Abstract
Both E-cadherin, a cell-cell adhesion molecule, and c-Met, the hepatocyte growth factor (HGF)/scatter factor (SF) receptor, were colocalized at cell-cell adhesion sites of MDCK cells. HGF/SF or a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), induced disruption of cell-cell adhesion, which was accompanied by endocytosis of both E-cadherin and c-Met. Reduction of medium Ca2+ to a micromolar range showed the same effects. Re-increase in medium Ca2+ to a millimolar range formed cell-cell adhesion, which was accompanied by exocytosis of E-cadherin and c-Met, followed by their re-colocalization at the cell-cell adhesion sites. These results suggest that E-cadherin and c-Met are colocalized at cell-cell adhesion sites and undergo co-endo-exocytosis. We have previously shown that TPA does not induce disruption of cell-cell adhesion and subsequent scattering of MDCK cells stably expressing a dominant active mutant of RhoA or Rac1 small G protein or a dominant negative mutant of Rab5 small G protein. In these cell lines, the HGF- or TPA-induced coendocytosis of E-cadherin and c-Met was inhibited, but the coendocytosis of E-cadherin and c-Met in response to reduction of medium Ca2+ was not affected. Wortmannin, an inhibitor of phosphoinositide (PI) 3-kinase, inhibited the HGF-induced disruption of cell-cell junction and endocytosis of E-cadherin and c-Met, but not the TPA-induced ones. These results suggest that disruption of cell-cell adhesion is involved in the HGF- or TPA-induced coendocytosis of E-cadherin and c-Met in MDCK cells, and that the Rho and Rab family members indirectly regulate this coendocytosis. In addition, coendocytosis of E-cadherin and c-Met in response to HGF is partly mediated by PI 3-kinase. The cross-talk between cell-cell and cell-matrix adherens junctions is discussed.
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Acknowledgements
We thank Dr W Birchmeier (Max-Delbruck-Center for Molecular Medicine, Berlin, Germany) for providing MDCK cells, Dr S Nagata (Osaka University, Osaka, Japan) for the pEF-BOS expression plasmid, Dr M Zerial (European Molecular Biology Laboratory, Heidelberg, Germany) for the cDNA of N34Rab5, and Dr T Nakamura (Osaka University, Osaka, Japan) for HGF/SF. This investigation was supported by grants-in-aid for scientific research and for cancer research from the Ministry of Education, Science, Sports and Culture, Japan (1998, 1999) and by grants from the Human Frontier Science Program (1998).
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Kamei, T., Matozaki, T., Sakisaka, T. et al. Coendocytosis of cadherin and c-Met coupled to disruption of cell-cell adhesion in MDCK cells – regulation by Rho, Rac and Rab small G proteins. Oncogene 18, 6776–6784 (1999). https://doi.org/10.1038/sj.onc.1203114
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DOI: https://doi.org/10.1038/sj.onc.1203114
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