InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Arrb2

Summary

InnateDB Protein

IDBP-264255.6

Last Modified

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

Gene Symbol

Arrb2

Protein Name

arrestin, beta 2

Synonyms

Species

Mus musculus

Ensembl Protein

ENSMUSP00000104208

InnateDB Gene

IDBG-194248 (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 IL8-mediated granule release in neutrophils (By similarity). 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 the internalization of the atypical chemokine receptor ACKR3 (By similarity). {ECO:0000250}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:12167659}. Nucleus {ECO:0000269PubMed:12167659}. Cell membrane {ECO:0000269PubMed:12167659}. Membrane, clathrin-coated pit {ECO:0000250}. Cytoplasmic vesicle {ECO:0000250}. Note=Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs.

Disease Associations

Tissue Specificity

Predominantly localized in neuronal tissues and in the spleen.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 26 experimentally validated interaction(s) in this database.
They are also associated with 292 interaction(s) predicted by orthology.

Experimentally validated
Total	26 [view]
Protein-Protein	26 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	292 [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:0019904	protein domain specific binding
GO:0031625	ubiquitin protein ligase binding
GO:0031691	alpha-1A adrenergic receptor binding
GO:0031692	alpha-1B adrenergic receptor binding
GO:0031701	angiotensin receptor binding
GO:0031702	type 1 angiotensin receptor binding
GO:0031748	D1 dopamine receptor binding
GO:0031762	follicle-stimulating hormone receptor binding
GO:0031826	type 2A serotonin receptor binding
GO:0032403	protein complex binding
GO:0032947	protein complex scaffold
GO:0043422	protein kinase B binding
GO:0051019	mitogen-activated protein kinase binding
GO:0071889	14-3-3 protein binding

Biological Process

GO:0001932	regulation of protein phosphorylation
GO:0001934	positive regulation of protein phosphorylation
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:0006309	apoptotic DNA fragmentation
GO:0006366	transcription from RNA polymerase II promoter
GO:0006897	endocytosis
GO:0007179	transforming growth factor beta receptor signaling pathway
GO:0007186	G-protein coupled receptor signaling pathway
GO:0007420	brain development
GO:0007628	adult walking behavior
GO:0008277	regulation of G-protein coupled receptor protein signaling pathway
GO:0015031	protein transport
GO:0016567	protein ubiquitination
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:0032226	positive regulation of synaptic transmission, dopaminergic
GO:0032691	negative regulation of interleukin-1 beta production
GO:0032695	negative regulation of interleukin-12 production
GO:0032715	negative regulation of interleukin-6 production
GO:0032720	negative regulation of tumor necrosis factor production
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0034122	negative regulation of toll-like receptor signaling pathway
GO:0034260	negative regulation of GTPase activity
GO:0034392	negative regulation of smooth muscle cell apoptotic process
GO:0042699	follicle-stimulating hormone signaling pathway
GO:0043065	positive regulation of apoptotic process
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0045953	negative regulation of natural killer cell mediated cytotoxicity
GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation
GO:0050965	detection of temperature stimulus involved in sensory perception of pain
GO:0051897	positive regulation of protein kinase B signaling
GO:0051928	positive regulation of calcium ion transport
GO:0060326	cell chemotaxis
GO:0060765	regulation of androgen receptor signaling pathway
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0090200	positive regulation of release of cytochrome c from mitochondria
GO:0090201	negative regulation of release of cytochrome c from mitochondria
GO:2000573	positive regulation of DNA biosynthetic process

Cellular Component

GO:0005622	intracellular
GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005886	plasma membrane
GO:0005905	coated pit
GO:0014069	postsynaptic density
GO:0016323	basolateral plasma membrane
GO:0030139	endocytic vesicle
GO:0031410	cytoplasmic vesicle
GO:0043197	dendritic spine
GO:0045211	postsynaptic membrane