New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases.
Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the repressive activity of class IIa HDACs is neutralized through their phosphorylation on multiple N-terminal serine residues and 14-3-3-mediated nuclear exclusion. Here, we demonstrate that class IIa HDACs are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. We identify EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family, as regulators of this process. We further show that EMK and C-TAK1 phosphorylate class IIa HDACs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function. Using HDAC7 as a paradigm, we extend these findings by demonstrating that signal-independent phosphorylation of the most N-terminal serine residue by the MARK/Par-1 kinases, i.e., Ser155, is a prerequisite for the phosphorylation of the nearby 14-3-3 site, Ser181. We propose that this multisite hierarchical phosphorylation by a variety of kinases allows for sophisticated regulation of class IIa HDACs function.
Dequiedt
Franck
F
Cellular and Molecular Biology Unit, Faculty of Agronomy, B-5030, Gembloux, Belgium. dequiedt.f@fsagx.ac.be
Martin
Maud
M
Von Blume
Julia
J
Vertommen
Didier
D
Lecomte
Emily
E
Mari
Nathalie
N
Heinen
Marie-France
MF
Bachmann
Malte
M
Twizere
Jean-Claude
JC
Huang
Mei Chris
MC
Rider
Mark H
MH
Piwnica-Worms
Helen
H
Seufferlein
Thomas
T
Kettmann
Richard
R
D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D013379:Substrate Specificity
D048948:14-3-3 Proteins; D010768:Phosphoserine; C094670:MARK2 protein, human; C111833:MARK3 protein, human; D017346:Protein Serine-Threonine Kinases; C543273:HDAC7 protein, human; D006655:Histone Deacetylases