Abstract
Protein kinase D 1 (PKD-1) is a signaling kinase important in fundamental cell functions including migration, proliferation, and differentiation. PKD-1 is also a key regulator of gene expression and angiogenesis that is essential for cardiovascular development and tumor progression. Further understanding molecular aspects of PKD-1 signaling in the regulation of angiogenesis may have translational implications in obesity, cardiovascular disease, and cancer. The author will summarize and provide the insights into molecular mechanisms by which PKD-1 regulates transcriptional expression of angiogenic genes, focusing on the transcriptional regulation of CD36 by PKD-1-FoxO1 signaling axis along with the potential implications of this axis in arterial differentiation and morphogenesis. He will also discuss a new concept of dynamic balance between proangiogenic and antiangiogenic signaling in determining angiogenic switch, and stress how PKD-1 signaling regulates VEGF signaling-mediated angiogenesis.
Highlights
The protein kinase PKD (PRKD) is a serine threonine kinase consisting of three isoforms PKD-1,2, and -3 (Rykx et al, 2003; Evans et al, 2010)
The PKD-FoxO1 signaling axis may function as a molecular link for a dynamic balance between pro- and anti-angiogenic signaling by controlling EC CD36 transcription, possibly regulating arteriogenesis via this axis
This understanding will provide insight into finding new and effective therapeutic targets and strategies against cardiovascular disease, cancer, and obesity
Summary
The protein kinase PKD (PRKD) is a serine threonine kinase consisting of three isoforms PKD-1,-2, and -3 (Rykx et al, 2003; Evans et al, 2010). VEGF-mediated PKD-1 signaling stimulates HDAC7 phosphorylation and cytoplasmic accumulation, modulating the expression of HDAC7-targeting and VEGF-response genes as well as VEGF-stimulated EC migration, tube formation, and sprouting angiogenesis (Mottet et al, 2007; Ha et al, 2008a). A similar mechanism is involved in the induction of PDGF-B/PDGFR-β expression and subsequent proangiogenic responses (Mottet et al, 2007) These studies indicate that PKD-1 interacts with specific HDACs to function as a molecular switch for controlling angiogenic gene transcription and VEGF-mediated angiogenesis. PKD-1 signaling interacts with HDAC5 to promote transcriptional activation of myocyte enhancer factor-2 (MEF2) and a specific subset of gene expression in response to VEGF including NR4A1, an orphan nuclear receptor. These findings suggest that PKD-1 signaling epigenetically regulates arteriogenic gene transcription via modulation of chromatin remodeling and is involved in microvascular remodeling
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