequence conflict||11||1||K → R in BAE41934. Ref.1|
|Sequence conflict||59||1||T → N in BAE41934. Ref.1|
|Sequence conflict||75||1||S → Y in BAE41934. Ref.1|
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Strain: C57BL/6J and NOD.
|||"Lineage-specific biology revealed by a finished genome assembly of the mouse."|
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
|||"Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin."|
Shenoy S.K., McDonald P.H., Kohout T.A., Lefkowitz R.J.
Science 294:1307-1313(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
|||"Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2."|
Scott M.G., Le Rouzic E., Perianin A., Pierotti V., Enslen H., Benichou S., Marullo S., Benmerah A.
J. Biol. Chem. 277:37693-37701(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, NUCLEOCYTOPLASMIC SHUTTLING, MUTAGENESIS OF LEU-395.
|||"The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor."|
Wu J.-H., Peppel K., Nelson C.D., Lin F.-T., Kohout T.A., Miller W.E., Exum S.T., Freedman N.J.
J. Biol. Chem. 278:44238-44245(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ENDOCYTOSIS OF LDLR, DISRUPTION PHENOTYPE.
|||"An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior."|
Beaulieu J.-M., Sotnikova T.D., Marion S., Lefkowitz R.J., Gainetdinov R.R., Caron M.G.
Cell 122:261-273(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AKT1 SIGNALING, ASSOCIATION WITH PP2A, INTERACTION WITH AKT1; GSK3A AND GSK3B, DISRUPTION PHENOTYPE.
|||"The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells."|
Lee N.Y., Blobe G.C.
J. Biol. Chem. 282:21507-21517(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTERNALIZATION OF ENG, FUNCTION IN TGF-BETA-MEDIATED ERK SIGNALING.
|||"Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle."|
Deshpande D.A., Theriot B.S., Penn R.B., Walker J.K.
FASEB J. 22:2134-2141(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN BETA-ADRENERGIC RECEPTOR REGULATION.
|||"Beta2-adrenergic receptor regulates Toll-like receptor-4-induced nuclear factor-kappaB activation through beta-arrestin 2."|
Kizaki T., Izawa T., Sakurai T., Haga S., Taniguchi N., Tajiri H., Watanabe K., Day N.K., Toba K., Ohno H.
Immunology 124:348-356(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CHUK.
|||"Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain."|
Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.
J. Proteome Res. 7:311-318(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-48, MASS SPECTROMETRY.
|||"An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer cells."|
Yu M.-C., Su L.-L., Zou L., Liu Y., Wu N., Kong L., Zhuang Z.-H., Sun L., Liu H.P., Hu J.-H., Li D., Strominger J.L., Zang J.-W., Pei G., Ge B.-X.
Nat. Immunol. 9:898-907(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF INNATE IMMUNE RESPONSE, DISRUPTION PHENOTYPE.
|||"Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance."|
Luan B., Zhao J., Wu H., Duan B., Shu G., Wang X., Li D., Jia W., Kang J., Pei G.
Nature 457:1146-1149(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INSULIN SIGNALING, INTERACTION WITH SRC; AKT1 AND INSR, DISRUPTION PHENOTYPE.
|+||Additional computationally mapped references.|
|AK154874 mRNA. Translation: BAE32894.1.|
AK159317 mRNA. Translation: BAE34984.1.
AK170647 mRNA. Translation: BAE41934.1.
AK170889 mRNA. Translation: BAE42096.1.
AL596096 Genomic DNA. Translation: CAI51985.1.
AL596096 Genomic DNA. Translation: CAI51987.1.
BC016642 mRNA. Translation: AAH16642.1.
|RefSeq||NP_001258287.1. NM_001271358.1. |
3D structure databases
|SMR||Q91YI4. Positions 6-394. |
Protein-protein interaction databases
|IntAct||Q91YI4. 4 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000079056; ENSMUSP00000078065; ENSMUSG00000060216. |
ENSMUST00000102563; ENSMUSP00000099623; ENSMUSG00000060216.
ENSMUST00000102564; ENSMUSP00000099624; ENSMUSG00000060216.
ENSMUST00000108568; ENSMUSP00000104208; ENSMUSG00000060216.
|UCSC||uc007jur.1. mouse. |
|MGI||MGI:99474. Arrb2. |
Gene expression databases
|GermOnline||ENSMUSG00000060216. Mus musculus. |
Family and domain databases
|Gene3D||126.96.36.1990. 1 hit. |
188.8.131.520. 1 hit.
|InterPro||IPR000698. Arrestin. |
|PANTHER||PTHR11792. PTHR11792. 1 hit. |
|Pfam||PF02752. Arrestin_C. 1 hit. |
PF00339. Arrestin_N. 1 hit.
|PRINTS||PR00309. ARRESTIN. |
|SMART||SM01017. Arrestin_C. 1 hit. |
|SUPFAM||SSF81296. Ig_E-set. 2 hits. |
|PROSITE||PS00295. ARRESTINS. 1 hit. |
|Accession||Primary (citable) accession number: Q91YI4|
Secondary accession number(s): Q3TCM2, Q5F2D8, Q5F2E0
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|