title: Roles of GRK2 in cell signaling beyond GPCR desensitization: GRK2-HDAC6 interaction modulates cell spreading and motility.
abstract: G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous, essential protein kinase that is emerging as an integrative node in many signaling networks. Moreover, changes in GRK2 abundance and activity have been identified in several inflammatory, cardiovascular disease, and tumor contexts, suggesting that those alterations may contribute to the initiation or development of pathologies. GRKs were initially identified as key players in the desensitization and internalization of multiple G protein-coupled receptors (GPCRs), but GRK2 also phosphorylates several non-GPCR substrates and dynamically associates with a variety of proteins related to signal transduction. Ongoing research in our laboratory is aimed at understanding how specific GRK2 interactomes are orchestrated in a stimulus-, context-, or cell type-specific manner. We have recently identified an interaction between GRK2 and histone deacetylase 6 (HDAC6) that modulates cell spreading and motility. HDAC6 is a major cytoplasmic a-tubulin deacetylase that is involved in cell motility and adhesion. GRK2 dynamically and directly associates with and phosphorylates HDAC6 to stimulate its a-tubulin deacetylase activity at specific cellular localizations, such as the leading edge of migrating cells, thus promoting local tubulin deacetylation and enhanced motility. GRK2-HDAC6-mediated regulation of tubulin acetylation also modulates cellular spreading. This GRK2-HDAC6 functional interaction may have important implications in pathological contexts related to epithelial cell migration.
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain. ppenela@cbm.uam.es
authors.forename: Petronila
authors.initials: P
authors.lastname: Penela
authors.forename: Vanesa
authors.initials: V
authors.lastname: Lafarga
authors.forename: Olga
authors.initials: O
authors.lastname: Tapia
authors.forename: Verónica
authors.initials: V
authors.lastname: Rivas
authors.forename: Laura
authors.initials: L
authors.lastname: Nogués
authors.forename: Elisa
authors.initials: E
authors.lastname: Lucas
authors.forename: Rocío
authors.initials: R
authors.lastname: Vila-Bedmar
authors.forename: Cristina
authors.initials: C
authors.lastname: Murga
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
mesh_terms: D000107:Acetylation; D002465:Cell Movement / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; D014404:Tubulin; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases