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J. Biol. Chem., Vol. 282, Issue 36, 25993-26001, September 7, 2007

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Involvement of the Snake Toxin Receptor CLEC-2, in Podoplanin-mediated Platelet Activation, by Cancer Cells^*

Katsue Suzuki-Inoue¹, Yukinari Kato, Osamu Inoue, Mika Kato Kaneko, Kazuhiko Mishima^¶, Yutaka Yatomi^||, Yasuo Yamazaki^**, Hisashi Narimatsu, and Yukio Ozaki

From the Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, the Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), OSL C2, 1-1-1, Umezono, Tsukuba 305-8568, the ^¶Saitama Medical University International Medical Center, 1397-1 Yamane Hidaka-shi, Saitama, the ^||Department of Laboratory Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, and the ^**Department of Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

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 C2 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 endogenously 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.

Received for publication, March 19, 2007 , and in revised form, June 11, 2007.

^* This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant 18591052) (to K. S.-I.), from the Mitsubishi Pharma Research Foundation (to K. S.-I.), from the Japan Society for the Promotion of Science for Young Scientists, Japan (to Y. K.), from the Kanae Foundation for Life and Socio-medical Science (to Y. K.), and from the Osaka Cancer Research Foundation (to Y. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed. Tel.: 81-55-273-9884; Fax: 81-55-273-6713; E-mail: katsuei{at}yamanashi.ac.jp.

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