title: Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis.
abstract: 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.
authors.affiliation: Cellular and Molecular Biology Unit, FUSAGx, 5030 Gembloux, Belgium.
authors.forename: Maud
authors.initials: M
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Potente
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
authors.forename: Didier
authors.initials: D
authors.lastname: Vertommen
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Twizere
authors.forename: Mark H
authors.initials: MH
authors.lastname: Rider
authors.forename: Jozef
authors.initials: J
authors.lastname: Goris
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Richard
authors.initials: R
authors.lastname: Kettmann
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*
chemical_list: D048948:14-3-3 Proteins; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D054648:Protein Phosphatase 2; C543273:HDAC7 protein, human; D006655:Histone Deacetylases