Protein: P32121

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. 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 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 other 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 GRK2. 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. Involved in IL8-mediated granule release in neutrophils. Involved in the internalization of the atypical chemokine receptor ACKR3. more..

Function 1: Endocytic function, cytosolic regulator and scaffold of 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): 12582207, 16820410

Module ID (MoonGO) GO ID (BP) GO Name
175 GO:0044267 cellular protein metabolic process
175 GO:0006139 nucleobase-containing compound metabolic process
175 GO:0010468 regulation of gene expression
549 GO:0008219 cell death
549 GO:0070887 cellular response to chemical stimulus
549 GO:0033554 cellular response to stress
549 GO:0035556 intracellular signal transduction
549 GO:0031325 positive regulation of cellular metabolic process
549 GO:0010604 positive regulation of macromolecule metabolic process
549 GO:0051173 positive regulation of nitrogen compound metabolic process
549 GO:0048584 positive regulation of response to stimulus
549 GO:0006468 protein phosphorylation
549 GO:0051252 regulation of RNA metabolic process
549 GO:2000112 regulation of cellular macromolecule biosynthetic process
549 GO:0032268 regulation of cellular protein metabolic process
549 GO:0010468 regulation of gene expression
549 GO:0009966 regulation of signal transduction
549 GO:0006351 transcription, DNA-templated
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
736 GO:0006139 nucleobase-containing compound metabolic process
736 GO:0060255 regulation of macromolecule metabolic process
Module ID (MoonGO) GO ID (CC) GO Name
175 GO:0005829 cytosol
175 GO:0005634 nucleus
317 GO:0005829 cytosol
549 GO:0005829 cytosol
549 GO:0005634 nucleus
706 GO:0005829 cytosol
706 GO:0031981 nuclear lumen
736 GO:0005829 cytosol
736 GO:0070013 intracellular organelle lumen
736 GO:0044428 nuclear part
GO ID (BP) GO Name Evidence Code (GO EC)
GO:0001933 negative regulation of protein phosphorylation IEA
GO:0002031 G-protein coupled receptor internalization TAS
GO:0002032 desensitization of G-protein coupled receptor protein signaling pathway by arrestin IMP
GO:0002092 positive regulation of receptor internalization IMP
GO:0006366 transcription from RNA polymerase II promoter IDA
GO:0007179 transforming growth factor beta receptor signaling pathway IDA
GO:0007186 G-protein coupled receptor signaling pathway TAS
GO:0007212 dopamine receptor signaling pathway NAS
GO:0007420 brain development IEA
GO:0007628 adult walking behavior IEA
GO:0010628 positive regulation of gene expression IEA
GO:0015031 protein transport IEA
GO:0016567 protein ubiquitination IMP
GO:0016579 protein deubiquitination TAS
GO:0030168 platelet activation TAS
GO:0031397 negative regulation of protein ubiquitination IDA
GO:0031398 positive regulation of protein ubiquitination IGI
GO:0031623 receptor internalization IDA
GO:0032088 negative regulation of NF-kappaB transcription factor activity IDA
GO:0032226 positive regulation of synaptic transmission, dopaminergic IEA
GO:0032691 negative regulation of interleukin-1 beta production IEA
GO:0032695 negative regulation of interleukin-12 production IEA
GO:0032715 negative regulation of interleukin-6 production IEA
GO:0032720 negative regulation of tumor necrosis factor production IEA
GO:0033138 positive regulation of peptidyl-serine phosphorylation IEA
GO:0034122 negative regulation of toll-like receptor signaling pathway IEA
GO:0034260 negative regulation of GTPase activity IEA
GO:0034392 negative regulation of smooth muscle cell apoptotic process IEA
GO:0042699 follicle-stimulating hormone signaling pathway IEA
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:0045953 negative regulation of natural killer cell mediated cytotoxicity IMP
GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation IEA
GO:0050965 detection of temperature stimulus involved in sensory perception of pain IEA
GO:0051897 positive regulation of protein kinase B signaling IEA
GO:0051898 negative regulation of protein kinase B signaling NAS
GO:0051928 positive regulation of calcium ion transport IEA
GO:0060071 Wnt signaling pathway, planar cell polarity pathway TAS
GO:0060326 cell chemotaxis IMP
GO:0060765 regulation of androgen receptor signaling pathway IDA
GO:0061024 membrane organization TAS
