Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras

Atsuko Sakurai, Julie Gavard, Yuliya Annas-Linhares, John R. Basile, Panomwat Amornphimoltham, Todd R. Palmby, Hiroshi Yagi, Fan Zhang, Paul A. Randazzo, Xuri Li, Roberto Weigert, J. Silvio Gutkind

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3086-3098
Number of pages13
JournalMolecular and cellular biology
Volume30
Issue number12
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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