Semaphorin 3E Initiates Antiangiogenic Signaling through Plexin D1 by Regulating Arf6 and R-Ras

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.

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We thank C. J. Edgell (UNC), J. G. Donaldson (NIH, NHLBI, Bethesda, MD), N. Mochizuki (National Cardiovascular Center Research Institute, Osaka, Japan), and T. Nagase (Kazusa DNA Research Institute, Kisarazu, Japan) for providing reagents and D. Martin (NIH, NIDCR) and N. Mochizuki and S. Fukuhara (NCVC, Osaka, Japan) for comments and discussions.

A.S. was supported by JSPS postdoctoral fellowships for research abroad and Y.A.-L. by the Howard Hughes Scholars Program. This research was supported by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research, and National Eye Institute.