Protein kinase C-related kinase targets nuclear localization signals in a subset of class IIa histone deacetylases.
Class IIa histone deacetylases (HDACs) -4, -5, -7 and -9 undergo signal-dependent nuclear export upon phosphorylation of conserved serine residues that are targets for 14-3-3 binding. Little is known of other mechanisms for regulating the subcellular distribution of class IIa HDACs. Using a biochemical purification strategy, we identified protein kinase C-related kinase-2 (PRK2) as an HDAC5-interacting protein. PRK2 and the related kinase, PRK1, phosphorylate HDAC5 at a threonine residue (Thr-292) positioned within the nuclear localization signal (NLS) of the protein. HDAC7 and HDAC9 contain analogous sites that are phosphorylated by PRK, while HDAC4 harbors a non-phosphorylatable alanine residue at this position. We provide evidence to suggest that the unique phospho-acceptor cooperates with the 14-3-3 target sites to impair HDAC nuclear import.
Harrison
Brooke C
BC
Gilead Colorado, Inc., Boulder, CO, USA.
Huynh
Khai
K
Lundgaard
Greta L
GL
Helmke
Steven M
SM
Perryman
M Benjamin
MB
McKinsey
Timothy A
TA
D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D016384:Consensus Sequence; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D019913:Nuclear Localization Signals / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011493:Protein Kinase C / Q000378:metabolism*
D048948:14-3-3 Proteins; D019913:Nuclear Localization Signals; C061570:protein kinase N; D011493:Protein Kinase C; D006655:Histone Deacetylases