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

• Published in: The Journal of biological chemistry 2008-05, Vol.283 (21), p.14590-14599
• Main Authors: Ha, Chang Hoon, Wang, Weiye, Jhun, Bong Sook, Wong, Chelsea, Hausser, Angelika, Pfizenmaier, Klaus, McKinsey, Timothy A., Olson, Eric N., Jin, Zheng-Gen
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Animals; Cattle; Cell Movement; Cells, Cultured; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Gene Expression Regulation - drug effects; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Mechanisms of Signal Transduction; Neovascularization, Physiologic - drug effects; Phospholipase C gamma - metabolism; Phosphorylation - drug effects; Phosphoserine - metabolism; Protein Kinase C - genetics; Protein Kinase C - metabolism; Signal Transduction; Transcription Factors - metabolism; Transcriptional Activation - genetics; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M800264200

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 Cγ-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.