Abstract
Plexin-A4 is a receptor for sema6A and sema6B and associates with neuropilins to transduce signals of class-3 semaphorins. We observed that plexin-A1 and plexin-A4 are required simultaneously for transduction of inhibitory sema3A signals and that they form complexes. Unexpectedly, inhibition of plexin-A1 or plexin-A4 expression in endothelial cells using specific shRNAs resulted in prominent plexin type specific rearrangements of the actin cytoskeleton that were accompanied by inhibition of bFGF and VEGFinduced cell proliferation. The two responses were not interdependent since silencing plexin-A4 in U87MG glioblastoma cells inhibited cell proliferation and strongly inhibited the formation of tumors from these cells without affecting cytoskeletal organization. Plexin-A4 formed stable complexes with the FGFR1 and VEGFR-2 tyrosine-kinase receptors and enhanced VEGF-induced VEGFR-2 phosphorylation in endothelial cells as well as bFGF-induced cell proliferation. We also obtained evidence suggesting that some of the pro-proliferative effects of plexin-A4 are due to transduction of autocrine sema6B-induced pro-proliferative signals, since silencing sema6B expression in endothelial cells and in U87MG cells mimicked the effects of plexin-A4 silencing and also inhibited tumor formation from the U87MG cells. Our results suggest that plexin-A4 may represent a target for the development of novel anti-angiogenic and anti-tumorigenic drugs.
Original language | English |
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Pages (from-to) | 4285-4296 |
Number of pages | 12 |
Journal | Blood |
Volume | 118 |
Issue number | 15 |
DOIs | |
State | Published - Oct 13 2011 |
Keywords
- Autocrine Communication/genetics
- Cell Line, Tumor
- Cell Proliferation
- Drug Discovery
- Endothelial Cells/metabolism
- Fibroblast Growth Factor 2/genetics
- Gene Expression Regulation, Neoplastic/genetics
- Gene Silencing
- Glioblastoma/blood supply
- Humans
- Neoplasm Proteins/genetics
- Neovascularization, Pathologic/drug therapy
- Phosphorylation/genetics
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptors, Cell Surface/genetics
- Semaphorins/genetics
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor Receptor-2/genetics