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A novel GRK2/HDAC6 interaction modulates cell spreading and motility

Vanesa Lafarga, Ivette Aymerich, Olga Tapia, Federico Mayor, Petronila Penela

Author Affiliations

  1. Vanesa Lafarga1,2,
  2. Ivette Aymerich1,
  3. Olga Tapia3,
  4. Federico Mayor Jr*,1,2 and
  5. Petronila Penela*,1,2
  1. 1 Departamento de Biología Molecular, and Centro de Biología Molecular ‘Severo Ochoa’ (CSIC‐UAM), Universidad Autónoma de Madrid, Madrid, Spain
  2. 2 Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
  3. 3 Department of Anatomy and Cell Biology, University of Cantabria‐IFIMAV, Santander, Spain
  1. *Corresponding authors: Departamento de Biología Molecular, Centro de Biología Molecular ‘Severo Ochoa’, Universidad Autónoma de Madrid, Madrid 28049, Spain. Tel.: +34 91 196 4626; Fax: +34 91 196 4420; E-mail: fmayor{at}cbm.uam.es or Tel.: +34 91 196 4640; Fax: +34 91 196 4420; E-mail: ppenela{at}cbm.uam.es
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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.

  • Received April 29, 2011.
  • Accepted November 23, 2011.
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