Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

Li Zhu, Wolfgang Bergmeier, Jie Wu, Hong Jiang, Timothy J. Stalker, Marcin Cieslak, Ran Fan, Laurence Boumsell, Atsushi Kumanogoh, Hitoshi Kikutani, Luca Tamagnone, Denisa D. Wagner, Marcos E. Milla, Lawrence F. Brass

Research output: Contribution to journalArticlepeer-review


Semaphorin 4D (sema4D; CD100) is an integral membrane protein and the ligand for two receptors, CD72 and plexin-B1. Soluble sema4D has been shown to evoke angiogenic responses from endothelial cells and impair monocyte migration, but the origin of soluble sema4D, particularly at sites of vascular injury, has been unclear. Here we show that platelets express sema4D and both of its receptors and provide evidence that these molecules promote thrombus formation. We also show that the surface expression of sema4D and CD72 increases during platelet activation, followed by the gradual shedding of the sema4D extracellular domain. Shedding is blocked by metalloprotease inhibitors and abolished in mouse platelets that lack the metalloprotease ADAM17 (TACE). Mice that lack sema4D exhibit delayed arterial occlusion after vascular injury in vivo, and their platelets show impaired collagen responses in vitro. In resting platelets, as in B lymphocytes, CD72 is associated with the protein tyrosine phosphatase SHP-1. Platelet activation causes dissociation of the complex, as does the addition of soluble sema4D. These findings suggest a dual role for sema4D in vascular responses to injury. As thrombus formation begins, platelet-associated sema4D can bind to its receptors on nearby platelets, promoting thrombus formation. As thrombus formation continues, sema4D is shed from the platelet surface and becomes available to interact with receptors on endothelial cells and monocytes, as well as continuing to interact with platelets.

Original languageEnglish
Pages (from-to)1621-1626
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Publication statusPublished - Jan 30 2007


  • CD72
  • Metalloprotease
  • Plexin-B1
  • Signaling thrombosis

ASJC Scopus subject areas

  • Genetics
  • General


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