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Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis

Oncogene volume 23, pages 289–297 (2004)Cite this article

Abstract

Progression of human colon cancer is often associated with elevated expression and activity of the Src family tyrosine kinase (SFK). SFK is ordinarily in equilibrium between inactive and primed states by a balance of negative regulatory kinase Csk and its counteracting tyrosine phosphatase(s), both of which act on the regulatory C-terminal tyrosine of SFK. To evaluate the contribution of the regulatory system of SFK in cancer progression, we here modulated the equilibrium status of SFK by introducing wild-type or dominant-negative Csk in human epithelial colon cancer cells, HCT15 and HT29. Overexpression of wild-type Csk induced decreased SFK activation, increased cell–cell contacts mediated by E-cadherin, decreased the number of focal contacts and decreased cell adhesion/migration and in vitro invasiveness. Conversely, expression of a dominant-negative Csk resulted in elevated SFK activation, enhanced phosphorylation of FAK and paxilllin, enhanced cell scattering, an increased number of focal contacts, dramatic rearrangement of actin cytoskeleton and increased cell adhesion/migration and in vitro invasiveness. In these scattered cells, however, localization, expression and phosphorylation of either E-cadherin or β-catenin were not significantly affected, suggesting that the E-cadherin-mediated cell–cell contact is indirectly regulated by SFK. Furthermore, all these events occurred absolutely dependent on integrin-mediated cell adhesion. These findings demonstrate that Csk defines the ability of integrin-SFK-mediated cell adhesion signaling that influences the metastatic potential of cancer cells.

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Acknowledgements

We thank Wouter Hazenbos for helpful discussions. This work was supported by the Research Foundation of Japan Society for the Promotion of Science and by a grant-in-aid for Scientific Research of Priority Areas, Cancer, from Ministry of Education, Culture, Sports, Science and Technology. WR-C was supported by a fellowship from the Japanese Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan

    William Rengifo-Cam, Akio Konishi, Naoki Morishita, Hidetada Matsuoka, Shigeyuki Nada & Masato Okada

  2. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo, 170-8455, Japan

    Takao Yamori

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  1. William Rengifo-Cam
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Correspondence to Masato Okada.

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Rengifo-Cam, W., Konishi, A., Morishita, N. et al. Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis. Oncogene 23, 289–297 (2004). https://doi.org/10.1038/sj.onc.1207041

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