Endosomal signaling function of !-arrestin on GPCR trafficking
نویسندگان
چکیده
Beta-arrestins are signaling adaptors that bind to agonist-occupied G proteincoupled receptors (GPCRs) and target them for endocytosis; however, the mechanisms regulating receptor/!-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 !arrestin-1 or -2. We find a novel role for MAPK in the B2R/!-arrestin-2 complex formation, receptor trafficking and signaling mediated by an ERK1/2 regulatory motif in the hinge domain of the rat !-arrestin-2 (PET 178 P), but not rat !-arrestin-1 (PER 177 P). While the ERK1/2 regulatory motif is conserved between rat and mouse !-arrestin-2, it is surprisingly not conserved in human !-arrestin-2 (PEK 178 P). However, mutation of Lysine 178 to Threonine is sufficient to confer MAPK sensitivity to the human !-arrestin-2. Furthermore, substitution for a phosphomimetic residue in both the rat and the human !-arrestin-2 (T/K 178 D) significantly stabilizes B2R/!-arrestin complexes in endosomes, delays receptor recycling to the plasma membrane and maintains intracellular MAPK signaling. Similarly, the endosomal trafficking of !2adrenergic, angiotensin II type 1 and vasopressin V2 receptors was altered by the !arrestin-2 T 178 D mutant. Our findings unveil a novel subtype specific mode of MAPKdependent regulation of !-arrestins in intracellular trafficking and signaling of GPCRs and suggest differential endosomal receptor/!-arrestin-2 signaling roles amongst
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