ID:ARRB1_HUMAN DESCRIPTION: RecName: Full=Beta-arrestin-1; AltName: Full=Arrestin beta-1; FUNCTION: 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. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils. SUBUNIT: Monomer. Homodimer. Homooligomer; the self-association is mediated by InsP6-binding. Heterooligomer with ARRB2; the association is mediated by InsP6-binding. Interacts with GPR143. Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CASR. Interacts with AP2B1 (dephosphorylated at 'Tyr-737'); phosphorylation of AP2B1 at 'Tyr-737' 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 CHUK, IKBKB and MAP3K14. 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. 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) (By similarity). Interacts with MAP2K4/MKK4. Interacts with HCK and CXCR1 (phosphorylated). INTERACTION: P62158:CALM3; NbExp=3; IntAct=EBI-743313, EBI-397435; Q14749:GNMT; NbExp=5; IntAct=EBI-743313, EBI-744239; P06396:GSN; NbExp=3; IntAct=EBI-743313, EBI-351506; Q16665:HIF1A; NbExp=3; IntAct=EBI-743313, EBI-447269; P11142:HSPA8; NbExp=4; IntAct=EBI-743313, EBI-351896; P19338:NCL; NbExp=3; IntAct=EBI-743313, EBI-346967; Q14978:NOLC1; NbExp=3; IntAct=EBI-743313, EBI-396155; P14618:PKM; NbExp=3; IntAct=EBI-743313, EBI-353408; P35813:PPM1A; NbExp=4; IntAct=EBI-743313, EBI-989143; O75688:PPM1B; NbExp=4; IntAct=EBI-743313, EBI-1047039; Q13523:PRPF4B; NbExp=2; IntAct=EBI-743313, EBI-395940; P06702:S100A9; NbExp=2; IntAct=EBI-743313, EBI-1055001; Q15208:STK38; NbExp=3; IntAct=EBI-743313, EBI-458376; Q13428:TCOF1; NbExp=3; IntAct=EBI-743313, EBI-396105; P27348:YWHAQ; NbExp=3; IntAct=EBI-743313, EBI-359854; P25490:YY1; NbExp=4; IntAct=EBI-743313, EBI-765538; O95218:ZRANB2; NbExp=4; IntAct=EBI-743313, EBI-1051583; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane. Membrane, clathrin-coated pit (Probable). Cell projection, pseudopodium (By similarity). Cytoplasmic vesicle. 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). DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates interaction the AP-2 complex subunit AP2B1 (By similarity). Binding to phosphorylated GPCRs induces a conformationanl change that exposes the motif to the surface. DOMAIN: The N-terminus binds InsP6 with low affinity (By similarity). DOMAIN: The C-terminus binds InsP6 with high affinity (By similarity). PTM: Constitutively phosphorylated at Ser-412 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. PTM: 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. SIMILARITY: Belongs to the arrestin family. WEB RESOURCE: Name=Wikipedia; Note=Arrestin entry; URL="http://en.wikipedia.org/wiki/Arrestin";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P49407
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000187 activation of MAPK activity GO:0001933 negative regulation of protein phosphorylation GO:0001934 positive regulation of protein phosphorylation GO:0002031 G-protein coupled receptor internalization GO:0002092 positive regulation of receptor internalization GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006511 ubiquitin-dependent protein catabolic process GO:0006897 endocytosis GO:0006915 apoptotic process GO:0007165 signal transduction GO:0007186 G-protein coupled receptor signaling pathway GO:0007602 phototransduction GO:0008277 regulation of G-protein coupled receptor protein signaling pathway GO:0008284 positive