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Protein Kinase C-dependent Protein Kinase D Activation Modulates ERK Signal Pathway and Endothelial Cell Proliferation by Vascular Endothelial Growth Factor
- Source :
- Journal of Biological Chemistry. 280:33262-33269
- Publication Year :
- 2005
- Publisher :
- Elsevier BV, 2005.
-
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 Cgamma (PLCgamma) and protein kinase C (PKC) significantly inhibited VEGF-induced PKD activation, suggesting the involvement of the PLCgamma/PKC pathway. In particular, PKCalpha was critical for VEGF-induced PKD activation since both overexpression of adenovirus PKCalpha dominant negative mutant and reduction of PKCalpha expression by small interfering RNA markedly inhibited VEGF-induced PKD activation. Importantly, we found that small interfering RNA knockdown of PKD and PKCalpha 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/PLCgamma/PKCalpha pathway and revealed a critical role of PKD in VEGF-induced ERK signaling and endothelial cell proliferation.
- Subjects :
- Vascular Endothelial Growth Factor A
MAPK/ERK pathway
Umbilical Veins
Angiogenesis
Blotting, Western
Biology
Biochemistry
Article
Adenoviridae
Cell Line
chemistry.chemical_compound
Animals
Humans
Phosphorylation
RNA, Small Interfering
Protein kinase A
Molecular Biology
Aorta
Protein Kinase C
Protein kinase C
Cell Proliferation
Dose-Response Relationship, Drug
Kinase insert domain receptor
DNA
Cell Biology
musculoskeletal system
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Enzyme Activation
Isoenzymes
Vascular endothelial growth factor
Kinetics
Vascular endothelial growth factor A
chemistry
Mutation
cardiovascular system
Cancer research
Cattle
Endothelium, Vascular
Mitogen-Activated Protein Kinases
Signal transduction
Signal Transduction
Thymidine
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 280
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....225de9aefd617c788bc485f9d188e659