Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 12, Pages 4727-4732Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0708455105
Keywords
chromatin; shuttling; endothelial cells; thymocytes; 14-3-3
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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.
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