RGD Reference Report - Differential regulation of endosomal GPCR/ß-arrestin complexes and trafficking by MAPK. - Rat Genome Database

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Differential regulation of endosomal GPCR/ß-arrestin complexes and trafficking by MAPK.

Authors: Khoury, Etienne  Nikolajev, Ljiljana  Simaan, May  Namkung, Yoon  Laporte, Stéphane A 
Citation: Khoury E, etal., J Biol Chem. 2014 Aug 22;289(34):23302-17. doi: 10.1074/jbc.M114.568147. Epub 2014 Jul 11.
RGD ID: 13506837
Pubmed: PMID:25016018   (View Abstract at PubMed)
PMCID: PMC4156072   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M114.568147   (Journal Full-text)

ß-Arrestins are signaling adaptors that bind to agonist-occupied G protein-coupled receptors (GPCRs) and target them for endocytosis; however, the mechanisms regulating receptor/ß-arrestin complexes and trafficking in endosomes, remain ill defined. Here we show, in live cells, differential dynamic regulation of endosomal bradykinin B2 receptor (B2R) complexes with either ß-arrestin-1 or -2. We find a novel role for MAPK in the B2R/ß-arrestin-2 complex formation, receptor trafficking and signaling mediated by an ERK1/2 regulatory motif in the hinge domain of the rat ß-arrestin-2 (PET(178)P), but not rat ß-arrestin-1 (PER(177)P). While the ERK1/2 regulatory motif is conserved between rat and mouse ß-arrestin-2, it is surprisingly not conserved in human ß-arrestin-2 (PEK(178)P). However, mutation of lysine 178 to threonine is sufficient to confer MAPK sensitivity to the human ß-arrestin-2. Furthermore, substitution for a phosphomimetic residue in both the rat and the human ß-arrestin-2 (T/K178D) significantly stabilizes B2R/ß-arrestin complexes in endosomes, delays receptor recycling to the plasma membrane and maintains intracellular MAPK signaling. Similarly, the endosomal trafficking of ß2-adrenergic, angiotensin II type 1 and vasopressin V2 receptors was altered by the ß-arrestin-2 T178D mutant. Our findings unveil a novel subtype specific mode of MAPK-dependent regulation of ß-arrestins in intracellular trafficking and signaling of GPCRs, and suggest differential endosomal receptor/ß-arrestin-2 signaling roles among species.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
endosome  IDA 13506837; 13506837 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Arrb1  (arrestin, beta 1)
Arrb2  (arrestin, beta 2)


Additional Information