1. Protein Kinase D-dependent Phosphorylation and Nuclear Export of Histone Deacetylase 5 Mediates Vascular Endothelial Growth Factor-induced Gene Expression and Angiogenesis
- Author
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Timothy A. McKinsey, Angelika Hausser, Bong Sook Jhun, Chang Hoon Ha, Eric N. Olson, Chelsea Wong, Weiye Wang, Zheng Gen Jin, and Klaus Pfizenmaier
- Subjects
Transcriptional Activation ,Vascular Endothelial Growth Factor A ,Angiogenesis ,Active Transport, Cell Nucleus ,Neovascularization, Physiologic ,Biology ,Biochemistry ,Histone Deacetylases ,Phosphoserine ,chemistry.chemical_compound ,Cell Movement ,Animals ,Humans ,Phosphorylation ,Molecular Biology ,Cells, Cultured ,Protein Kinase C ,Protein kinase C ,Regulation of gene expression ,Histone deacetylase 5 ,Phospholipase C gamma ,Mechanisms of Signal Transduction ,Endothelial Cells ,Kinase insert domain receptor ,Cell Biology ,musculoskeletal system ,Vascular Endothelial Growth Factor Receptor-2 ,Cell biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Gene Expression Regulation ,chemistry ,cardiovascular system ,Cancer research ,Cattle ,Signal transduction ,Signal Transduction ,Transcription Factors - Abstract
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 Cgamma-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.
- Published
- 2008