A novel protein kinase C target site in protein kinase D is phosphorylated in response to signals for cardiac hypertrophy |
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Authors: | Phan Dillon Stratton Matthew S Huynh Q Khai McKinsey Timothy A |
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Institution: | aDepartment of Biology, Gilead Sciences, Palo Alto, CA 94304, United States;bDepartment of Biomedical Sciences, Colorado State University, United States;cDepartment of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, United States |
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Abstract: | Protein kinase D (PKD) regulates cardiac myocyte growth and contractility through phosphorylation of proteins such as class IIa histone deacetylases (HDACs) and troponin I (TnI). In response to agonists that activate G-protein-coupled receptors (GPCRs), PKD is phosphorylated by protein kinase C (PKC) on two serine residues (Ser-738 and Ser-742 in human PKD1) within an activation loop of the catalytic domain, resulting in stimulation of PKD activity. Here, we identify a novel PKC target site located adjacent to the auto-inhibitory pleckstrin homology (PH) domain in PKD. This site (Ser-412 in human PKD1) is conserved in each of the three PKD family members and is efficiently phosphorylated by multiple PKC isozymes in vitro. Employing a novel anti-phospho-Ser-412-specific antibody, we demonstrate that this site in PKD is rapidly phosphorylated in primary cardiac myocytes exposed to hypertrophic agonists, including norepinephrine (NE) and endothelin-1 (ET-1). Differential sensitivity of this event to pharmacological inhibitors of PKC, and data from in vitro enzymatic assays, suggest a predominant role for PKCδ in the control of PKD Ser-412 phosphorylation. Together, these data suggest a novel, signal-dependent mechanism for controlling PKD function in cardiac myocytes. |
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Keywords: | Abbreviations: CHK checkpoint kinase CRD cysteine rich domain DAG diacylglycerol ET-1 endothelin-1 GPCR G-protein-coupled receptor GSK-3β glycogen synthase kinase-3β HDAC histone deacetylase IKK IκB kinase ISO isoproterenol MARK microtubule associated kinase MyBP-C myosin binding protein-C NE norepinephrine nPKC novel protein kinase C NRVM neonatal rat ventricular myocyte PE phenylephrine PH pleckstrin homology PKC protein kinase C PKD protein kinase D PMA phorbol myristate acetate TnI troponin I |
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