2007 Fiscal Year Final Research Report Summary
The novel platelet activation receptor CLEC-2:the novel target protein of anti-platelet drug?
| Project/Area Number |
18591052
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | University of Yamanashi |
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Principal Investigator |
INOUE Katsue University of Yamanashi, Interdisciplinary Graduate School Of Medicine And Engineering, Faculty Of Medicine, Department Of Clinical And Laboratory Medicine, Associate Professor (10324211)
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| Co-Investigator(Kenkyū-buntansha) |
OZAKI Yukio University of Yamanashi, Intmterdisciplinary Graduate School Of Medicine And Engineering, Faculty Of Medicine, Department Of Clinical And Laboratory Medicine, Professor (30134539)
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| Project Period (FY) |
2006 – 2007
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| Keywords | blood platelets / CLEC-2 / rhodocvtin / podoplanin / tumor metastasis |
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| Research Abstract |
We have recently identified the novel platelet activation receptor CLEC-2 as a receptor for the snake venom rhodocytin, which stimulates strong platelet aggregation. CLEC-2 belongs to C-type lectin-like receptor and its mechanism of platelet activation is different from other known platelet activation receptors. The aim of this study is to identify an internal ligand of CLEC-2 and generate CLEC-2-deficient mice.
1) CLEC-2-deficient mice: We made the knockout vector for CLEC-2-deficient mice in May, 2006, but failed to generate Fl hetero mice because of the bad quality of ES cells we used. Therefore, we utilized new ES cells in April, 2007 and we have got nine Fl hetero mice at the moment.
2) the internal ligand of CLEC-2: A proteoglycan, versican has similar amino acid sequence as rhodocytin. Based on the hypothesis that versican is an internal ligand of CLEC-2, we sought to define the association between CLEC-2 and versican using Biacore. We successfully observed the association, but pe
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rcially-purified versican failed to stimulate platelet. Moreover, we found difficulty in purification of versican from a bovine aorta. Therefore, we decided to look for another internal ligand for CLEC-2. Podoplanin, which express on the surface of tumor cells, induces platelet aggregation and stimulates tumor metastasis, but its receptor on the surface of platelets has not been identified to date. We noticed that both podoplanin- and rhodocytin-induced platelet aggregation has a long lag phase before starting aggregation and hypothesized that podoplanin is a ligand for rhodocytin. The association between podoplanin-expressing CHO cells and the recombinant CLEC-2 was confirmed by a flow cytometer. Moreover, podoplanin-induced platelet aggregation was completely inhibited by the recombinant CLEC-2, confirming that podoplanin is an internal ligand of CLEC-2. This paper has been awarded "Papers of the Week" of the Journal of Biological Chemistry and widely reported as science news. We further confirmed that anti-podoplanin antibody, NZ-1 inhibited lung metastasis of podoplanin-expressing cells, which was injected through the tail vein in a mouse model. Taken together, we proposed that CLEC-2/podoplanin is a good therapeutic target for tumor metastasis. We are now preparing for the international patent with the help of JST. Less
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[Journal Article] Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2.2008
Author(s)
Kato Y, Kaneko MK, Kunita A, Ito H, Kameyama A, Ogasawara S, Matsuura N, Hasegawa Y, Suzuki-Inoue K, Inoue O, Ozaki Y, Narimatsu H.
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Journal Title
Cancer Sci. 99
Pages: 54-61
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-22008
Author(s)
Kato, Y., Kaneko, MK., Kunita, A., Ito, H., Kameyama, A., Ogasawara, S., Matsuura, N., Hasegawa, Y., Suzuki-Inoue, K., Inoue, O., Ozaki, Y., Narimatsu, H
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Journal Title
Cancer Sci 99(1)
Pages: 54-61
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.(Papers of the Week)2007
Author(s)
Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y.
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Journal Title
J Biol Chem. 282
Pages: 25993-6001
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[Journal Article] Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells2007
Author(s)
Suzuki-Inoue K., Kato Y., Inoue O., Kaneko MK., Mishima K., Yatomi Y., Yamazaki Y., Narimatsu H., Ozaki Y.
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Journal Title
J Biol Chem 282(36)
Pages: 25993-6001
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Involvement of the snake toxin receptor CLEC-2, in podoplanin- mediated platelet activation, by cancer cells2007
Author(s)
Suzuki-Inoue K., Kato Y, Inoue O, Kaneko MX, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y
Organizer
the 5th blood-vessel Orbis
Place of Presentation
Tokyo, Japan
Year and Date
2007-08-25
Description
「研究成果報告書概要(欧文)」より
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