title: Multiple scaffolding functions of {beta}-arrestins in the degradation of G protein-coupled receptor kinase 2.
abstract: G protein-coupled receptor kinase 2 (GRK2) plays a fundamental role in the regulation of G protein-coupled receptors (GPCRs), and changes in GRK2 expression levels can have an important impact on cell functions. GRK2 is known to be degraded by the proteasome pathway. We have shown previously that β-arrestins participate in enhanced kinase turnover upon GPCR stimulation by facilitating GRK2 phosphorylation by c-Src or by MAPK or by recruiting the Mdm2 E3 ubiquitin ligase to the receptor complex. In this report, we have investigated how such diverse β-arrestin scaffold functions are integrated to modulate GRK2 degradation. Interestingly, we found that in the absence of GPCR activation, β-arrestins do not perform an adaptor role for GRK2/Mdm2 association, but rather compete with GRK2 for direct Mdm2 binding to regulate basal kinase turnover. Upon agonist stimulation, β-arrestins-mediated phosphorylation of GRK2 at serine 670 by MAPK facilitates Mdm2-mediated GRK2 degradation, whereas c-Src-dependent phosphorylation would support the action of an undetermined β-arrestin-recruited ligase in the absence of GPCR activation. The ability of β-arrestins to play different scaffold functions would allow coordination of both Mdm2-dependent and -independent processes aimed at the specific modulation of GRK2 turnover in different signaling contexts.
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nogués
authors.forename: Alicia
authors.initials: A
authors.lastname: Salcedo
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.forename: Petronila
authors.initials: P
authors.lastname: Penela
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D005347:Fibroblasts / Q000166:cytology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D016296:Mutagenesis; D010766:Phosphorylation / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D018411:Spodoptera; D000071557:beta-Arrestins; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D019390:Arrestins; D000071557:beta-Arrestins; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019061:src-Family Kinases; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2