Tissue-Specific Expression of β-Catenin in Normal Mesenchyme and Uveal Melanomas and Its Effect on Invasiveness

Abstract

This paper is the first in a series aimed at understanding the role of β-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 mesenchymal, the latter including normal avian and mammalian fibroblasts and malignant human uveal melanoma cells. Previously, it was proposed thatsrcinitiates EMT by tyrosine phosphorylation of the cadherin/catenin complex resulting in a negative effect on epithelial gene expression. On the contrary, we found that although β-catenin becomes diffuse in the cytoplasm during embryonic EMT, the cytoplasmic β-catenin of the embryonic and adult mesenchymal cells we examined is not tyrosine phosphorylated. Pervanadate experiments indicate that cytoplasmic PTPases maintain this dephosphorylation. GSK-3β is present, but little or no APC occurs in normal and neoplastic mesenchymal cells. The function of the nonphosphorylated cytoplasmic β-catenin in mesenchyme may be related to invasive motility. Indeed, in order to invade extracellular matrix, transitional (Mel 252) melanoma cells transform from an epithelial to a mesenchymal phenotype with increased cytoplasmic β-catenin. Moreover, antisense β-catenin and plakoglobin ODNs inhibit Mel 252 and corneal fibroblast invasion of collagen. All fibroblastic, transitional, and spindle melanoma cells contain nuclear as well as cytoplasmic β-catenin, but they are not significantly more invasive than normal fibroblasts that contain only cytoplasmic β-catenin.