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J. Biol. Chem., Vol. 283, Issue 25, 17009-17019, June 20, 2008

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Protein Kinase D Links G_q-coupled Receptors to cAMP Response Element-binding Protein (CREB)-Ser¹³³ Phosphorylation in the Heart^*

Nazira Ozgen¹, Maria Obreztchikova¹, Jianfen Guo¹, Hasnae Elouardighi, Gerald W. Dorn, II, Brenda A. Wilson^¶, and Susan F. Steinberg²

From the Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, the University of Cincinnati, Cincinnati, Ohio 45229, and the ^¶Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Many growth regulatory stimuli promote cAMP response element-binding protein (CREB) Ser¹³³ phosphorylation, but the physiologically relevant CREB-Ser¹³³ kinase(s) in the heart remains uncertain. This study identifies a novel role for protein kinase D (PKD) as an in vivo cardiac CREB-Ser¹³³ kinase. We show that thrombin activates a PKC-PKD pathway leading to CREB-Ser¹³³ phosphorylation in cardiomyocytes and cardiac fibroblasts. ₁-Adrenergic receptors also activate a PKC-PKD-CREB-Ser¹³³ phosphorylation pathway in cardiomyocytes. Of note, while the epidermal growth factor (EGF) promotes CREB-Ser¹³³ phosphorylation via an ERK-RSK pathway in cardiac fibroblasts, the thrombin-dependent EGFR transactivation pathway leading to ERK-RSK activation does not lead to CREB-Ser¹³³ phosphorylation in this cell type. Adenoviral-mediated overexpression of PKC (but not PKC or PKC) activates PKD; PKC and PKD1-S744E/S748E overexpression both promote CREB-Ser¹³³ phosphorylation. Pasteuralla multocida toxin (PMT), a direct G_q agonist that induces robust cardiomyocyte hypertrophy, also activates the PKD-CREB-Ser¹³³ phosphorylation pathway, leading to the accumulation of active PKD and Ser¹³³-phosphorylated CREB in the nucleus, activation of a CRE-responsive promoter, and increased Bcl-2 (CREB target gene) expression in cardiomyocyte cultures. Cardiac-specific G_q overexpression also leads to an increase in PKD-Ser⁷⁴⁴/Ser⁷⁴⁸ and CREB-Ser¹³³ phosphorylation as well as increased Bcl-2 protein expression in the hearts of transgenic mice. Collectively, these studies identify a novel G_q-PKC-PKD-CREB-Ser¹³³ phosphorylation pathway that is predicted to contribute to cardiac remodeling and could be targeted for therapeutic advantage in the setting of heart failure phenotypes.

Received for publication, December 3, 2007 , and in revised form, March 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL77860, HL-67101, and HL-28958. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this study.

² To whom correspondence should be addressed: College of Physicians and Surgeons, Columbia University, 630 West 168 St., New York, NY 10032. Tel.: 212-305-4297; Fax: 212-305-8780; E-mail: sfs1{at}columbia.edu.

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