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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 Article has an altmetric score of 9

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

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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 4

Mapping the CaMKII-responsive region of HDAC4.

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Mapping the CaMKII-responsive region of HDAC4.
(A) Chimeric HDAC4/5 prot...
(A) Chimeric HDAC4/5 proteins (as indicated) were expressed in COS cells in the presence of CaMKIIδB-T287D. Subcellular localization was verified by immunocytochemistry. Amino acids 529–657 were revealed to be required for cytosolic accumulation of HDAC4 in response to CaMKIIδB-T287D. (B) An HDAC5 mutant, in which the CaMKII consensus sites were mutated to the corresponding sites in HDAC4, was expressed in COS cells alone or with CaMKI c.a. and CaMKIIδB-T287D. This mutant was responsive to CaMKI but not to CaMKIIδB-T287D. Magnification, ×40. (C–F) Coimmunoprecipitation assays with COS cell lysates. (C) COS cells were cotransfected with FLAG-pcDNA, -HDAC4, or -HDAC5 and Myc-CaMKIIδB-T287D. Various stringency conditions of the immunoprecipitation buffer were tested as indicated. Only HDAC4 binds strongly to CaMKII. (D) Cotransfection of FLAG-HDAC4 with either WT or constitutively activated Myc–CaMKIIδB-T287D. Only the activated form of CaMKIIδB physically interacted with HDAC4. (E) IP of FLAG-HDAC4 deletion mutants coexpressed with Myc-CaMKIIδB-T287D to identify a domain of HDAC4 that binds to activated CaMKIIδB. (F) Based on the coimmunoprecipitation data, amino acids 585–608 of HDAC4 were identified to be required for physical interaction with CaMKIIδB-T287D and, therefore, define a CaMKII docking site.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 12 patents
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