title: A novel GRK2/HDAC6 interaction modulates cell spreading and motility.
abstract: Cell motility and adhesion involves dynamic microtubule (MT) acetylation/deacetylation, a process regulated by enzymes as HDAC6, a major cytoplasmic α-tubulin deacetylase. We identify G protein-coupled receptor kinase 2 (GRK2) as a key novel stimulator of HDAC6. GRK2, which levels inversely correlate with the extent of α-tubulin acetylation in epithelial cells and fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate α-tubulin deacetylase activity. Remarkably, phosphorylation of GRK2 itself at S670 specifically potentiates its ability to regulate HDAC6. GRK2 and HDAC6 colocalize in the lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced motility. Consistently, cells expressing GRK2-K220R or GRK2-S670A mutants, unable to phosphorylate HDAC6, exhibit highly acetylated cortical MTs and display impaired migration and protrusive activity. Finally, we find that a balanced, GRK2/HDAC6-mediated regulation of tubulin acetylation differentially modulates the early and late stages of cellular spreading. This novel GRK2/HDAC6 functional interaction may have important implications in pathological contexts.
authors.affiliation: Departamento de Biología Molecular, and Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Lafarga
authors.forename: Ivette
authors.initials: I
authors.lastname: Aymerich
authors.forename: Olga
authors.initials: O
authors.lastname: Tapia
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.forename: Petronila
authors.initials: P
authors.lastname: Penela
mesh_terms: D000107:Acetylation; D002465:Cell Movement / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D014404:Tubulin / Q000378:metabolism
chemical_list: D014404:Tubulin; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases