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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury
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Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury

机译：调节的表面表达和脱落支持信号素4D在血小板对血管损伤的反应中起双重作用

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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 mono-cytes, as well as continuing to interact with platelets.
机译：Semaphorin 4D（sema4D; CD100）是必不可少的膜蛋白，是两个受体CD72和plexin-B1的配体。已显示可溶性sema4D会引起内皮细胞的血管生成反应并损害单核细胞迁移，但尚不清楚可溶性sema4D的起源，尤其是在血管损伤部位。在这里，我们显示血小板表达sema4D及其两个受体，并提供这些分子促进血栓形成的证据。我们还显示sema4D和CD72的表面表达在血小板激活过程中增加，随后sema4D细胞外结构域逐渐脱落。脱落被金属蛋白酶抑制剂所阻断，并在缺乏金属蛋白酶ADAM17（TACE）的小鼠血小板中被清除。缺乏sema4D的小鼠在体内血管损伤后表现出延迟的动脉闭塞，其血小板在体外显示出受损的胶原反应。在静止的血小板中，如在B淋巴细胞中，CD72与酪氨酸磷酸酶SHP-1蛋白相关。血小板激活会导致复合物解离，可溶性sema4D也会添加。这些发现表明sema4D在血管对损伤的反应中具有双重作用。随着血栓形成的开始，与血小板相关的sema4D可以与其附近血小板上的受体结合，从而促进血栓形成。随着血栓形成的继续，sema4D从血小板表面脱落，可与内皮细胞和单细胞上的受体相互作用，并继续与血小板相互作用。

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