regulation of cell proliferation GO:0009968 negative regulation of signal transduction GO:0015031 protein transport GO:0016567 protein ubiquitination GO:0030168 platelet activation GO:0031397 negative regulation of protein ubiquitination GO:0031398 positive regulation of protein ubiquitination GO:0032088 negative regulation of NF-kappaB transcription factor activity GO:0032092 positive regulation of protein binding GO:0032715 negative regulation of interleukin-6 production GO:0032717 negative regulation of interleukin-8 production GO:0033138 positive regulation of peptidyl-serine phosphorylation GO:0034260 negative regulation of GTPase activity GO:0034393 positive regulation of smooth muscle cell apoptotic process GO:0035025 positive regulation of Rho protein signal transduction GO:0035066 positive regulation of histone acetylation GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus GO:0042493 response to drug GO:0042699 follicle-stimulating hormone signaling pathway GO:0042981 regulation of apoptotic process GO:0043066 negative regulation of apoptotic process GO:0043149 stress fiber assembly GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043524 negative regulation of neuron apoptotic process GO:0043547 positive regulation of GTPase activity GO:0045746 negative regulation of Notch signaling pathway GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0061024 membrane organization GO:0070373 negative regulation of ERK1 and ERK2 cascade GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0090240 positive regulation of histone H4 acetylation
AL157484 - Homo sapiens mRNA; cDNA DKFZp762M127 (from clone DKFZp762M127). AK293758 - Homo sapiens cDNA FLJ53544 complete cds. JD132015 - Sequence 113039 from Patent EP1572962. JD277842 - Sequence 258866 from Patent EP1572962. JD227893 - Sequence 208917 from Patent EP1572962. JD320615 - Sequence 301639 from Patent EP1572962. JD246207 - Sequence 227231 from Patent EP1572962. JD521872 - Sequence 502896 from Patent EP1572962. JD047974 - Sequence 28998 from Patent EP1572962. JD290834 - Sequence 271858 from Patent EP1572962. JD109754 - Sequence 90778 from Patent EP1572962. JD356948 - Sequence 337972 from Patent EP1572962. JD224506 - Sequence 205530 from Patent EP1572962. JD268137 - Sequence 249161 from Patent EP1572962. JD343931 - Sequence 324955 from Patent EP1572962. JD418873 - Sequence 399897 from Patent EP1572962. JD272301 - Sequence 253325 from Patent EP1572962. JD338161 - Sequence 319185 from Patent EP1572962. JD506420 - Sequence 487444 from Patent EP1572962. JD061517 - Sequence 42541 from Patent EP1572962. JD171224 - Sequence 152248 from Patent EP1572962. JD347979 - Sequence 329003 from Patent EP1572962. JD355867 - Sequence 336891 from Patent EP1572962. JD500448 - Sequence 481472 from Patent EP1572962. JD313696 - Sequence 294720 from Patent EP1572962. JD180997 - Sequence 162021 from Patent EP1572962. JD108832 - Sequence 89856 from Patent EP1572962. JD200862 - Sequence 181886 from Patent EP1572962. JD189664 - Sequence 170688 from Patent EP1572962. JD540053 - Sequence 521077 from Patent EP1572962. JD561567 - Sequence 542591 from Patent EP1572962. JD422966 - Sequence 403990 from Patent EP1572962. JD205168 - Sequence 186192 from Patent EP1572962. JD484887 - Sequence 465911 from Patent EP1572962. JD433934 - Sequence 414958 from Patent EP1572962. BC003636 - Homo sapiens arrestin, beta 