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.