Q8BWG8 (ARRB1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 93. 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||418 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. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. 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). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. 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). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. 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. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. 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 IL8-mediated granule release in neutrophils. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) By similarity. Required for atypical chemokine receptor ACKR2-induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. Involved in the internalization of the atypical chemokine receptor ACKR3 By similarity. Ref.3 Ref.5
Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated); phosphorylation of AP2B1 disrupts the interaction. Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CCR2 and ADRBK1. Interacts with CRR5. Interacts with PTAFR (phosphorylated on serine residues). Interacts with CLTC and MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. Interacts with SRC (via the SH3 domain and the protein kinase domain); the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with TACR1. Interacts with RAF1. Interacts with DVL1; the interaction is enhanced by phosphorylation of DVL1. Interacts with DVL2; the interaction is enhanced by phosphorylation of DVL2. Interacts with IGF1R. Interacts with CHUK, IKBKB and MAP3K14. Associates with MAP kinase p38. Part of a MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 (activated) and MAPK3 (activated). Part of a MAPK signaling complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and MAPK3 (activated). Interacts with GPR143 By similarity. Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated) By similarity. Interacts with ACKR3 and ACKR4 By similarity.
Cytoplasm By similarity. Nucleus By similarity. Cell membrane By similarity. Membrane › clathrin-coated pit Probable. Cell projection › pseudopodium By similarity. Cytoplasmic vesicle By similarity. Note: Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs. The monomeric form is predominantly located in the nucleus. The oligomeric form is located in the cytoplasm. Translocates to the nucleus upon stimulation of OPRD1 By similarity.
The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1. Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface By similarity.
The N-terminus binds InsP6 with low affinity By similarity.
The C-terminus binds InsP6 with high affinity By similarity.
Constitutively phosphorylated at in the cytoplasm. At the plasma membrane, is rapidly dephosphorylated, a process that is required for clathrin binding and ADRB2 endocytosis but not for ADRB2 binding and desensitization. Once internalized, is rephosphorylated By similarity.
The ubiquitination status appears to regulate the formation and trafficking of beta-arrestin-GPCR complexes and signaling. Ubiquitination appears to occur GPCR-specific. 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 By similarity.
Belongs to the arrestin family.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1A (identifier: Q8BWG8-1) |
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 1B (identifier: Q8BWG8-2) |
The sequence of this isoform differs from the canonical sequence as follows:
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 418||418||Beta-arrestin-1||PRO_0000205195|
|Region||1 – 163||163||Interaction with SRC By similarity|
|Region||45 – 86||42||Interaction with CHRM2 By similarity|
|Region||318 – 418||101||Interaction with TRAF6 By similarity|
|Binding site||250||1||Inositol hexakisphosphate By similarity|
|Binding site||255||1||Inositol hexakisphosphate By similarity|
|Binding site||324||1||Inositol hexakisphosphate By similarity|
|Binding site||326||1||Inositol hexakisphosphate By similarity|
Amino acid modifications
|Modified residue||47||1||Phosphotyrosine Ref.4|
|Modified residue||412||1||Phosphoserine; by GRK5 By similarity|
|Alternative sequence||334 – 341||8||Missing in isoform 1B.||VSP_019545|
|||"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 1A AND 1B).
Tissue: Colon and Kidney.
|||"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 1B).
|||"Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis."|
Povsic T.J., Kohout T.A., Lefkowitz R.J.
J. Biol. Chem. 278:51334-51339(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AKT1 SIGNALING.
|||"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling."|
Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R.
J. Immunol. 179:5864-5876(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-47, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Mast cell.
|||"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.
|+||Additional computationally mapped references.|
|AK052588 mRNA. Translation: BAC35050.1.|
AK090090 mRNA. Translation: BAC41087.1.
AK144054 mRNA. Translation: BAE25673.1.
AK147508 mRNA. Translation: BAE27962.1.
AK165514 mRNA. Translation: BAE38230.1.
BC108969 mRNA. Translation: AAI08970.1.
BC108970 mRNA. Translation: AAI08971.1.
|RefSeq||NP_796205.1. NM_177231.2. |
3D structure databases
|SMR||Q8BWG8. Positions 5-393. |
Protein-protein interaction databases
|BioGrid||224960. 5 interactions.|
|IntAct||Q8BWG8. 15 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000032995; ENSMUSP00000032995; ENSMUSG00000018909. [Q8BWG8-2]|
ENSMUST00000098266; ENSMUSP00000095866; ENSMUSG00000018909. [Q8BWG8-1]
|UCSC||uc009ilu.1. mouse. [Q8BWG8-1]|
uc009ilv.1. mouse. [Q8BWG8-2]
|MGI||MGI:99473. Arrb1. |
Gene expression databases
Family and domain databases
|Gene3D||220.127.116.110. 1 hit. |
18.104.22.1680. 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. SSF81296. 2 hits. |
|PROSITE||PS00295. ARRESTINS. 1 hit. |
|Accession||Primary (citable) accession number: Q8BWG8|
Secondary accession number(s): Q3UH95, Q8BTJ5
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|