Protein phosphatase 2A controls the activity of histone deacetylase 7 during T cell apoptosis and angiogenesis.
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.
Martin
Maud
M
Cellular and Molecular Biology Unit, FUSAGx, 5030 Gembloux, Belgium.
Potente
Michael
M
Janssens
Veerle
V
Vertommen
Didier
D
Twizere
Jean-Claude
JC
Rider
Mark H
MH
Goris
Jozef
J
Dimmeler
Stefanie
S
Kettmann
Richard
R
Dequiedt
Franck
F
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*
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