Much attention has been focused recently on E (epithelial)-cadherin and its role in cell-cell adhesion and tumor invasiveness. Indeed, the vast majority (approximately 90%) of human tumors are of epithelial origin (carcinomas), and epithelial cell-cell adhesion is mediated primarily by E-cadherin. In approximately 50% of metastatic carcinomas, E-cadherin expression is downregulated or lost altogether, and this is thought to figure prominently in tumor metastasis. The cytoplasmic regulators of E- cadherin, termed Catenins, have also been implicated in tumor progression: defects in these proteins may in fact explain metastatic events in the presence of apparently normal E-cadherin expression. Research in the applicant's laboratory has identified a novel 120 kDa catenin, designated p120, whose structural characteristics and direct binding to E-cadherin suggest a catenin-like role in cell-cell adhesion and signaling. Earlier studies characterized p120 as a protein tyrosine kinase (PTK) substrate whose phosphorylation correlates with Src-induced cell transformation. These observations, together with evidence linking the catenins to signaling pathways mediated by the Wnt oncoprotein and the adenomatous polyposis- coli (APC) tumor suppressor, suggest that chronic tyrosine phosphorylation of p120 contributes to the malignant phenotype by interfering with cadherin function or perhaps the Wnt- and APC-related signaling pathways. Thus, it becomes important to understand the role of p120 in PTK signaling and cadherin function. The proposed research seeks to determine the biological consequences of uncoupling cadherin and p120 functions by identifying and mutating the structural motifs in E-cadherin that specifically mediate its binding to p12O. In addition, the role of pl20 tyrosine phosphorylation in malignant cell behavior will be addressed by mapping the major phosphorylation site(s) on the pl2O molecule, with the long-range goal of mutating these sites and assaying the mutants for their effects on cell phenotype. Antibodies against the major pl20 phosphoepitopes will be used to dissect the signaling pathways relevant to pl20 and to determine the function of pl20 phosphorylation in cell-cell adhesion and signaling. Ultimately, the findings should contribute fresh insight into the role of this novel catenin in cadherin-mediated adhesion and signaling pathways and may suggest means by which one could suppress the metastatic changes associated with malignant tumors, including breast carcinoma.
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