1. Protein Kinase C-dependent Protein Kinase D Activation Modulates ERK Signal Pathway and Endothelial Cell Proliferation by Vascular Endothelial Growth Factor.
- Author
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Wong, Chelsea and Zheng-Gen Un
- Subjects
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PROTEIN kinases , *ENDOTHELIUM , *CELL proliferation , *VASCULAR endothelial growth factors , *CELLULAR signal transduction , *PHOSPHORYLATION , *DNA synthesis , *BIOCHEMISTRY - Abstract
Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal conditions and in pathological conditions. However, the signaling pathways involved in VEGF-induced angiogenesis are not well defined. Protein kinase D (PKD), a newly described serine/threonine protein kinase, has been implicated in many signal transduction pathways and in cell proliferation. We hypothesized that PKD would mediate VEGF signaling and function in endothelial cells. Here we found that VEGF rapidly and strongly stimulated PKD phosphorylation and activation in endothelial cells via VEGF receptor 2 (VEGFR2). The pharmacological inhibitors for phospholipase Cγ (PLCγ) and protein kinase C (PKC) significantly inhibited VEGF-induced PKD activation, suggesting the involvement of the PLCγ/PKC pathway. In particular, PKCα was critical for VEGF-induced PKD activation since both overexpression of adenovirus PKCα dominant negative mutant and reduction of PKCα expression by small interfering RNA markedly inhibited VEGF-induced PKD activation. Importantly, we found that small interfering RNA knockdown of PKD and PKCα expression significantly attenuated ERK activation and DNA synthesis in endothelial cells by VEGF. Taken together, our results demonstrated for the first time that VEGF activates PKD via the VEGFR2/PLCγ/PKCα pathway and revealed a critical role of PKD in VEGF-induced ERK signaling and endothelial cell proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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