Regulation of cardiac stress signaling by protein kinase D1

Brooke C. Harrison, Mi Sung Kim, Eva Van Rooij, Craig F. Plato, Philip J. Papst, Rick B. Vega, John A. McAnally, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson, Timothy A. McKinsey

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

In response to pathological stresses such as hypertension or myocardial infarction, the heart undergoes a remodeling process that is associated with myocyte hypertrophy, myocyte death, and fibrosis. Histone deacetylase 5 (HDAC5) is a transcriptional repressor of cardiac remodeling that is subject to phosphorylation-dependent neutralization in response to stress signaling. Recent studies have suggested a role for protein kinase C (PKC) and its downstream effector, protein kinase D1 (PKD1), in the control of HDAC5 phosphorylation. While PKCs are well-documented regulators of cardiac signaling, the function of PKD1 in heart muscle remains unclear. Here, we demonstrate that PKD1 catalytic activity is stimulated in cardiac myocytes by diverse hypertrophic agonists that signal through G protein-coupled receptors (GPCRs) and Rho GTPases. PKD1 activation in cardiomyocytes occurs through PKC-dependent and -independent mechanisms. In vivo, cardiac PKD1 is activated in multiple rodent models of pathological cardiac remodeling. PKD1 activation correlates with phosphorylation-dependent nuclear export of HDAC5, and reduction of endogenous PKD1 expression with small interfering RNA suppresses HDAC5 shuttling and associated cardiomyocyte growth. Conversely, ectopic overexpression of constitutively active PKD1 in mouse heart leads to dilated cardiomyopathy. These findings support a role for PKD1 in the control of pathological remodeling of the heart via its ability to phosphorylate and neutralize HDAC5.

Original languageEnglish (US)
Pages (from-to)3875-3888
Number of pages14
JournalMolecular and Cellular Biology
Volume26
Issue number10
DOIs
StatePublished - May 2006

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Heat-Shock Proteins
Protein Kinases
Histone Deacetylases
Cardiac Myocytes
Phosphorylation
Muscle Cells
Protein Kinase C
rho GTP-Binding Proteins
Cell Nucleus Active Transport
Dilated Cardiomyopathy
G-Protein-Coupled Receptors
Hypertrophy
Small Interfering RNA
Rodentia
Myocardium
Fibrosis
Myocardial Infarction
Hypertension
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Harrison, B. C., Kim, M. S., Van Rooij, E., Plato, C. F., Papst, P. J., Vega, R. B., ... McKinsey, T. A. (2006). Regulation of cardiac stress signaling by protein kinase D1. Molecular and Cellular Biology, 26(10), 3875-3888. https://doi.org/10.1128/MCB.26.10.3875-3888.2006

Regulation of cardiac stress signaling by protein kinase D1. / Harrison, Brooke C.; Kim, Mi Sung; Van Rooij, Eva; Plato, Craig F.; Papst, Philip J.; Vega, Rick B.; McAnally, John A.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.; McKinsey, Timothy A.

In: Molecular and Cellular Biology, Vol. 26, No. 10, 05.2006, p. 3875-3888.

Research output: Contribution to journalArticle

Harrison, BC, Kim, MS, Van Rooij, E, Plato, CF, Papst, PJ, Vega, RB, McAnally, JA, Richardson, JA, Bassel-Duby, R, Olson, EN & McKinsey, TA 2006, 'Regulation of cardiac stress signaling by protein kinase D1', Molecular and Cellular Biology, vol. 26, no. 10, pp. 3875-3888. https://doi.org/10.1128/MCB.26.10.3875-3888.2006
Harrison BC, Kim MS, Van Rooij E, Plato CF, Papst PJ, Vega RB et al. Regulation of cardiac stress signaling by protein kinase D1. Molecular and Cellular Biology. 2006 May;26(10):3875-3888. https://doi.org/10.1128/MCB.26.10.3875-3888.2006
Harrison, Brooke C. ; Kim, Mi Sung ; Van Rooij, Eva ; Plato, Craig F. ; Papst, Philip J. ; Vega, Rick B. ; McAnally, John A. ; Richardson, James A. ; Bassel-Duby, Rhonda ; Olson, Eric N. ; McKinsey, Timothy A. / Regulation of cardiac stress signaling by protein kinase D1. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 10. pp. 3875-3888.
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