title: Receptor activity-independent recruitment of betaarrestin2 reveals specific signalling modes.
abstract: The roles of betaarrestins in regulating G protein coupling and receptor endocytosis following agonist stimulation of G protein-coupled receptors are well characterised. However, their ability to act on their own as direct modulators or activators of signalling remains poorly characterised. Here, betaarrestin2 intrinsic signalling properties were assessed by forcing the recruitment of this accessory protein to vasopressin V1a or V2 receptors independently of agonist-promoted activation of the receptors. Such induction of a stable interaction with betaarrestin2 initiated receptor endocytosis leading to intracellular accumulation of the betaarrestin/receptor complexes. Interestingly, betaarrestin2 association to a single receptor protomer was sufficient to elicit receptor dimer internalisation. In addition to recapitulating betaarrestin2 classical actions on receptor trafficking, the receptor activity-independent recruitment of betaarrestin2 activated the extracellular signal-regulated kinases. In the latter case, recruitment to the receptor itself was not required since kinase activation could be mediated by betaarrestin2 translocation to the plasma membrane in the absence of any interacting receptor. These data demonstrate that betaarrestin2 can act as a 'bonafide' signalling molecule even in the absence of activated receptor.
authors.affiliation: Department of Biochemistry and Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Québec, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Terrillon
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
mesh_terms: D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D007700:Kinetics; D008561:Membrane Fusion; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D017483:Receptors, Vasopressin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus