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  2. A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase

A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase

  • FEBS Lett. 2010 Feb 5;584(3):631-7. doi: 10.1016/j.febslet.2009.12.014.
Lauren Monovich 1 Richard B Vega Erik Meredith Karl Miranda Chang Rao Michael Capparelli Douglas D Lemon Dillon Phan Keith A Koch Joseph A Chapo David B Hood Timothy A McKinsey
Affiliations

Affiliation

  • 1 Novartis Institutes for Biomedical Research, Boulder, CO 80301, USA. lauren.monovich@novartis.com
Abstract

Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD Inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase.

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