Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.
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 Cgamma2 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.
Suzuki-Inoue
Katsue
K
Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. katsuei@yamanashi.ac.jp
Kato
Yukinari
Y
Inoue
Osamu
O
Kaneko
Mika Kato
MK
Mishima
Kazuhiko
K
Yatomi
Yutaka
Y
Yamazaki
Yasuo
Y
Narimatsu
Hisashi
H
Ozaki
Yukio
Y
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011134:Polysaccharides / Q000378:metabolism; D011994:Recombinant Proteins; D014757:Viper Venoms / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism; D000098853:Podoplanin
D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D019158:N-Acetylneuraminic Acid; D051966:Phospholipase C gamma; D011134:Polysaccharides; D011994:Recombinant Proteins; D014757:Viper Venoms; D019061:src-Family Kinases; C104778:CLEC2B protein, human; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C117468:PDPN protein, human; C112292:rhodocytin protein, Calloselasma rhodostoma