Tumor-derived mutated E-cadherin influences beta-catenin localization and increases susceptibility to actin cytoskeletal changes induced by pervanadate

E-cadherin participates in homophilic cell-to-cell adhesion and is localize d to intercellular junctions of the adherens type. In the present study, we investigated the localization of adherens junction components in cells exp ressing mutant E-cadherin derivatives which had been previously cloned from diffuse-type gastric carcinoma. The mutations are in frame deletions of ex ons 8 or 9 and a point mutation in exon 8 and affect the extracellular doma in of E-cadherin. Our findings indicate that E-cadherin mutated in exon 8 c auses beta-catenin staining at lateral cell-to-cell contact sites and, in a ddition, abnormally located beta-catenin in the perinuclear region. Moreove r, the various mutant E-cadherin derivatives increased the steady-state lev els of alpha- and beta-catenin and were found in association with these cat enins even after induction of tyrosine phosphorylation by pervanadate. Sust ained pervanadate treatment led, however, to rounding-up of cells and induc tion of filopodia, changes which were first detectable in cells expressing E-cadherin mutated in exon 8. The deterioration of the cell contact was not accompanied with disassembly of the E-cadherin-catenin complex. Based on t hese observations, we propose a model whereby in the presence of mutant E-c adherin tyrosine phosphorylation of components of the cell adhesion complex triggers loss of cell-to-cell contact and actin cytoskeletal changes which are not caused by the disruption of the E-cadherin-catenin complex per se, but instead might be due to phosphorylation of other signaling molecules o r activation of proteins involved in the regulation of the actin cytoskelet on.