Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2 EMBRYONIC/NEONATAL LETHALITY OF CLEC-2-DEFICIENT MICE BY BLOOD/LYMPHATIC MISCONNECTIONS AND IMPAIRED THROMBUS FORMATION OF CLEC-2-DEFICIENT PLATELETS
Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2 EMBRYONIC/NEONATAL LETHALITY OF CLEC-2-DEFICIENT MICE BY BLOOD/LYMPHATIC MISCONNECTIONS AND IMPAIRED THROMBUS FORMATION OF CLEC-2-DEFICIENT PLATELETS
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DOI：
10.1074/jbc.m110.130575
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发表时间：
2010-08-06
影响因子：
4.8
通讯作者：
Ozaki, Yukio
中科院分区：
文献类型：
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作者：
Suzuki-Inoue, Katsue;Inoue, Osamu;Ozaki, Yukio
最近，CLEC-2被描述为在血栓形成/止血、肿瘤转移和淋巴管生成中发挥着关键作用。蛇毒蛇毒蛋白被称为强血小板激活剂，我们已经证明这种作用是由 CLEC-2 介导的（Suzuki-Inoue, K.、Fuller, G. L.、Garc a, A.、Eble, J. A.、Pohlmann, S.、Inoue, O.、Gartner, T. K.、Hughan, S. C.、Pearce, A. C.、Laing, G. D.、Theakston, R.D.、Schweighoffer, E.、Zitzmann, N.、Morita, T.、Tybulewicz, V. L.、Ozaki, Y. 和 Watson, S. P. (2006) Blood 107, 542-549)。 Podoplanin 表达于肿瘤细胞表面，是 CLEC-2 的内源性配体，通过诱导血小板聚集促进肿瘤转移。缺乏足足蛋白（也在淋巴内皮细胞表面表达）的小鼠表现出异常的淋巴管形成模式。在这项研究中，我们报告了 CLEC-2 缺陷小鼠的产生和表型。这些小鼠在胚胎/新生儿阶段是致命的，与紊乱和充满血液的淋巴管以及严重水肿有关。此外，通过移植来自Clec-2(-/-)或Clec-2(+/+)胚胎的胎儿肝细胞，我们能够证明CLEC-2可能通过同源相互作用参与体外和体内的血栓稳定，而没有明显增加出血倾向。我们认为CLEC-2可能是抗血小板药物的理想新型靶蛋白，它抑制病理性血栓形成，但不抑制生理性止血。
CLEC-2 has been described recently as playing crucial roles in thrombosis/hemostasis, tumor metastasis, and lymphangiogenesis. The snake venom rhodocytin is known as a strong platelet activator, and we have shown that this effect is mediated by CLEC-2 (Suzuki-Inoue, K., Fuller, G. L., Garc a, A., Eble, J. A., Pohlmann, S., Inoue, O., Gartner, T. K., Hughan, S. C., Pearce, A. C., Laing, G. D., Theakston, R. D., Schweighoffer, E., Zitzmann, N., Morita, T., Tybulewicz, V. L., Ozaki, Y., and Watson, S. P. (2006) Blood 107, 542-549). Podoplanin, which is expressed on the surface of tumor cells, is an endogenous ligand for CLEC-2 and facilitates tumor metastasis by inducing platelet aggregation. Mice deficient in podoplanin, which is also expressed on the surface of lymphatic endothelial cells, show abnormal patterns of lymphatic vessel formation. In this study, we report on the generation and phenotype of CLEC-2-deficient mice. These mice are lethal at the embryonic/neonatal stages associated with disorganized and blood-filled lymphatic vessels and severe edema. Moreover, by transplantation of fetal liver cells from Clec-2(-/-) or Clec-2(+/+) embryos, we were able to demonstrate that CLEC-2 is involved in thrombus stabilization in vitro and in vivo, possibly through homophilic interactions without apparent increase in bleeding tendency. We propose that CLEC-2 could be an ideal novel target protein for an anti-platelet drug, which inhibits pathological thrombus formation but not physiological hemostasis.