CPLM-005745

Genbank Nucleotide ID

Protein Synonyms/Alias

Rattus norvegicus (Rat)

Position	Peptide	Type	References
17	KKASPNGKLTVYLGK	acetylation	[1]

[1] Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns.
Lundby A, Lage K, Weinert BT, Bekker-Jensen DB, Secher A, Skovgaard T, Kelstrup CD, Dmytriyev A, Choudhary C, Lundby C, Olsen JV.
Cell Rep. 2012 Aug 30;2(2):419-31. [PMID: 22902405]

Functional Description

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.

REGION 1 163 Interaction with SRC.
REGION 45 86 Interaction with CHRM2 (By similarity).
REGION 318 418 Interaction with TRAF6 (By similarity).
BINDING 250 250 Inositol hexakisphosphate (By
BINDING 255 255 Inositol hexakisphosphate (By
BINDING 324 324 Inositol hexakisphosphate (By
BINDING 326 326 Inositol hexakisphosphate (By
MOD_RES 47 47 Phosphotyrosine (By similarity).
MOD_RES 412 412 Phosphoserine; alternate.
MOD_RES 412 412 Phosphoserine; by GRK5; alternate (By

3D-structure; Cell membrane; Cell projection; Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle; Membrane; Nucleus; Phosphoprotein; Protein transport; Reference proteome; Signal transduction inhibitor; Transcription; Transcription regulation; Transport; Ubl conjugation.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0016323; C:basolateral plasma membrane; IDA:RGD.
GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
GO:0005829; C:cytosol; IDA:RGD.
GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
GO:0014069; C:postsynaptic density; IDA:RGD.
GO:0045211; C:postsynaptic membrane; IDA:RGD.
GO:0031143; C:pseudopodium; IEA:UniProtKB-SubCell.
GO:0031692; F:alpha-1B adrenergic receptor binding; IDA:RGD.
GO:0035612; F:AP-2 adaptor complex binding; IDA:BHF-UCL.
GO:0035615; F:clathrin adaptor activity; IDA:BHF-UCL.
GO:0045309; F:protein phosphorylated amino acid binding; IMP:RGD.
GO:0031896; F:V2 vasopressin receptor binding; IMP:RGD.
GO:0000187; P:activation of MAPK activity; IDA:RGD.
GO:0007188; P:adenylate cyclase-modulating G-protein coupled receptor signaling pathway; TAS:RGD.
GO:0006309; P:apoptotic DNA fragmentation; IMP:RGD.
GO:0002032; P:desensitization of G-protein coupled receptor protein signaling pathway by arrestin; TAS:RGD.
GO:0006897; P:endocytosis; IDA:RGD.
GO:0042699; P:follicle-stimulating hormone signaling pathway; IDA:RGD.
GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:RGD.
GO:0034260; P:negative regulation of GTPase activity; IDA:RGD.
GO:0001933; P:negative regulation of protein phosphorylation; IMP:RGD.
GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:RGD.
GO:0031398; P:positive regulation of protein ubiquitination; IMP:RGD.
GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IMP:RGD.
GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:UniProtKB.
GO:0015031; P:protein transport; IEA:UniProtKB-KW.
GO:0030817; P:regulation of cAMP biosynthetic process; TAS:RGD.
GO:0030820; P:regulation of cAMP catabolic process; TAS:RGD.
GO:0019233; P:sensory perception of pain; TAS:RGD.
GO:0050975; P:sensory perception of touch; TAS:RGD.
GO:0006366; P:transcription from RNA polymerase II promoter; IDA:UniProtKB.

IPR000698; Arrestin.
IPR011021; Arrestin-like_N.
IPR014752; Arrestin_C.
IPR011022; Arrestin_C-like.
IPR017864; Arrestin_CS.
IPR014753; Arrestin_N.
IPR014756; Ig_E-set.

PF02752; Arrestin_C
PF00339; Arrestin_N