A TRUNCATED BETA-CATENIN DISRUPTS THE INTERACTION BETWEEN E-CADHERIN AND ALPHA-CATENIN - A CAUSE OF LOSS OF INTERCELLULAR ADHESIVENESS IN HUMAN CANCER CELL-LINES

Cadherin cell adhesion molecules play an essential role in creating ti ght intercellular association and are considered to work as an invasio n suppresser system of cancer cells. They form a molecular complex wit h catenins, a group of cytoplasmic proteins including alpha- and beta- catenins. While alpha-catenin has been demonstrated to be crucial for cadherin function, the role of beta-catenin is not yet fully understoo d. 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 s ignet ring cell carcinoma of stomach. These cells grow as loose aggreg ates or single cells, suggesting that their cadherin system is not fun ctional. In these cell lines, an identical 321-base pair in-frame mRNA deletion of beta-catenin was identified; this led to a 107-amino-acid deletion in the NH2-terminal region of the protein. Southern blot ana lysis disclosed a homozygous deletion in part of the beta-catenin gene . On the other hand, these cells expressed E-cadherin, alpha-catenin, and plakoglobin of normal size. Immunoprecipitation analyses shelved t hat E-cadherin was coprecipitated with the mutated beta-catenin but no t with alpha-catenin, and antibodies against beta-catenin did not copu rify alpha-catenin. However, the recombinant fusion protein containing wild-type beta-catenin precipitated alpha-catenin from these cells. T hese results suggest that the dysfunction of E-cadherin in these cell lines is due primarily to its failure to interact with alpha-catenin, and that this defect results from the mutation in beta-catenin. Thus, it is most likely that the association between E-cadherin and alpha-ca tenin is mediated by beta-catenin, and that this process is blocked by NH2-terminal deletion in beta-catenin. These findings indicate that g enetic abnormality of beta-catenin is one of the mechanisms responsibl e for loosening of cell-cell contact, and may be involved in enhanceme nt of tumor invasion in human cancers.