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J. Biol. Chem., Vol. 283, Issue 21, 14590-14599, May 23, 2008

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Protein Kinase D-dependent Phosphorylation and Nuclear Export of Histone Deacetylase 5 Mediates Vascular Endothelial Growth Factor-induced Gene Expression and Angiogenesis^*

Chang Hoon Ha, Weiye Wang, Bong Sook Jhun, Chelsea Wong, Angelika Hausser, Klaus Pfizenmaier, Timothy A. McKinsey^¶, Eric N. Olson^||, and Zheng-Gen Jin¹

From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14586, the Institute of Cell Biology and Immunology, University of Stuttgart, 70659 Stuttgart, Germany, ^¶Myogen, Inc., Westminster, Colorado 80021, and the ^||Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Vascular endothelial growth factor (VEGF) is essential for normal and pathological angiogenesis. However, the signaling pathways linked to gene regulation in VEGF-induced angiogenesis are not fully understood. Here we demonstrate a critical role of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) in VEGF-induced gene expression and angiogenesis. We found that VEGF stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase C-protein kinase C-PKD-dependent pathway. We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an orphan nuclear receptor involved in angiogenesis. Specifically, inhibition of PKD by overexpression of the PKD kinase-negative mutant prevents VEGF-induced HDAC5 phosphorylation and nuclear export as well as NR4A1 induction. Moreover, a mutant of HDAC5 specifically deficient in PKD-dependent phosphorylation inhibited VEGF-mediated NR4A1 expression, endothelial cell migration, and in vitro angiogenesis. These findings suggest that the PKD-HDAC5 pathway plays an important role in VEGF regulation of gene transcription and angiogenesis.

Received for publication, January 10, 2008 , and in revised form, February 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 HL-080611. This work was also supported by American Diabetes Association Thomas R. Lee Career Development Award 1-06-CD-13 and American Heart Association Grant-in-Aid 0755916T (to Z. G. J.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S–3S and Table S1.

¹ To whom correspondence should be addressed: 211 Bailey Rd., West Henrietta, Rochester, NY 14586. Tel.: 585-276-9783; Fax: 585-276-9829; E-mail: zheng-gen_jin{at}urmc.rochester.edu.

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