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 VEGF-induced 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autocrine Communication / genetics
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Cell Line, Tumor
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Cell Proliferation
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Drug Discovery
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism*
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Gene Expression Regulation, Neoplastic / genetics
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Gene Silencing
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Glioblastoma / blood supply
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Glioblastoma / drug therapy
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Glioblastoma / genetics
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Phosphorylation / genetics
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Receptor, Fibroblast Growth Factor, Type 1 / genetics
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Semaphorins / genetics
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Semaphorins / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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Neoplasm Proteins
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Plxna4 protein, human
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Receptors, Cell Surface
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SEMA6A protein, human
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Semaphorins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Fibroblast Growth Factor 2
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FGFR1 protein, human
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Receptor, Fibroblast Growth Factor, Type 1
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Vascular Endothelial Growth Factor Receptor-2