Protein: P49407

Uniprot: 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. 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. Negatively regulates the NOTCH signaling pathway by mediating the ubiquitination and degradation of NOTCH1 by ITCH. Participates to the recruitment of the ubiquitin-protein ligase to the receptor (PubMed:23886940). more..

Function 1: Endocytic function, cytosolic regulator and scaffold of GPCR signaling. Condition: present in plasma membrane or cytoplasm.

Function 2: Positive regulation of transcription from RNA polymerase II promoter by facilitating the binding of transcription factors. Condition: nuclear localisation.

Publications (PMID): 26909598, 24837709

Module ID (MoonGO) GO ID (BP) GO Name
477 GO:0044271 cellular nitrogen compound biosynthetic process
477 GO:0090304 nucleic acid metabolic process
477 GO:1901362 organic cyclic compound biosynthetic process
477 GO:2000112 regulation of cellular macromolecule biosynthetic process
477 GO:0007165 signal transduction
706 GO:0044267 cellular protein metabolic process
706 GO:0090304 nucleic acid metabolic process
706 GO:0034654 nucleobase-containing compound biosynthetic process
706 GO:2000112 regulation of cellular macromolecule biosynthetic process
706 GO:0010468 regulation of gene expression
706 GO:0019219 regulation of nucleobase-containing compound metabolic process
706 GO:0007165 signal transduction
Module ID (MoonGO) GO ID (CC) GO Name
317 GO:0005829 cytosol
477 GO:0005829 cytosol
477 GO:0070013 intracellular organelle lumen
477 GO:0044428 nuclear part
706 GO:0005829 cytosol
706 GO:0031981 nuclear lumen
GO ID (BP) GO Name Evidence Code (GO EC)
GO:0000187 activation of MAPK activity IEA
GO:0001934 positive regulation of protein phosphorylation IMP
GO:0002031 G-protein coupled receptor internalization IMP
GO:0002092 positive regulation of receptor internalization IMP
GO:0006366 transcription from RNA polymerase II promoter IMP
GO:0006511 ubiquitin-dependent protein catabolic process IMP
GO:0006915 apoptotic process IEA
GO:0007186 G-protein coupled receptor signaling pathway TAS
GO:0007602 phototransduction IEA
GO:0015031 protein transport IEA
GO:0016567 protein ubiquitination IMP
GO:0030168 platelet activation TAS
GO:0031397 negative regulation of protein ubiquitination IDA
GO:0031398 positive regulation of protein ubiquitination IEA
GO:0032088 negative regulation of NF-kappaB transcription factor activity IDA
GO:0032092 positive regulation of protein binding IEA
GO:0032715 negative regulation of interleukin-6 production IDA
GO:0032717 negative regulation of interleukin-8 production IDA
GO:0033138 positive regulation of peptidyl-serine phosphorylation IEA
GO:0034260 negative regulation of GTPase activity IEA
GO:0034393 positive regulation of smooth muscle cell apoptotic process IEA
GO:0035025 positive regulation of Rho protein signal transduction IMP
GO:0035066 positive regulation of histone acetylation IMP
GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus IEA
GO:0042493 response to drug IEA
GO:0042699 follicle-stimulating hormone signaling pathway IEA
GO:0043149 stress fiber assembly IMP
GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process IEA
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process IMP
GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process IEA
GO:0043547 positive regulation of GTPase activity IEA
GO:0045746 negative regulation of Notch signaling pathway IMP
GO:0045944 positive regulation of transcription from RNA polymerase II promoter IMP
GO:0061024 membrane organization TAS
GO:0070373 negative regulation of ERK1 and ERK2 cascade IEA
GO:0070374 positive regulation of ERK1 and ERK2 cascade IDA
GO:0090240 positive regulation of histone H4 acetylation IMP
GO ID (CC) GO Name Evidence Code (GO EC)
GO:0000139 Golgi membrane TAS
GO:0000785 chromatin IDA
GO:0005634 nucleus IDA
GO:0005654 nucleoplasm IDA
GO:0005737 cytoplasm IDA
GO:0005765 lysosomal membrane TAS
GO:0005829 cytosol TAS
GO:0005834 heterotrimeric G-protein complex TAS
GO:0005886 plasma membrane TAS
GO:0005905 clathrin-coated pit IEA
GO:0014069 postsynaptic density IEA
GO:0016323 basolateral plasma membrane IEA
GO:0016604 nuclear body IDA
GO:0030659 cytoplasmic vesicle membrane TAS
GO:0031143 pseudopodium IEA
GO:0031410 cytoplasmic vesicle IDA
GO:0043197 dendritic spine IEA
GO:0045211 postsynaptic membrane IEA
GO ID 1 Component 1 GO ID 2 Component 2 Association Probability (PrOnto) Interaction Probability (PrOnto)
GO:0000139 Golgi membrane GO:0000785 chromatin 1.38e-03 1.45e-74
GO:0000139 Golgi membrane GO:0005634 nucleus 1.09e-30 1.17e-81
GO:0000139 Golgi membrane GO:0005654 nucleoplasm 1.29e-15 1.09e-99
GO:0000139 Golgi membrane GO:0016604 nuclear body 7.78e-05 1.07e-91
