title: Engagement of β-arrestin by transactivated insulin-like growth factor receptor is needed for V2 vasopressin receptor-stimulated ERK1/2 activation.
abstract: G protein-coupled receptors (GPCRs) have been shown to activate the mitogen-activated protein kinases, ERK1/2, through both G protein-dependent and -independent mechanisms. Here, we describe a G protein-independent mechanism that unravels an unanticipated role for β-arrestins. Stimulation of the V2 vasopressin receptor (V2R) in cultured cells or in vivo in rat kidney medullar collecting ducts led to the activation of ERK1/2 through the metalloproteinase-mediated shedding of a factor activating the insulin-like growth factor receptor (IGFR). This process was found to be both Src- and β-arrestin-dependent. Whereas Src was found to act upstream of the metalloproteinase activation and be required for the release of the IGFR-activating factor, β-arrestins were found to act downstream of the IGFR transactivation. Unexpectedly, the engagement of β-arrestins by the IGFR but not by the V2R was needed to promote the vasopressin-stimulated ERK1/2 activation, indicating that a pool of β-arrestins distinct from those β-arrestins recruited to the V2R acts downstream of the receptor tyrosine kinase to activate ERK1/2. Such a dual site of action for β-arrestins helps explain the pleiotropic actions of this scaffolding protein. Given the role that V2R-stimulated ERK1/2 plays in kidney cell proliferation, this transactivation mechanism may have important implications for renal pathophysiology. Still, the role of β-arrestins downstream of a transactivation event is not limited to the V2R, because we observed a similar involvement for an unrelated GPCR (the platelet-activating factor receptor), indicating that it may be a general mechanism shared among GPCRs.
authors.affiliation: Institut de Recherche en Immunologie et Cancérologie, Département de Biochimie and Groupe de Recherche Universitaire sur le Médicament,  Université de Montréal, Montréal, QC,  Canada H3C 3J7.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Oligny-Longpré
authors.forename: Maithé
authors.initials: M
authors.lastname: Corbani
authors.forename: Joris
authors.initials: J
authors.lastname: Zhou
authors.forename: Mireille
authors.initials: M
authors.lastname: Hogue
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillon
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D007679:Kidney Medulla / Q000166:cytology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051381:Rats; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism*; D015533:Transcriptional Activation; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D017451:Receptors, Somatomedin; D017483:Receptors, Vasopressin; D000071557:beta-Arrestins; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3