Abstract
Cadherins are major cell – cell adhesion molecules in both tumor and normal tissues. Although serum levels of soluble E-cadherin have been shown to be higher in the cancer patients than in healthy volunteers, the detail mechanism regulating release of soluble E-cadherin remains to be elucidated. Here we show that the ectodomain of E-cadherin is proteolytically cleaved from some cancer cells by a membrane-bound metalloprotease to yield soluble form, and the residual membrane-tethered cleavage product is subsequently degraded by intracellular proteolytic pathway. Futhermore, we show that extracellular calcium influx, that is induced by mechanical scraping of cells or ionomycin treatment, enhances the metalloprotease-mediated E-cadherin cleavage and the subsequent degradation of the cytoplasmic domain. Immunocytochemical analysis demonstrates that the sequential proteolysis of E-cadherin triggered by the calcium influx results in translocation of β-catenin from the cell – cell contacts to cytoplasm. Our data suggest that calcium influx-induced proteolysis of E-cadherin not only disrupts the cell – cell adhesion but also activates β-catenin-mediated intracellular signaling pathway, potentially leading to alterations in motility and proliferation activity of cells.
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Acknowledgements
We are grateful to Dr Motowo Nakajima (Novartis Pharmaceutical, Takarazuka, Japan) for providing BB2516 and CGS27023A; Dr Masaki Mori (Kyushu University, Fukuoka, Japan) for providing Colo205 cells; Dr Koga for technical advice and valuable discussion. We wish to thank Dr Jon K Moon for editorial assistance and Takako Arino for secretarial assistance. This work was supported by research grant of the Princess Takamatsu Cancer Research Fund (97-22906) and a grant for Cancer Research from the Ministry of Education, Science and Culture of Japan (H Saya).
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Ito, K., Okamoto, I., Araki, N. et al. Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell – cell contacts. Oncogene 18, 7080–7090 (1999). https://doi.org/10.1038/sj.onc.1203191
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DOI: https://doi.org/10.1038/sj.onc.1203191
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