J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/12/1337/12 $2.00
Volume 139, Number 5, December 1, 1997 1337-1348

Epithelial Cell Adhesion Molecule (Ep-CAM) Modulates Cell-Cell Interactions Mediated by Classic Cadherins

Sergey V. Litvinov, Maarten Balzar, Manon J. Winter, Hellen A.M. Bakker, Inge H. Briaire-de Bruijn, Frans Prins, Gert Jan Fleuren, and Sven O. Warnaar

Department of Pathology, Leiden University, Leiden 2300 RC, The Netherlands

The contribution of noncadherin-type, Ca²⁺-independent cell-cell adhesion molecules to the organization of epithelial tissues is, as yet, unclear. A homophilic, epithelial Ca²⁺-independent adhesion molecule (Ep-CAM) is expressed in most epithelia, benign or malignant proliferative lesions, or during embryogenesis. Here we demonstrate that ectopic Ep-CAM, when expressed in cells interconnected by classic cadherins (E- or N-cadherin), induces segregation of the transfectants from the parental cell type in coaggregation assays and in cultured mixed aggregates, respectively. In the latter assay, Ep-CAM-positive transfectants behave like cells with a decreased strength of cell-cell adhesion as compared to the parental cells. Using transfectants with an inducible Ep-CAM-cDNA construct, we demonstrate that increasing expression of Ep-CAM in cadherin-positive cells leads to the gradual abrogation of adherens junctions. Overexpression of Ep-CAM has no influence on the total amount of cellular cadherin, but affects the interaction of cadherins with the cytoskeleton since a substantial decrease in the detergent-insoluble fraction of cadherin molecules was observed. Similarly, the detergent-insoluble fractions of - and -catenins decreased in cells overexpressing Ep-CAM. While the total -catenin content remains unchanged, a reduction in total cellular -catenin is observed as Ep-CAM expression increases. As the cadherin-mediated cell-cell adhesions diminish, Ep-CAM-mediated intercellular connections become predominant. An adhesion-defective mutant of Ep-CAM lacking the cytoplasmic domain has no effect on the cadherin-mediated cell-cell adhesions. The ability of Ep-CAM to modulate the cadherin-mediated cell-cell interactions, as demonstrated in the present study, suggests a role for this molecule in development of the proliferative, and probably malignant, phenotype of epithelial cells, since an increase of Ep-CAM expression was observed in vivo in association with hyperplastic and malignant proliferation of epithelial cells.

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