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. 2008 May 23;283(21):14590-9. doi: 10.1074/jbc.M800264200. Epub 2008 Mar 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • Phosphoserine
  • protein kinase D
  • Vascular Endothelial Growth Factor Receptor-2
  • Protein Kinase C
  • Phospholipase C gamma
  • Histone Deacetylases