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PMID:18332134

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Citation

Ha, CH, Wang, W, Jhun, BS, Wong, C, Hausser, A, Pfizenmaier, K, McKinsey, TA, Olson, EN and Jin, ZG (2008) Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. J. Biol. Chem. 283:14590-9

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.

Links

PubMed PMC2386927 Online version:10.1074/jbc.M800264200

Keywords

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; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KPCD1

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0035924: cellular response to vascular endothelial growth factor stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0045766: positive regulation of angiogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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