Arrb2 (rat, UniProt P29067): manual literature synthesis

No deep-research provider was available for this review. This file was written by hand
from the cached publications in publications/ and the UniProt record
(genes/rat/Arrb2/Arrb2-uniprot.txt). Every assertion carries a provenance tag.

Identity

• Rat beta-arrestin-2 (arrestin-3), 410 aa, gene Arrb2 (RGD:2157, GeneID 25388). It belongs
  to the arrestin family [UniProtKB:P29067 "Belongs to the arrestin family."], with arrestin N
  and C domains (Pfam PF00339, PF02752).
• Cloned from rat brain as a novel beta-arrestin with 78% identity to beta-arrestin-1
  PMID:1517224.

Canonical function: GPCR desensitization and internalization

• In reconstituted systems, beta-arrestin-2 quenched coupling of the phosphorylated
  beta2-adrenergic receptor to Gs PMID:1517224.
• UniProt summary of the mechanism [UniProtKB:P29067 "During homologous desensitization,
  beta-arrestins bind to the GPCR-phosphorylated receptor and sterically preclude its
  coupling to the cognate G protein"].
• Endocytic adaptor (clathrin-associated sorting protein) binding clathrin and AP-2
  [UniProtKB:P29067 "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)."]. The
  rat protein's LIEF motif mutant loses clathrin binding (UniProt MUTAGEN 374..377, PMID:10097102).
• In rat vascular smooth muscle cells AT1R stimulation forms an endogenous c-Src/beta-arrestin/AP-2
  complex PMID:15498833.
• Receptor-specific evidence in rat cells: alpha1B-adrenergic receptor endocytosis depends
  mostly on beta-arrestin-2 PMID:18523139; mu-opioid receptor endocytosis in striatal
  neurons is blocked by dominant-negative arrestin-3 PMID:16120787; FSH receptor recruits
  endogenous beta-arrestins in Sertoli cells PMID:16899567; AT1R binds beta-arrestin-2 in
  aorta PMID:19522833; PAF receptor PMID:23911909; D1 dopamine receptor in striatal
  neurons PMID:19200235.
• Endosomal trafficking: class B receptor/beta-arrestin complexes travel to endosomes
  [PMID:14757828; PMID:25016018 "We find a novel role for MAPK in the B2R/β-arrestin-2
  complex formation, receptor trafficking and signaling mediated by an ERK1/2
  regulatory motif in the hinge domain of the rat β-arrestin-2 (PET(178)P)"].

Arrestin-dependent signalling (scaffold)

• ERK1/2 scaffold [UniProtKB:P29067 "Acts as a signaling scaffold for MAPK pathways such as
  MAPK1/3 (ERK1/2) and MAPK10 (JNK3)."]. In rat VSMCs beta-arrestin-2 siRNA reduced AT1R
  ERK activation by angiotensin and SII PMID:19254952, and mediated an
  anti-apoptotic ERK/p90RSK + PI3K/AKT pathway converging on BAD PMID:19171933.
• Rat striatal neurons: D1 receptor, beta-arrestin-2 and p-ERK co-immunoprecipitate
  PMID:19200235. Rat astrocytes: kappa-opioid sustained ERK and proliferation require
  beta-arrestin-2 PMID:19014370. Rat hippocampal neurons: beta-blocker biased agonism of a
  beta-arrestin-2/ERK calcium signal PMID:21078978. Rat kidney fibroblasts: SII-AT1R ERK
  and ECM synthesis PMID:28274926. PAF receptor/ERK/MMP-2 in VSMCs PMID:23911909.
• AKT/GSK3 scaffold with PP2A (mouse in vivo) [PMID:16051150; PMID:18191226].
• MDM2 binding by oligomeric beta-arrestin-2 and nucleocytoplasmic shuttling PMID:17984062.
• Opposite to beta-arrestin-1 in TRPV4 ubiquitination PMID:20650893.
• Centrosome/primary cilium; binds 14-3-3 PMID:19008961.
• Heterodimerizes with alpha-arrestin ARRDC1 for Itch-driven Notch degradation PMID:23886940.

Physiology (downstream, mostly perturbation phenotypes)

• Intrathecal beta-arrestin-2 siRNA enhances morphine analgesia and reduces tolerance
  PMID:21926413. Morphine changes Arrb2 mRNA in brain PMID:12614678. Diurnal Arrb2
  expression in nucleus accumbens PMID:34919270.
• Neuroprotection via mGluR7/ERK in sevoflurane neurotoxicity PMID:26621121.

Citation problems noticed

• PMID:157224 (cited by RGD for GPCR signalling and postsynaptic membrane IDA) is a 1979
  bone-resorbing-factor paper; almost certainly a typo of PMID:1517224.
• PMID:12890920 (cited for D2 receptor domain-specific binding) is a dystrophin/reperfusion
  report with no arrestin content in the abstract.
• PMID:24719556 (cited for positive regulation of epithelial cell apoptotic process) is a
  mesenteric artery contractility study; the full text has no epithelial apoptosis data.