Semaphorin 3E initiates antiangiogenic signaling through plexin D1 by regulating Arf6 and R-Ras.
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.
Sakurai
Atsuko
A
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Rm. 211, MSC 4340, Bethesda, MD 20892, USA.
Gavard
Julie
J
Annas-Linhares
Yuliya
Y
Basile
John R
JR
Amornphimoltham
Panomwat
P
Palmby
Todd R
TR
Yagi
Hiroshi
H
Zhang
Fan
F
Randazzo
Paul A
PA
Li
Xuri
X
Weigert
Roberto
R
Gutkind
J Silvio
JS
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039961:Semaphorins; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; D020533:Angiogenesis Inhibitors; D015816:Cell Adhesion Molecules, Neuronal; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C493082:PLXND1 protein, human; C473552:Plxnd1 protein, mouse; C111150:Sema3e protein, mouse; D039961:Semaphorins; C085929:RRAS protein, human; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; D018631:ras Proteins
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