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Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells

Oncogene volume 18, pages 3996–4006 (1999)Cite this article

Abstract

The Rho small G protein family consists of the Rho, Rac, and Cdc42 subfamilies and regulates various cell functions through reorganization of the actin cytoskeleton. We previously showed that the Rho subfamily regulates the formation of stress fibers and focal adhesions whereas the Rac subfamily regulates the E-cadherin-based cell-cell adhesion in MDCK cells. We studied here the function of the Cdc42 subfamily, consisting of two members, Cdc42Hs and G25k, in cell adhesion, migration, and morphology of MDCK cells. For this purpose, we made and used MDCK cell lines stably expressing each of dominant active mutants of Cdc42Hs (sMDCK-Cdc42HsDA) and G25K (sMDCK-G25KDA). Actin filaments at the cell-cell adhesion sites increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Both E-cadherin and β-catenin, adherens junctional proteins, at the cell-cell adhesion sites also increased in both sMDCK-Cdc42HsDA and -G25KDA cells. Electron microscopic analysis revealed that sMDCK-Cdc42HsDA cells tightly contacted with each other throughout the lateral membranes. Moreover, both the HGF- and TPA-induced disruption of the cadherin-based cell-cell adhesion and the subsequent cell migration were inhibited in both sMDCK-Cdc42HsDA and -G25KDA cells. Co-expression of the dominant negative mutant of Rac1, a member of the Rac subfamily, with the dominant active mutant of Cdc42Hs did not inhibit the increased accumulation of actin filaments at the cell-cell adhesion sites. These results suggest that the Cdc42 subfamily is involved in the cadherin-based cell-cell adhesion in a manner independent of the Rac subfamily. Furthermore, the cells were frequently enveloped by the large multinuclear cells in both sMDCK-Cdc42HsDA and -G25KDA cells. Video microscopic analysis revealed that the cells were engulfed by the large cells during cytokinesis.

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Acknowledgements

We thank Dr W Birchmeier (Max-Delbruck-Center for Molecular Medicine, Berlin, Germany) for providing MDCK cells, Dr A Hall (University College London, London, UK) for the cDNA of N17Racl, Dr A Miyajima (Tokyo University, Tokyo, Japan) for the pSRαneo expression plasmid, Dr S Nagata (Osaka University, Osaka, Japan) for the pEF-BOS expression plasmid, Dr T Nakamura (Osaka University, Osaka, Japan) for HGF/SF, Dr DW Russell (University of Texas Southwestern Medical Center, Dallas, USA) for the pCMV5 expression plasmid, Dr K Takahashi and Dr H Nakanishi (ERATO, Kobe, Japan) for the cDNA of Cdc42Hs, Dr SH Tsukita (Kyoto University, Kyoto, Japan) for the anti-ZO-1 mAb, and Dr MJ Wheelock (University of Toledo, Ohio, USA) for the anti-β-catenin mAb. 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 (1997, 1998), by grants-in-aid for Abnormalities in Hormone Receptor Mechanisms and for Aging and Health from the Ministry of Health and Welfare, Japan (1997, 1998), and by grants from the Human Frontier Science Program (1997, 1998).

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  1. Department of Molecular Biology and Biochemistry, Osaka University Medical School, Suita, 565-0871, Japan

    Atsuko Kodama, Kenji Takaishi, Katsutoshi Nakano & Yoshimi Takai

  2. Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co., Ltd., 2-2-10 Murotani, Nishi-ku, Kobe, 651-2241, Japan

    Hideo Nishioka & Yoshimi Takai

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Kodama, A., Takaishi, K., Nakano, K. et al. Involvement of Cdc42 small G protein in cell-cell adhesion, migration and morphology of MDCK cells. Oncogene 18, 3996–4006 (1999). https://doi.org/10.1038/sj.onc.1202773

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