1, mRNA (cDNA clone MGC:4082 IMAGE:3604829), complete cds. DL491304 - Novel nucleic acids. DL489941 - Novel nucleic acids. AK289718 - Homo sapiens cDNA FLJ75454 complete cds, highly similar to Homo sapiens arrestin, beta 1 (ARRB1), transcript variant 1, mRNA. AF084040 - Homo sapiens beta-arrestin 1A mRNA, complete cds. AF084940 - Homo sapiens beta-arrestin 1B mRNA, complete cds. JD476259 - Sequence 457283 from Patent EP1572962. JD369267 - Sequence 350291 from Patent EP1572962. FJ348262 - Homo sapiens arrestin beta 1 transcript variant 2 (ARRB1) mRNA, complete cds. HQ447288 - Synthetic construct Homo sapiens clone IMAGE:100070599; CCSB004044_01 arrestin, beta 1 (ARRB1) gene, encodes complete protein. KJ890712 - Synthetic construct Homo sapiens clone ccsbBroadEn_00106 ARRB1 gene, encodes complete protein. L04685 - Homo sapiens beta-arrestin 1 mRNA, 5` end. AB462955 - Synthetic construct DNA, clone: pF1KB4976, Homo sapiens ARRB1 gene for arrestin, beta 1, without stop codon, in Flexi system. AK074660 - Homo sapiens cDNA FLJ90179 fis, clone MAMMA1000652. CU678548 - Synthetic construct Homo sapiens gateway clone IMAGE:100019311 5' read ARRB1 mRNA. HI979367 - Sequence 1 from Patent WO2010142603.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_barr-mapkPathway - Role of ¿-arrestins in the activation and targeting of MAP kinases h_bArrestinPathway - ¿-arrestins in GPCR Desensitization h_bArrestin-srcPathway - Roles of ¿-arrestin-dependent Recruitment of Src Kinases in GPCR Signaling h_agpcrPathway - Attenuation of GPCR Signaling
Reactome (by CSHL, EBI, and GO)
Protein P49407 (Reactome details) participates in the following event(s):
R-HSA-418091 Activated PAR1 binds Beta-arrestin-1 R-HSA-421833 Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture R-HSA-432712 Vamp And trans-Golgi Network AP-1 Binding Coupled With Cargo Capture On Lysosome Vesicle Destined Golgi Membrane R-HSA-421836 trans-Golgi Network Derived Vesicle Uncoating R-HSA-432688 trans-Golgi Network Derived Lysosomal Vesicle Uncoating R-HSA-418170 Beta-arrestin-1 acts as scaffold for a PAR1 signalling complex R-HSA-1980123 DTX recruits beta-arrestin (ARRB) to NOTCH R-HSA-5632667 SMO dimer binds ARRB and KIF3A R-HSA-8852167 ADRB2:Catecholamine binds ARRB1, ARRB2 R-HSA-8866269 ARRB bind GPCRs R-HSA-5672972 MAP2Ks and MAPKs bind to the activated RAF complex R-HSA-6802912 High kinase activity BRAF mutants bind MAP2Ks and MAPKs R-HSA-6802914 RAS:GTP:moderate kinase activity p-RAF complexes bind MAP2Ks and MAPKs R-HSA-6802925 Mutant RAS:p-RAF complexes bind MAP2Ks and MAPKs R-HSA-6802934 p-BRAF and RAF fusion dimers bind MAP2Ks and MAPKs R-HSA-6802942 RAS:GTP:p-RAF complexes paradoxically bind MAP2Ks and MAPKs R-HSA-5672980 Dissociation of RAS:RAF complex R-HSA-6802932 Dissociation of BRAF/RAF fusion complex R-HSA-6803227 Dissociation of high activity BRAF complexes R-HSA-6803230 Dissociation of moderate activity BRAF complexes R-HSA-6803233 Dissociation of oncogenic RAS:RAF complex R-HSA-6803234 Dissociation of paradoxically activated RAS:BRAF complexes R-HSA-421831 trans-Golgi Network Coat Assembly R-HSA-432706 trans-Golgi Network Lysosome Vesicle Destined Membrane Coat Assembly R-HSA-421835 trans-Golgi Network Vesicle Scission R-HSA-432707 trans-Golgi Network Lysosomal Vesicle Scission R-HSA-8866283 ARBB recruits GPCRs into clathrin-coated pits R-HSA-5672978 RAF phosphorylates