Tissue-specific expression of beta-catenin in normal mesenchyme and uveal melanomas and its effect on invasiveness

This paper is the first in a series aimed at understanding the role of beta -catenin in epithelial-mesenchymal transformation (EMT) and acquisition of mesenchymal invasive motility. Here, we compare the expression of this and related molecules in the two major tissue phenotypes, epithelial and mesenc hymal, the latter including normal avian and mammalian fibroblasts and mali gnant human uveal melanoma cells. Previously, it was proposed that src init iates EMT by tyrosine phosphorylation of the cadherin/catenin complex resul ting in a negative effect on epithelial gene expression. On the contrary, w e found that although beta-catenin becomes diffuse in the cytoplasm during embryonic EMT, the cytoplasmic beta-catenin of the embryonic and adult mese nchymal cells we examined is not tyrosine phosphorylated. Pervanadate exper iments indicate that cytoplasmic PTPases maintain this dephosphorylation. G SK-3 beta is present, but little or no APC occurs in normal and neoplastic mesenchymal cells. The function of the nonphosphorylated cytoplasmic beta-c atenin in mesenchyme may be related to invasive motility. Indeed, in order to invade extracellular matrix, transitional (Mel 252) melanoma cells trans form from an epithelial to a mesenchymal phenotype with increased cytoplasm ic beta-catenin. Moreover, antisense beta-catenin and plakoglobin ODNs inhi bit Mel 252 and corneal fibroblast invasion of collagen. All fibroblastic, transitional, and spindle melanoma cells contain nuclear as well as cytopla smic beta-catenin, but they are not significantly more invasive than normal fibroblasts that contain only cytoplasmic beta-catenin. (C) 1998 Academic Press.