Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis
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.
%0 Journal Article
%1 Ha2008
%A Chang, Hoon Ha
%A Wang, Weiye
%A Bong, Sook Jhun
%A Wong, Chelsea
%A Hausser, Angelika
%A Pfizenmaier, Klaus
%A McKinsey, Timothy A.
%A Olson, Eric N.
%A Jin, Zheng Gen
%D 2008
%J Journal of Biological Chemistry
%K 2008 hausser izi pfizenmaier
%N 21
%P 14590--14599
%R 10.1074/jbc.M800264200
%T Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis
%U https://www.ncbi.nlm.nih.gov/pubmed/18332134
%V 283
%X 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.
%7 2008/03/12
%@ 0021-9258 (Print)$\backslash$r0021-9258 (Linking)
@article{Ha2008,
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.},
added-at = {2023-06-29T13:07:55.000+0200},
author = {Chang, Hoon Ha and Wang, Weiye and Bong, Sook Jhun and Wong, Chelsea and Hausser, Angelika and Pfizenmaier, Klaus and McKinsey, Timothy A. and Olson, Eric N. and Jin, Zheng Gen},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2eee10ee7af4e57c8a0f8cab2dd7465a6/fabian},
doi = {10.1074/jbc.M800264200},
edition = {2008/03/12},
interhash = {40aa81a2816d9b99b93684ddda601b39},
intrahash = {eee10ee7af4e57c8a0f8cab2dd7465a6},
isbn = {0021-9258 (Print)$\backslash$r0021-9258 (Linking)},
issn = {00219258},
journal = {Journal of Biological Chemistry},
keywords = {2008 hausser izi pfizenmaier},
number = 21,
pages = {14590--14599},
pmid = {18332134},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18332134},
volume = 283,
year = 2008
}