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J. Biol. Chem., Vol. 280, Issue 51, 42164-42171, December 23, 2005

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Tumor Suppressor in Lung Cancer (TSLC)1 Suppresses Epithelial Cell Scattering and Tubulogenesis^*

Mari Masuda1, Shinji Kikuchi2, Tomoko Maruyama, Mika Sakurai-Yageta2, Yuko N. Williams, Hara P. Ghosh, and Yoshinori Murakami3

From the Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan and the Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

The tumor suppressor in lung cancer 1 (TSLC1/IGSF4) encodes an immunoglobulin-superfamily cell adhesion molecule whose cytoplasmic domain contains a protein 4.1-binding motif (protein 4.1-BM) and a PDZ-binding motif (PDZ-BM). Loss of TSLC1 expression is frequently observed in advanced cancers implying its involvement in tumor invasion and/or metastasis. Using Madin-Darby canine kidney cells expressing a full-length TSLC1 or various cytoplasmic deletion mutants of TSLC1, we examined the role of TSLC1 in epithelial mesenchymal transitions during the hepatocyte growth factor (HGF)-induced tubulogenesis and cell scattering. In a three-dimensional culture, the full-length TSLC1, which was localized to the lateral membrane of Madin-Darby canine kidney cysts, inhibited HGF-induced tubulogenesis. In contrast, the mutants lacking either the protein 4.1-BM or the PDZ-BM abolished the inhibitory effect on tubulogenesis. In addition, these mutants showed aberrant subcellular localization indicating that lateral localization is correlated with the effect of TSLC1. In a two-dimensional culture, the full-length TSLC1, but not the mutants lacking the protein 4.1-BM or the PDZ-BM, suppressed HGF-induced cell scattering. Furthermore, the cells expressing full-length TSLC1 retained E-cadherin-based cell-cell adhesion even after being treated with HGF. These cells showed prolonged activation of Rac and low activity of Rho, whereas the HGF-treated parental cells induced transient activation of Rac and sustained activation of Rho. Prolonged Rac activation caused by the expression of TSLC1 required its cytoplasmic tail. These findings, taken together, suggest that TSLC1 plays a role in suppressing induction of epithelial mesenchymal transitions by regulating the activation of small Rho GTPases.

Received for publication, June 30, 2005 , and in revised form, September 12, 2005.

^* This work was supported in part by a grant-in-aid for the Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor, and Welfare of Japan, a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a grant from the Program for the Promotion of Fundamental Studies in Health Sciences of Pharmaceutical and Medical Devices Agency (PMDA) of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Research Fellowship from PMDA.

² Recipients of Research Resident Fellowships from the Foundation for Promotion of Cancer Research (Japan).

³ To whom correspondence should be addressed. Tel.: 81-3-3547-5295; Fax: 81-3-5565-9535; E-mail: ymurakam{at}gan2.res.ncc.go.jp.

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