par Martin, Maud ;Potente, Michael;Janssens, Veerle;Vertommen, Didier;Twizere, Jean-Claude;Rider, Mark H;Goris, Jozef;Dimmeler, Stefanie;Kettmann, Richard;Dequiedt, Franck
Référence Proceedings of the National Academy of Sciences of the United States of America, 105, 12, page (4727-4732)
Publication Publié, 2008-03
Référence Proceedings of the National Academy of Sciences of the United States of America, 105, 12, page (4727-4732)
Publication Publié, 2008-03
Article révisé par les pairs
Résumé : | Class IIa histone deacetylases (HDACs) act as key transcriptional regulators in several important developmental programs. Their activities are controlled via phosphorylation-dependent nucleocytoplasmic shuttling. Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. Although a lot of effort has been made toward the identification of the inactivating kinases that phosphorylate class IIa HDAC 14-3-3 motifs, the existence of an antagonistic protein phosphatase remains elusive. Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. Interestingly, dephosphorylation of class IIa HDACs by PP2A is prevented by competitive association of 14-3-3 proteins. Using both okadaic acid treatment and RNA interference, we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. This study unravels a dynamic interplay among 14-3-3s, protein kinases, and PP2A and provides a model for the regulation of class IIa HDACs. |