Article
- The EMBO Journal (2007) 26, 1373 - 1384
- doi:10.1038/sj.emboj.7601589
Published online: 22 February 2007
Subject Categories:
Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1
Toshihiko Toyofuku1,2,4, Masanori Yabuki1,4, Junko Kamei1, Motohiro Kamei3, Nobuhiko Makino1,2, Atsushi Kumanogoh2 and Masatsugu Hori1
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
- Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- These authors contributed equally to this work
Correspondence to:
Toshihiko Toyofuku, Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel.: +8 6 6879 8333; Fax: +8 6 6879 8332; E-mail: toyofuku@medone.med.osaka-u.ac.jp
Received 5 May 2006; Accepted 9 January 2007
Abstract
Originally identified as axon guidance molecules, semaphorins are now known to be widely expressed mediators that play significant roles in immune responses and organ morphogenesis. However, not much is known about the signaling pathways via which they exert their organ-specific effects. Here we demonstrate that Sema4A, previously identified as an activator of T-cell-mediated immunity, is expressed in endothelial cells, where it suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mice lacking Sema4A exhibit enhanced angiogenesis in response to VEGF or inflammatory stimuli. In addition, binding and functional experiments revealed Plexin-D1 to be a receptor for Sema4A on endothelial cells, indicating that Sema4A exerts organ-specific activities via different receptor-mediated signaling pathways: via Plexin-D1 in the endothelial cells and via T-cell immunoglobulin and mucin domain-2 in T cells. The effects of Sema4A on endothelial cells are dependent on its ability to suppress VEGF-mediated Rac activation and integrin-dependent cell adhesion. It thus appears that Sema4A–Plexin-D1 signaling negatively regulates angiogenesis.
Keywords:
- angiogenesis,
- Plexin-D1,
- Semaphorin 4A,
- VEGF
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Common mechanisms of nerve and blood vessel wiring
Nature Review (14 Jul 2005)
EMBO reports Review (01 Apr 2004)
NEWS AND VIEWS
Semaphorin pathways orchestrate osteogenesis
Nature Cell Biology News and Views (01 Jun 2006)
Tinker to Evers to Chance: semaphorin signaling takes teamwork
Nature Neuroscience News and Views (01 Dec 2005)
RESEARCH
Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function
Nature Article (24 Jul 2003)
