dbPTM

ARRB2_MOUSE - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	ARRB2_MOUSE
UniProt AC	Q91YI4
Protein Name	Beta-arrestin-2
Gene Name	Arrb2
Organism	Mus musculus (Mouse).
Sequence Length	410
Subcellular Localization	Cytoplasm . Nucleus . Cell membrane . Membrane, clathrin-coated pit. Cytoplasmic vesicle. Translocates to the plasma membrane and colocalizes with antagonist-stimulated GPCRs.
Protein 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. 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 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 the internalization of the atypical chemokine receptor ACKR3 (By similarity)..
Protein Sequence	MGEKPGTRVFKKSSPNCKLTVYLGKRDFVDHLDKVDPVDGVVLVDPDYLKDRKVFVTLTCAFRYGREDLDVLGLSFRKDLFIATYQAFPPMPNPPRPPTRLQDRLLKKLGQHAHPFFFTIPQNLPCSVTLQPGPEDTGKACGVDFEIRAFCAKSIEEKSHKRNSVRLIIRKVQFAPETPGPQPSAETTRHFLMSDRRSLHLEASLDKELYYHGEPLNVNVHVTNNSAKTVKKIRVSVRQYADICLFSTAQYKCPVAQLEQDDQVSPSSTFCKVYTITPLLSDNREKRGLALDGQLKHEDTNLASSTIVKEGANKEVLGILVSYRVKVKLVVSRGGDVSVELPFVLMHPKPHDHITLPRPQSAPRETDVPVDTNLIEFDTNYATDDDIVFEDFARLRLKGMKDDDCDDQFC

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
18	Ubiquitination	KKSSPNCKLTVYLGK CCCCCCCEEEEEECC	54.56	-
48	Phosphorylation	VVLVDPDYLKDRKVF EEEECHHHHCCCEEE	22.50	17242355
75	Phosphorylation	DLDVLGLSFRKDLFI CCEEEEEEECCCEEE	22.62	21183079
107	Ubiquitination	RLQDRLLKKLGQHAH HHHHHHHHHHCCCCC	51.01	-
108	Ubiquitination	LQDRLLKKLGQHAHP HHHHHHHHHCCCCCC	58.79	-
154	Phosphorylation	IRAFCAKSIEEKSHK HHHEEEHHHHHHCCC	19.39	28059163
164	Phosphorylation	EKSHKRNSVRLIIRK HHCCCCCEEEEEEEE	16.79	-
176	Hydroxylation	IRKVQFAPETPGPQP EEEEECCCCCCCCCC	47.48	-
178	Phosphorylation	KVQFAPETPGPQPSA EEECCCCCCCCCCCH	32.27	28066266
181	Hydroxylation	FAPETPGPQPSAETT CCCCCCCCCCCHHHH	44.08	-
184	Phosphorylation	ETPGPQPSAETTRHF CCCCCCCCHHHHHHH	33.23	28066266
198	Phosphorylation	FLMSDRRSLHLEASL HHHCCCCCEEEEEEC	22.49	27180971
207	Ubiquitination	HLEASLDKELYYHGE EEEEECCCCEEECCC	55.71	-
296	Ubiquitination	LALDGQLKHEDTNLA EECCCCCCCCCCCCC	36.74	-
332	Phosphorylation	VKVKLVVSRGGDVSV EEEEEEEECCCCEEE	20.09	24719451
355	Phosphorylation	PKPHDHITLPRPQSA CCCCCCCCCCCCCCC	27.56	29472430
361 (in isoform 2)	Phosphorylation	-	42.81	21454597
361	Phosphorylation	ITLPRPQSAPRETDV CCCCCCCCCCCCCCC	42.81	26824392
381	Phosphorylation	LIEFDTNYATDDDIV CEEEECCCCCCCCCE	16.99	28494245
383	Phosphorylation	EFDTNYATDDDIVFE EEECCCCCCCCCEEH	29.60	28494245

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
383	T	Phosphorylation	Kinase	CSNK2A1	P68400	GPS
-	K	Ubiquitination	E3 ubiquitin ligase	Mdm2	P23804	PMID:22199232

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
383	T	Phosphorylation		-
Phosphorylated at Thr-383 in the cytoplasm; probably dephosphorylated at the plasma membrane.

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of ARRB2_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
PP2AA_MOUSE	Ppp2ca	physical	16051150
2ABB_MOUSE	Ppp2r2b	physical	16051150
GSK3B_MOUSE	Gsk3b	physical	16051150
GSK3A_MOUSE	Gsk3a	physical	16051150
AKT1_MOUSE	Akt1	physical	19122674
SRC_MOUSE	Src	physical	19122674
ARRB1_MOUSE	Arrb1	physical	19122674
VPS51_HUMAN	VPS51	physical	26496610
FLNA_HUMAN	FLNA	physical	26496610
HMMR_HUMAN	HMMR	physical	26496610
JAK1_HUMAN	JAK1	physical	26496610
PP1A_HUMAN	PPP1CA	physical	26496610
PP1B_HUMAN	PPP1CB	physical	26496610
SPTB2_HUMAN	SPTBN1	physical	26496610
STRN_HUMAN	STRN	physical	26496610
TCOF_HUMAN	TCOF1	physical	26496610
TFE3_HUMAN	TFE3	physical	26496610
NOLC1_HUMAN	NOLC1	physical	26496610
PJA2_HUMAN	PJA2	physical	26496610
BASP1_HUMAN	BASP1	physical	26496610
WDR6_HUMAN	WDR6	physical	26496610
RASF8_HUMAN	RASSF8	physical	26496610
COBL_HUMAN	COBL	physical	26496610
FBX46_HUMAN	FBXO46	physical	26496610
PHOCN_HUMAN	MOB4	physical	26496610
RFIP5_HUMAN	RAB11FIP5	physical	26496610
PKN3_HUMAN	PKN3	physical	26496610
STRN3_HUMAN	STRN3	physical	26496610
CT2NL_HUMAN	CTTNBP2NL	physical	26496610
MUC13_HUMAN	MUC13	physical	26496610
INF2_HUMAN	INF2	physical	26496610

Drug and Disease Associations

Kegg Drug
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of ARRB2_MOUSE

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"Large-scale identification and evolution indexing of tyrosinephosphorylation sites from murine brain."; Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.; J. Proteome Res. 7:311-318(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-48, AND MASSSPECTROMETRY.	18034455 [Abstract]

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