InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ARRB1

Summary

InnateDB Protein

IDBP-64691.7

Last Modified

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

Gene Symbol

ARRB1

Protein Name

arrestin, beta 1

Synonyms

ARB1; ARR1;

Species

Homo sapiens

Ensembl Protein

ENSP00000353124

InnateDB Gene

IDBG-64687 (ARRB1)

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. 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. {ECO:0000250, ECO:0000269PubMed:12464600, ECO:0000269PubMed:14711824, ECO:0000269PubMed:15475570, ECO:0000269PubMed:15611106, ECO:0000269PubMed:15671180, ECO:0000269PubMed:15878855, ECO:0000269PubMed:16144840, ECO:0000269PubMed:16280323, ECO:0000269PubMed:16378096, ECO:0000269PubMed:16492667, ECO:0000269PubMed:16709866, ECO:0000269PubMed:18337459, ECO:0000269PubMed:18419762, ECO:0000269PubMed:19620252, ECO:0000269PubMed:19643177, ECO:0000269PubMed:22457824, ECO:0000269PubMed:23341447, ECO:0000269PubMed:23633677}.

Subcellular Localization

Cytoplasm. Nucleus. Cell membrane. Membrane, clathrin-coated pit {ECO:0000305}. Cell projection, pseudopodium {ECO:0000250}. 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). {ECO:0000250}.

Disease Associations

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 293 experimentally validated interaction(s) in this database.
They are also associated with 17 interaction(s) predicted by orthology.

Experimentally validated
Total	293 [view]
Protein-Protein	292 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	17 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004857	enzyme inhibitor activity
GO:0005096	GTPase activator activity
GO:0005159	insulin-like growth factor receptor binding
GO:0005515	protein binding
GO:0008134	transcription factor binding
GO:0031625	ubiquitin protein ligase binding
GO:0031701	angiotensin receptor binding
GO:0044212	transcription regulatory region DNA binding

Biological Process

GO:0001934	positive regulation of protein phosphorylation
GO:0002031	G-protein coupled receptor internalization
GO:0002092	positive regulation of receptor internalization
GO:0006366	transcription from RNA polymerase II promoter
GO:0006892	post-Golgi vesicle-mediated transport
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:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0032715	negative regulation of interleukin-6 production
GO:0032717	negative regulation of interleukin-8 production
GO:0035025	positive regulation of Rho protein signal transduction
GO:0035066	positive regulation of histone acetylation
GO:0043149	stress fiber assembly
GO:0043161	proteasome-mediated ubiquitin-dependent protein catabolic process
GO:0043547	positive regulation of GTPase activity
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0061024	membrane organization
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0090240	positive regulation of histone H4 acetylation

Cellular Component

GO:0000139	Golgi membrane
GO:0000785	chromatin
GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005765	lysosomal membrane
GO:0005829	cytosol
GO:0005834	heterotrimeric G-protein complex
GO:0005886	plasma membrane
GO:0005905	coated pit
GO:0030659	cytoplasmic vesicle membrane
GO:0031143	pseudopodium
GO:0031410	cytoplasmic vesicle