ELUDICATION OF ASSOCIATION AND SIGNAL TRANSDUCTION PATHWAY BETWEEN BETA-KATENIN AND GROWTH FACTOR RECEPTOR AT THE CANCER INVASION

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1) Down regulation of the cadherin-mediated cell adhesion and tyrosine phosphoryaltion of β-catenin was stimulated by growth factors as epidermal growth factor (EGF) and transforming growth factor α (TGF α) using human cancer cell lines. Tyrosine phosphrylation of β-catenin was confirmed to be present in human colon cancer tissue at the invasive front where cancer cells dissociate from cancer nests in a single cells.2) Physical association between β-catenin and c-erB-2 was confirmed using deletion mutants of β-catenin. The 12th armadillo repeat which locates at the center of β-catenin was found to bind the growth factor receptors as EGF receptor and c-erB-2. Tyrosine phosphoryaltion of the 12th armadillo repeat was occurred by EGF and TGF α stimulation. These results indicate the presence of signal transduction pathway between growth factor receptor and β-catenin.3) A monoclonal antibody which recognizes tyrosine phosphorylated 12th armadillo repeat of β-catenin was generated using tyrosine phosphoryalted peptides. This antibody allows us to analyze the molecular mechanism of dysfunction of cadherin-mediated cell adhesion system through the growth factor receptor that activation of growth factor receptor phosphoryaltes β-catenin and stimulates dissociation between α and β-catenin.4) Immunohistochemical staining of β-catenin in human colon cancer tissues showed that tyrosine phosphorylation of b-catenin at the 12th armadillo repeat specifically occurs at the invasive front where cancer cells dissociate from cancer nests. These results confirm the presence of signal transduction pathway between growth factor receptor and β-catenin in human cancer tissues and importance of this signal transduction in the cancer invasion and metastasis.