51. Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras.
- Author
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Sakurai A, Gavard J, Annas-Linhares Y, Basile JR, Amornphimoltham P, Palmby TR, Yagi H, Zhang F, Randazzo PA, Li X, Weigert R, and Gutkind JS
- Subjects
- ADP-Ribosylation Factor 6, Animals, Cell Adhesion drug effects, Cell Movement drug effects, Cytoskeletal Proteins, Cytoskeleton drug effects, Cytoskeleton metabolism, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells metabolism, Extracellular Matrix drug effects, Extracellular Matrix metabolism, Glycoproteins pharmacology, Humans, Integrins metabolism, Intracellular Signaling Peptides and Proteins, Membrane Proteins pharmacology, Mice, Models, Biological, Neovascularization, Physiologic drug effects, Semaphorins, ADP-Ribosylation Factors metabolism, Angiogenesis Inhibitors metabolism, Cell Adhesion Molecules, Neuronal metabolism, Glycoproteins metabolism, Membrane Glycoproteins metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Signal Transduction drug effects, ras Proteins metabolism
- Abstract
Recent studies revealed that a class III semaphorin, semaphorin 3E (Sema3E), acts through a single-pass transmembrane receptor, plexin D1, to provide a repulsive cue for plexin D1-expressing endothelial cells, thus providing a highly conserved and developmentally regulated signaling system guiding the growth of blood vessels. We show here that Sema3E acts as a potent inhibitor of adult and tumor-induced angiogenesis. Activation of plexin D1 by Sema3E causes the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix (ECM) and causing the retraction of filopodia in endothelial tip cells. Sema3E acts on plexin D1 to initiate a two-pronged mechanism involving R-Ras inactivation and Arf6 stimulation, which affect the status of activation of integrins and their intracellular trafficking, respectively. Ultimately, our present study provides a molecular framework for antiangiogenesis signaling, thus impinging on a myriad of pathological conditions that are characterized by aberrant increase in neovessel formation, including cancer.
- Published
- 2010
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