GO:0000785 chromatin GO:0005737 cytoplasm 2.75e-08 6.83e-23
GO:0000785 chromatin GO:0005886 plasma membrane 3.25e-35 5.24e-112
GO:0000785 chromatin GO:0030659 cytoplasmic vesicle membrane 5.34e-04 2.56e-83
GO:0000785 chromatin GO:0031410 cytoplasmic vesicle 3.82e-16 5.69e-185
GO:0005634 nucleus GO:0005765 lysosomal membrane 3.45e-10 9.81e-32
GO:0005634 nucleus GO:0005886 plasma membrane 5.35e-300 7.52e-165
GO:0005634 nucleus GO:0030659 cytoplasmic vesicle membrane 4.71e-30 7.28e-80
GO:0005634 nucleus GO:0031410 cytoplasmic vesicle 9.49e-36 4.91e-56
GO:0005634 nucleus GO:0045211 postsynaptic membrane 4.18e-05 1.09e-18
GO:0005654 nucleoplasm GO:0005765 lysosomal membrane 7.59e-07 1.29e-14
GO:0005654 nucleoplasm GO:0005886 plasma membrane 9.14e-199 6.17e-196
GO:0005654 nucleoplasm GO:0016323 basolateral plasma membrane 7.74e-03 2.03e-05
GO:0005654 nucleoplasm GO:0030659 cytoplasmic vesicle membrane 1.28e-24 2.03e-103
GO:0005654 nucleoplasm GO:0031410 cytoplasmic vesicle 2.02e-39 4.57e-107
GO:0005654 nucleoplasm GO:0045211 postsynaptic membrane 4.67e-04 3.99e-53
GO:0005886 plasma membrane GO:0016604 nuclear body 1.42e-38 3.32e-172
GO:0016604 nuclear body GO:0030659 cytoplasmic vesicle membrane 9.09e-03 3.59e-97
GO:0016604 nuclear body GO:0031410 cytoplasmic vesicle 2.75e-08 1.99e-132
PMID Article Title
8486659 Molecular analysis of human beta-arrestin-1: cloning, tissue distribution, and regulation of expression. Identification of two isoforms generated by alternative splicing.
9501202 Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2.
9924018 Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
10066734 Targeted construction of phosphorylation-independent beta-arrestin mutants with constitutive activity in cells.
10748214 Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors.
10973280 Regulation of tyrosine kinase activation and granule release through beta-arrestin by CXCRI.
12464600 Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway.
14711824 Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.
15475570 Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking.
15489334 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).
15611106 beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation.
15671180 Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.
15878855 {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase.
16144840 G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers.
16280323 beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor.
16325578 A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription.
16378096 Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling.
16492667 Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation.
16516836 Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly.
16524428 The melanosomal/lysosomal protein OA1 has properties of a G protein-coupled receptor.
16709866 Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation.
16903783 Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly.
17456551 Src-dependent phosphorylation of beta2-adaptin dissociates the beta-arrestin-AP-2 complex.
18337459 Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle.
18419762 Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms.
19363159 Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
19413330 Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach.
19620252 An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages.
19643177 Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and activation of ERK1/2.
19661922 Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling.
19782076 A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex.
20068231 Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.
21269460 Initial characterization of the human central proteome.
21406692 System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.
22457824 Ubiquitination of CXCR7 controls receptor trafficking.
23186163 Toward a comprehensive characterization of a human cancer cell phosphoproteome.
23341447 Beta-arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR.
23633677 Beta-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6.
23886940 Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals.
24275569 An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.
28827538 Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor reciprocally modulate their signaling functions.
No results found.
Domain Name Domain ID Source
B46682 B46682 PIR
Arrestin IPR000698 InterPro
Arrestin-like_N IPR011021 InterPro
Arrestin_C-like IPR011022 InterPro
Arrestin_C IPR014752 InterPro
Arrestin_N IPR014753 InterPro
Ig_E-set IPR014756 InterPro
Arrestin_CS IPR017864 InterPro
Arrestin_N PF00339 Pfam
Arrestin_C PF02752 Pfam
Arrestin_C SM01017 SMART
SSF81296 SSF81296 SUPFAM