CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy
Johannes Backs, … , Shurong Chang, Eric N. Olson
Johannes Backs, … , Shurong Chang, Eric N. Olson
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1853-1864. https://doi.org/10.1172/JCI27438.
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Research Article Cardiology

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

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.

Authors

Johannes Backs, Kunhua Song, Svetlana Bezprozvannaya, Shurong Chang, Eric N. Olson

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Figure 3

Detection of 14-3-3 binding sites of HDAC4 in response to CaMKI and CaMKII.

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Detection of 14-3-3 binding sites of HDAC4 in response to CaMKI and CaMK...
(A and B) Coimmunoprecipitation assays with COS cell lysates were analyzed with an antibody directed against endogenous 14-3-3 protein. The effects of CaMKI and CaMKII on various FLAG-HDAC4 mutants were tested. HDAC4-input, HDAC4 present in the COS cell lysate before IP was performed; CaMK-input, CaMKI or CaMKIIδB-T287D present in the COS cell lysate before IP was performed. (B) Fold-increase in 14-3-3 binding in response to CaMKII or CaMKI as compared with baseline. (C) The N terminal half of HDAC4 (amino acids 1–740) was fused to the GAL4 DNA-binding domain, and 14-3-3 was fused to the VP16 transcription activation domain. If GAL4-HDAC4 is not phosphorylated, it cannot recruit VP16–14-3-3 and cannot activate the GAL4-dependent luciferase reporter. (D) As indicated, different GAL4-HDAC constructs were used in this assay in the absence and presence of CaMKIIδB-T287D. COS cells were transfected with the indicated constructs. Increase in 14-3-3 binding is expressed as compared with control conditions without kinase. (E) CaMKI and CaMKII phosphorylation sites of HDAC4 are shown. ND, not detectable; NES, nuclear export signal.