ARRB2_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: ARRB2_RAT
• UniProt AC: P29067
• Protein Name: Beta-arrestin-2
• Gene Name: Arrb2
• Organism: Rattus norvegicus (Rat).
• 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: MGEKPGTRVFKKSSPNCKLTVYLGKRDFVDHLDKVDPVDGVVLVDPDYLKDRKVFVTLTCAFRYGREDLDVLGLSFRKDLFIATYQAFPPMPNPPRPPTRLQDRLLKKLGQHAHPFFFTIPQNLPCSVTLQPGPEDTGKACGVDFEIRAFCAKSIEEKSHKRNSVRLIIRKVQFAPETPGPQPSAETTRHFLMSDRRSLHLEASLDKELYYHGEPLNVNVHVTNNSAKTVKKIRVSVRQYADICLFSTAQYKCPVAQLEQDDQVSPSSTFCKVYTITPLLSDNREKRGLALDGQLKHEDTNLASSTIVKEGANKEVLGILVSYRVKVKLVVSRGGDVSVELPFVLMHPKPHDHITLPRPQSAPREIDIPVDTNLIEFDTNYATDDDIVFEDFARLRLKGMKDDDCDDQFC

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
11	Ubiquitination	KPGTRVFKKSSPNCK CCCCEEECCCCCCCE	49.22	PubMed
48	Phosphorylation	VVLVDPDYLKDRKVF EEEECHHHHCCCEEE	22.50	-
75	Phosphorylation	DLDVLGLSFRKDLFI CCEEEEEEECCCEEE	22.62	22673903
176	Hydroxylation	IRKVQFAPETPGPQP EEEEECCCCCCCCCC	47.48	-
178	Phosphorylation	KVQFAPETPGPQPSA EEECCCCCCCCCCCH	32.27	-
181	Hydroxylation	FAPETPGPQPSAETT CCCCCCCCCCCHHHH	44.08	-
361	Phosphorylation	ITLPRPQSAPREIDI CCCCCCCCCCCCCCC	42.81	25403869
383	Phosphorylation	EFDTNYATDDDIVFE EEECCCCCCCCCEEH	29.60	10747877
410	S-nitrosocysteine	DDCDDQFC------- CCCCCCCC-------	4.53	-
410	S-nitrosylation	DDCDDQFC------- CCCCCCCC-------	4.53	22178444

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
178	T	Phosphorylation	Kinase	ERK1	P27361	PSP
383	T	Phosphorylation	Kinase	MEK1	Q02750	PSP
383	T	Phosphorylation	Kinase	CAMK2	-	Uniprot

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.	12186555

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of ARRB2_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
ADRB2_HUMAN	ADRB2	physical	17666399
CLH1_HUMAN	CLTC	physical	17666399
AP2M1_HUMAN	AP2M1	physical	17666399
RAF1_HUMAN	RAF1	physical	17666399
TRAF6_HUMAN	TRAF6	physical	26839314
UBP20_HUMAN	USP20	physical	26839314

Drug and Disease Associations

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

Related Literatures of Post-Translational Modification

Phosphorylation

"Phosphorylation of beta-arrestin2 regulates its function ininternalization of beta(2)-adrenergic receptors.";
Lin F.-T., Chen W., Shenoy S., Cong M., Exum S.T., Lefkowitz R.J.;
Biochemistry 41:10692-10699(2002).
Cited for: PHOSPHORYLATION AT SER-361 AND THR-383, INTERACTION WITH CLTC, ANDMUTAGENESIS OF SER-361 AND THR-383.
PubMed: 12186555