InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ARRB2

Summary

InnateDB Protein

IDBP-19267.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ARRB2

Protein Name

arrestin, beta 2

Synonyms

ARB2; ARR2; BARR2;

Species

Homo sapiens

Ensembl Protein

ENSP00000269260

InnateDB Gene

IDBG-19263 (ARRB2)

Protein Structure

UniProt Annotation

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. 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 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. Involved in IL8-mediated granule release in neutrophils. Involved in the internalization of the atypical chemokine receptor ACKR3. {ECO:0000269PubMed:10644702, ECO:0000269PubMed:11877451, ECO:0000269PubMed:12488444, ECO:0000269PubMed:12582207, ECO:0000269PubMed:12949261, ECO:0000269PubMed:12958365, ECO:0000269PubMed:14711824, ECO:0000269PubMed:15054093, ECO:0000269PubMed:15125834, ECO:0000269PubMed:15205453, ECO:0000269PubMed:15475570, ECO:0000269PubMed:15618519, ECO:0000269PubMed:15635042, ECO:0000269PubMed:15671180, ECO:0000269PubMed:15699339, ECO:0000269PubMed:15878855, ECO:0000269PubMed:16144840, ECO:0000269PubMed:16280323, ECO:0000269PubMed:16378096, ECO:0000269PubMed:16492667, ECO:0000269PubMed:16820410, ECO:0000269PubMed:17540773, ECO:0000269PubMed:18419762, ECO:0000269PubMed:18604210, ECO:0000269PubMed:19325136, ECO:0000269PubMed:19620252, ECO:0000269PubMed:19643177, ECO:0000269PubMed:20048153, ECO:0000269PubMed:22457824}.

Subcellular Localization

Cytoplasm. Nucleus. Cell membrane. Membrane, clathrin-coated pit {ECO:0000250}. Cytoplasmic vesicle. Note=Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs.

Disease Associations

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 388 experimentally validated interaction(s) in this database.
They are also associated with 6 interaction(s) predicted by orthology.

Experimentally validated
Total	388 [view]
Protein-Protein	386 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	6 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001664	G-protein coupled receptor binding
GO:0005102	receptor binding
GO:0005515	protein binding
GO:0019899	enzyme binding
GO:0031625	ubiquitin protein ligase binding
GO:0031701	angiotensin receptor binding
GO:0032947	protein complex scaffold

Biological Process

GO:0002031	G-protein coupled receptor internalization
GO:0002032	desensitization of G-protein coupled receptor protein signaling pathway by arrestin
GO:0002092	positive regulation of receptor internalization
GO:0006366	transcription from RNA polymerase II promoter
GO:0007179	transforming growth factor beta receptor signaling pathway
GO:0007219	Notch signaling pathway
GO:0007596	blood coagulation
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:0031623	receptor internalization
GO:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0045087	innate immune response (InnateDB)
GO:0045953	negative regulation of natural killer cell mediated cytotoxicity
GO:0060326	cell chemotaxis
GO:0060765	regulation of androgen receptor signaling pathway
GO:0070374	positive regulation of ERK1 and ERK2 cascade

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005905	coated pit
GO:0030139	endocytic vesicle
GO:0031410	cytoplasmic vesicle