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 mesenchymal, the latter including normal avian and mammalian fibroblasts and malignant human uveal melanoma cells. Previously, it was proposed that src initiates 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 beta-catenin becomes diffuse in the cytoplasm during embryonic EMT, the cytoplasmic beta-catenin of the embryonic and adult mesenchymal cells we examined is not tyrosine phosphorylated. Pervanadate experiments indicate that cytoplasmic PTPases maintain this dephosphorylation. GSK-3beta is present, but little or no APC occurs in normal and neoplastic mesenchymal cells. The function of the nonphosphorylated cytoplasmic beta-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 beta-catenin. Moreover, antisense beta-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 beta-catenin, but they are not significantly more invasive than normal fibroblasts that contain only cytoplasmic beta-catenin.
Kim
K
K
Department of Cell Biology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts, 02115, USA.
Daniels
K J
KJ
Hay
E D
ED
D016475:3T3 Cells; D011125:Adenomatous Polyposis Coli; D000328:Adult; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D013194:Staining and Labeling; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D014604:Uveal Neoplasms / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; C076715:pervanadate; D014638:Vanadates; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D017027:Protein Tyrosine Phosphatases