Reference : Crucial role of reversible phosphorylation in the mechanisms governing the biological fu...
Dissertations and theses : Doctoral thesis
Life sciences : Biochemistry, biophysics & molecular biology
Crucial role of reversible phosphorylation in the mechanisms governing the biological functions of class IIa Histone Deacetylases
Martin, Maud[Université de Liège - ULg > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie cell. et moléc. >]
Faculuté universitaires des sciences agronomiques de Gembloux, Belgique
Docteur en sciences agronomiques et ingénierie biologique
[en] HDAC7 ; PP2A ; angiogenesis
[en] Regulation of class IIa histone deacetylases (HDACs) phosphorylation is crucial because it provides the opportunity to control important developmental processes associated with these key enzymes. Indeed, the transcriptional repressor activity of class IIa HDAC is controlled via their phosphorylation-dependent nucleo-cytoplasmic shuttling. While a lot of efforts have been directed towards the identification of the inactivating kinases that phosphorylate class IIa HDACs, the identity of the antagonist phosphatase remained an open question. During this work, we found that protein phosphatase 2A (PP2A) is responsible for dephosphorylating the class IIa HDACs member HDAC7, thereby regulating its subcellular localization and repressor activity. In order to validate our model, functional consequences of these findings was illustrated during the two main biological processes involving HDAC7, i.e. T-cells apoptosis during negative selection and endothelial cells angiogenic activities during vascular network formation. Cellular PP2A represents a large population of trimeric holoenzymes containing a variable regulatory subunit, whose identity has a crucial role in determining the specificity of PP2A catalytic activity. In an effort to characterize the regulation of HDAC7 dephopshorylation, we identified the relevant PP2A holoenzyme regulating HDAC7 function during vasculogenesis and we found that, among diverse regulatory subunit isoforms, PP2A-Bα uniquely regulates endothelial cell angiogenic properties. PP2A-Bα silencing using small interfering RNAs results in a significant inhibition of endothelial cell tube formation and migration. These results establish PP2A, and more precisely the Bα containg PP2A holoenzyme, as an essential element in the regulation of the class IIa HDACs HDAC7 and unravel a first developmental function for the PP2A regulatory subunit Bα in the genesis of blood vessels.