CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy

Johannes Backs; Kunhua Song; Svetlana Bezprozvannaya; Shurong Chang; Eric N Olson

doi:10.1172/JCI27438

CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy

J Clin Invest. 2006 Jul;116(7):1853-64. doi: 10.1172/JCI27438. Epub 2006 Jun 8.

Authors

Johannes Backs¹, Kunhua Song, Svetlana Bezprozvannaya, Shurong Chang, Eric N Olson

Affiliation

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA.

Abstract

Class IIa histone deacetylases (HDACs) regulate a variety of cellular processes, including cardiac growth, bone development, and specification of skeletal muscle fiber type. Multiple serine/threonine kinases control the subcellular localization of these HDACs by phosphorylation of common serine residues, but whether certain class IIa HDACs respond selectively to specific kinases has not been determined. Here we show that calcium/calmodulin-dependent kinase II (CaMKII) signals specifically to HDAC4 by binding to a unique docking site that is absent in other class IIa HDACs. Phosphorylation of HDAC4 by CaMKII promotes nuclear export and prevents nuclear import of HDAC4, with consequent derepression of HDAC target genes. In cardiomyocytes, CaMKII phosphorylation of HDAC4 results in hypertrophic growth, which can be blocked by a signal-resistant HDAC4 mutant. These findings reveal a central role for HDAC4 in CaMKII signaling pathways and have implications for the control of gene expression by calcium signaling in a variety of cell types.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

14-3-3 Proteins / metabolism
Active Transport, Cell Nucleus / physiology
Amino Acid Sequence
Animals
Binding Sites
COS Cells
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases / genetics
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cell Nucleus / metabolism
Chlorocebus aethiops
Enzyme Activation
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Hypertrophy
Isoenzymes / genetics
Isoenzymes / metabolism*
Molecular Sequence Data
Myocytes, Cardiac* / cytology
Myocytes, Cardiac* / metabolism
Myocytes, Cardiac* / pathology
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Sequence Alignment
Signal Transduction / physiology*
Two-Hybrid System Techniques

Substances

14-3-3 Proteins
Isoenzymes
Recombinant Fusion Proteins
Repressor Proteins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
HDAC4 protein, human
Histone Deacetylases