Abstract |
The mucin-type sialoglycoprotein podoplanin (aggrus) is involved in tumor cell-induced platelet aggregation and tumor metastasis. C-type lectin-like receptor-2 (CLEC-2) was recently identified as an endogenous receptor of podoplanin on platelets. However, the pathophysiological importance and function of CLEC-2 have not been elucidated. Here we clarified the pathophysiological interaction between podoplanin and CLEC-2 in vitro and in vivo. Using several deletion mutants of CLEC-2 expressed as Fc chimeras, we first identified an important podoplanin-recognition domain in CLEC-2. Furthermore, the podoplanin-CLEC-2 interaction was confirmed using several deletion mutants of podoplanin expressed as Fc chimeras. Not only the disialyl-core1-attached glycopeptide but also the stereostructure of the podoplanin protein was found to be critical for the CLEC-2-binding activity of podoplanin. We next synthesized various glycopeptides of podoplanin that included both the platelet aggregation-stimulating domain and O- glycan on Thr52. Interestingly, a disialyl-core1-attached glycopeptide was recognized specifically by CLEC-2. Moreover, the anti-podoplanin monoclonal antibody NZ-1 suppressed both the podoplanin-CLEC-2 interaction and podoplanin-induced pulmonary metastasis, suggesting that CLEC-2 is the first pathophysiological receptor of podoplanin to be identified. In summary, we clarified the molecular interaction in vitro and in vivo between a platelet aggregation-inducing factor, podoplanin, and its specific pathophysiological receptor on platelets, CLEC-2. Podoplanin and CLEC-2 might represent promising therapeutic targets in cancer metastasis.
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Authors | Yukinari Kato, Mika Kato Kaneko, Akiko Kunita, Hiromi Ito, Akihiko Kameyama, Satoshi Ogasawara, Nana Matsuura, Yasushi Hasegawa, Katsue Suzuki-Inoue, Osamu Inoue, Yukio Ozaki, Hisashi Narimatsu |
Journal | Cancer science
(Cancer Sci)
Vol. 99
Issue 1
Pg. 54-61
(Jan 2008)
ISSN: 1349-7006 [Electronic] England |
PMID | 17944973
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CLEC2B protein, human
- Glycopeptides
- Immunoglobulin Fc Fragments
- Lectins, C-Type
- Membrane Glycoproteins
- PDPN protein, human
- Recombinant Fusion Proteins
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Topics |
- Animals
- CHO Cells
- Cell Line, Tumor
- Chimera
(metabolism)
- Cricetinae
- Cricetulus
- Female
- Glioblastoma
(genetics, metabolism, secondary)
- Glycopeptides
(metabolism)
- Humans
- Immunoglobulin Fc Fragments
(genetics, metabolism)
- Lectins, C-Type
(genetics, metabolism)
- Lung Neoplasms
(genetics, metabolism, secondary)
- Membrane Glycoproteins
(antagonists & inhibitors, genetics, metabolism)
- Mice
- Mice, Inbred BALB C
- Platelet Aggregation
- Protein Binding
- Recombinant Fusion Proteins
(genetics, metabolism)
- Sequence Deletion
- Transfection
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