Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury.
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.
Zhu
Li
L
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bergmeier
Wolfgang
W
Wu
Jie
J
Jiang
Hong
H
Stalker
Timothy J
TJ
Cieslak
Marcin
M
Fan
Ran
R
Boumsell
Laurence
L
Kumanogoh
Atsushi
A
Kikutani
Hitoshi
H
Tamagnone
Luca
L
Wagner
Denisa D
DD
Milla
Marcos E
ME
Brass
Lawrence F
LF
D051722:ADAM Proteins / Q000737:chemistry; D000072198:ADAM17 Protein; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D001792:Blood Platelets / Q000378:metabolism*; D001808:Blood Vessels / Q000293:injuries* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D015539:Platelet Activation; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D039961:Semaphorins / Q000737:chemistry*; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism
D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492118:Plxnb1 protein, mouse; D011956:Receptors, Cell Surface; D039961:Semaphorins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse