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Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2.

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.
AuthorsYukinari 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
JournalCancer science (Cancer Sci) Vol. 99 Issue 1 Pg. 54-61 (Jan 2008) ISSN: 1349-7006 [Electronic] England
PMID17944973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CLEC2B protein, human
  • Glycopeptides
  • Immunoglobulin Fc Fragments
  • Lectins, C-Type
  • Membrane Glycoproteins
  • PDPN protein, human
  • Recombinant Fusion Proteins
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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