MAP2K dimer R-HSA-5672973 MAP2Ks phosphorylate MAPKs R-HSA-6802918 Activated MAP2Ks phosphorylate MAPKs downstream of inactive BRAF mutants R-HSA-6802943 RAS:GTP:inactive p-RAF complexes phosphorylate MAP2Ks R-HSA-6802919 RAS:GTP:moderate kinase activity p-RAF complexes phosphorylate MAP2Ks R-HSA-6802921 Activated MAP2Ks phosphorylate MAPKs downstream of moderate kinase activity BRAF mutants R-HSA-6802911 High kinase activity BRAF complexes phosphorylate MAP2Ks R-HSA-6802910 Activated MAP2Ks phosphorylate MAPKs downstream of high kinase activity BRAF mutants R-HSA-6802926 Mutant RAS:p-RAF complexes phosphorylate MAP2Ks R-HSA-6802922 Activated MAP2Ks phosphorylate MAPKs downstream of oncogenic RAS R-HSA-6802933 p-BRAF and RAF fusion dimers phosphorylate MAP2Ks R-HSA-6802935 MAPKs are phosphorylated downstream of BRAF and RAF fusion dimers R-HSA-5696945 USP33 deubiquitinates CCP110,ARRB R-HSA-8867756 CLASP proteins and cargo are recruited to the nascent clathrin-coated pit R-HSA-8868071 Clathrin recruits PIK3C2A R-HSA-8868661 Dynamin-mediated GTP hydrolysis promotes vesicle scission R-HSA-8868648 SYNJ hydrolyze PI(4,5)P2 to PI(4)P R-HSA-8871194 RAB5 and GAPVD1 bind AP-2 R-HSA-8868658 HSPA8-mediated ATP hydrolysis promotes vesicle uncoating R-HSA-8868659 Clathrin recruits auxilins to the clathrin-coated vesicle R-HSA-8868660 Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle R-HSA-8867754 F- and N- BAR domain proteins bind the clathrin-coated pit R-HSA-8868230 SNX9 recruits components of the actin polymerizing machinery R-HSA-8868072 Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2 R-HSA-8868236 BAR domain proteins recruit dynamin R-HSA-8868651 Endophilins recruit synaptojanins to the clathrin-coated pit R-HSA-456926 Thrombin signalling through proteinase activated receptors (PARs) R-HSA-432722 Golgi Associated Vesicle Biogenesis R-HSA-432720 Lysosome Vesicle Biogenesis R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus R-HSA-5635838 Activation of SMO R-HSA-418555 G alpha (s) signalling events R-HSA-8856825 Cargo recognition for clathrin-mediated endocytosis R-HSA-5674135 MAP2K and MAPK activation R-HSA-6802948 Signaling by high-kinase activity BRAF mutants R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants R-HSA-6802949 Signaling by RAS mutants R-HSA-6802952 Signaling by BRAF and RAF fusions R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF R-HSA-76002 Platelet activation, signaling and aggregation R-HSA-421837 Clathrin derived vesicle budding R-HSA-1980143 Signaling by NOTCH1 R-HSA-5632684 Hedgehog 'on' state R-HSA-388396 GPCR downstream signalling R-HSA-8856828 Clathrin-mediated endocytosis R-HSA-5673001 RAF/MAP kinase cascade R-HSA-6802957 Oncogenic MAPK signaling R-HSA-5689880 Ub-specific processing proteases R-HSA-109582 Hemostasis R-HSA-199992 trans-Golgi Network Vesicle Budding R-HSA-157118 Signaling by NOTCH R-HSA-5358351 Signaling by Hedgehog R-HSA-372790 Signaling by GPCR R-HSA-199991 Membrane Trafficking R-HSA-5684996 MAPK1/MAPK3 signaling R-HSA-5663202 Diseases of signal transduction R-HSA-5688426 Deubiquitination R-HSA-162582 Signal Transduction R-HSA-5653656 Vesicle-mediated transport R-HSA-5683057 MAPK family signaling cascades R-HSA-1643685 Disease R-HSA-597592 Post-translational protein modification R-HSA-392499 Metabolism of proteins
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