GO:0070374 positive regulation of ERK1 and ERK2 cascade IMP
GO:0090201 negative regulation of release of cytochrome c from mitochondria IEA
GO:0099565 chemical synaptic transmission, postsynaptic NAS
GO:2000573 positive regulation of DNA biosynthetic process IEA
GO:2000727 positive regulation of cardiac muscle cell differentiation IEA
GO ID (CC) GO Name Evidence Code (GO EC)
GO:0005634 nucleus IDA
GO:0005737 cytoplasm IDA
GO:0005829 cytosol TAS
GO:0005886 plasma membrane TAS
GO:0005905 clathrin-coated pit IEA
GO:0014069 postsynaptic density IEA
GO:0016323 basolateral plasma membrane IEA
GO:0030139 endocytic vesicle IDA
GO:0031410 cytoplasmic vesicle IDA
GO:0043197 dendritic spine IEA
GO:0043231 intracellular membrane-bounded organelle IDA
GO:0045211 postsynaptic membrane IEA
GO ID 1 Component 1 GO ID 2 Component 2 Association Probability (PrOnto) Interaction Probability (PrOnto)
GO:0005634 nucleus GO:0005886 plasma membrane 5.35e-300 7.52e-165
GO:0005634 nucleus GO:0030139 endocytic vesicle 6.33e-08 3.61e-43
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:0005886 plasma membrane GO:0043231 intracellular membrane-bounded organelle 0.00e+00 3.79e-47
GO:0043231 intracellular membrane-bounded organelle GO:0045211 postsynaptic membrane 8.76e-11 1.68e-02
PMID Article Title
1587386 Cloning of a member of the arrestin family from a human thyroid cDNA library.
9346876 A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation.
10644702 beta-arrestin differentially regulates the chemokine receptor CXCR4-mediated signaling and receptor internalization, and this implicates multiple interaction sites between beta-arrestin and CXCR4.
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.
11279203 Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*.
11877451 Regulation of arrestin-3 phosphorylation by casein kinase II.
12488444 Beta-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2.
12582207 Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference.
12949261 Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.
12958365 Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling.
14702039 Complete sequencing and characterization of 21,243 full-length human cDNAs.
14711824 Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.
15054093 Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7.
15125834 Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways.
15205453 Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor.
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).
15618519 Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2.
15635042 Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis.
15671180 Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor.
15699339 beta-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform.
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.
15888437 Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2.
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.
16319069 A beta-arrestin binding determinant common to the second intracellular loops of rhodopsin family G protein-coupled receptors.
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.
16625196 DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.
16820410 Novel function of beta-arrestin2 in the nucleus of mature spermatozoa.
17540773 The interaction of endoglin with beta-arrestin2 regulates transforming growth factor-beta-mediated ERK activation and migration in endothelial cells.
18419762 Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms.
18604210 An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer cells.
19325136 The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2.
19363159 Beta-arrestin-dependent signaling and trafficking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2.
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.
19782076 A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex.
20048153 Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling.
21255264 Prolyl hydroxylase 2: a novel regulator of beta2 -adrenoceptor internalization.
22300987 Carboxy-terminus of CXCR7 regulates receptor localization and function.
22457824 Ubiquitination of CXCR7 controls receptor trafficking.
23341447 Beta-arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR.
23886940 Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals.
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
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
S18984 S18984 PIR
Arrestin_C SM01017 SMART
SSF81296 SSF81296 SUPFAM