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A Truncated ß-Catenin Disrupts the Interaction between E-Cadherin and -Catenin: A Cause of Loss of Intercellular Adhesiveness in Human Cancer Cell Lines¹

Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104 [T. Oy., Y. K., A. O., S. A., T. Od., S. H.]; First Department of Surgery, Osaka University School of Medicine, 2-2 Yamadaoka, Suita 565 [T. Oy., H. M.]; Department of Pathology, Research Institute for Nuclear Medicine and Biology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734 [K. Y.]; Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji-cho, Okazaki 444 [A. N., S. T.]; Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-01 [S. S., F. I.]; and Department of Biophysics, Faculty of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606 [M. T.], Japan

Cadherin cell adhesion molecules play an essential role in creating tight intercellular association and are considered to work as an invasion suppressor system of cancer cells. They form a molecular complex with catenins, a group of cytoplasmic proteins including - and ß-catenins. While -catenin has been demonstrated to be crucial for cadherin function, the role of ß-catenin is not yet fully understood. In this study, we analyzed the cadherin-catenin system in two human cell lines, HSC-39 and its putative subline HSC-40A, derived from a signet ring cell carcinoma of stomach. These cells grow as loose aggregates or single cells, suggesting that their cadherin system is not functional. In these cell lines, an identical 321-base pair in-frame mRNA deletion of ß-catenin was identified; this led to a 107-amino-acid deletion in the NH₂-terminal region of the protein. Southern blot analysis disclosed a homozygous deletion in part of the ß-catenin gene. On the other hand, these cells expressed E-cadherin, -catenin, and plakoglobin of normal size. Immunoprecipitation analyses showed that E-cadherin was coprecipitated with the mutated ß-catenin but not with -catenin, and antibodies against ß-catenin did not copurify -catenin. However, the recombinant fusion protein containing wild-type ß-catenin precipitated -catenin from these cells. These results suggest that the dysfunction of E-cadherin in these cell lines is due primarily to its failure to interact with -catenin, and that this defect results from the mutation in ß-catenin. Thus, it is most likely that the association between E-cadherin and -catenin is mediated by ß-catenin, and that this process is blocked by NH₂-terminal deletion in ß-catenin. These findings indicate that genetic abnormality of ß-catenin is one of the mechanisms responsible for loosening of cell-cell contact, and may be involved in enhancement of tumor invasion in human cancers.

¹ This study was supported in part by a Grant-in-Aid for the Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health and Welfare, and in part by Special Coordination Funds of the Science and Technology Agency of Japan. T. Oyama and T. Oda are awardees of Research Resident Fellowships from the Foundation for Promotion of Cancer Research, Tokyo.

² To whom requests for reprints should be addressed.

Received 7/22/94. Accepted 10/ 3/94.

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