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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
- Source :
- Journal of Biological Chemistry. 283:14590-14599
- Publication Year :
- 2008
- Publisher :
- Elsevier BV, 2008.
-
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.
- 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
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 283
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....af0872367347b8c9efc2906d84333eb6