Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells
Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells
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DOI：
10.1074/jbc.m702327200
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发表时间：
2007-09-07
影响因子：
4.8
通讯作者：
Ozaki, Yukio
中科院分区：
文献类型：
--
作者：
Suzuki-Inoue, Katsue;Kato, Yukinari;Ozaki, Yukio
Podoplanin (agrus) 是一种跨膜唾液酸糖蛋白，参与肿瘤细胞诱导的血小板聚集、肿瘤转移和淋巴管形成。然而，迄今为止，podoplanin 诱导这些细胞过程（包括其受体）的机制尚未阐明。 Podoplanin 诱导血小板聚集，具有较长的滞后期，这取决于 Src 和磷脂酶 C γ 2 的激活。然而，它不与糖蛋白 VI 结合。这种血小板激活模式让人想起蛇毒素蛇毒蛋白，其受体已被我们鉴定为一种新型血小板激活受体，即 C 型凝集素样受体 2 (CLEC-2)（Suzuki-Inoue, K.、Fuller, G. L.、Garcia, 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)。因此，我们试图评估 CLEC-2 是否可以作为足足蛋白的生理对应物。通过流式细胞术证实了 CLEC-2 和 podoplanin 之间的关联。此外，它们的关联依赖于平足蛋白O-聚糖上的唾液酸。重组CLEC-2抑制由表达足足蛋白的肿瘤细胞或淋巴内皮细胞诱导的血小板聚集，表明CLEC-2负责由细胞表面内源表达的足足蛋白诱导的血小板聚集。这些发现表明CLEC-2是podoplanin的生理靶蛋白，并暗示它参与podoplanin诱导的血小板聚集、肿瘤转移和与podoplanin相关的其他细胞反应。
Podoplanin ( aggrus), a transmembrane sialoglycoprotein, is involved in tumor cell-induced platelet aggregation, tumor metastasis, and lymphatic vessel formation. However, the mechanism by which podoplanin induces these cellular processes including its receptor has not been elucidated to date. Podoplanin induced platelet aggregation with a long lag phase, which is dependent upon Src and phospholipase C gamma 2 activation. However, it does not bind to glycoprotein VI. This mode of platelet activation was reminiscent of the snake toxin rhodocytin, the receptor of which has been identified by us as a novel platelet activation receptor, C-type lectin-like receptor 2 ( CLEC-2) ( Suzuki-Inoue, K., Fuller, G. L., Garcia, 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). Therefore, we sought to evaluate whether CLEC-2 serves as a physiological counterpart for podoplanin. Association between CLEC-2 and podoplanin was confirmed by flow cytometry. Furthermore, their association was dependent on sialic acid on O-glycans of podoplanin. Recombinant CLEC-2 inhibited platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, suggesting that CLEC-2 is responsible for platelet aggregation induced by endo-genously expressed podoplanin on the cell surfaces. These findings suggest that CLEC-2 is a physiological target protein of podoplanin and imply that it is involved in podoplanin-induced platelet aggregation, tumor metastasis, and other cellular responses related to podoplanin.