TGF-BETA INDUCED TRANSDIFFERENTIATION OF MAMMARY EPITHELIAL-CELLS TO MESENCHYMAL CELLS - INVOLVEMENT OF TYPE-I RECEPTORS

Citation
Pj. Miettinen et al., TGF-BETA INDUCED TRANSDIFFERENTIATION OF MAMMARY EPITHELIAL-CELLS TO MESENCHYMAL CELLS - INVOLVEMENT OF TYPE-I RECEPTORS, The Journal of cell biology, 127(6), 1994, pp. 2021-2036
Citations number
66
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell Biology
Journal title
ISSN journal
0021-9525
Volume
127
Issue
6
Year of publication
1994
Part
2
Pages
2021 - 2036
Database
ISI
SICI code
0021-9525(1994)127:6<2021:TITOME>2.0.ZU;2-T
Abstract
The secreted polypeptide transforming growth factor-beta (TGF beta) ex erts its multiple activities through type I and II cell surface recept ors. In epithelial cells, activation of the TGF beta signal transducti on pathways leads to inhibition of cell proliferation and an increase in extracellular matrix production. TGF-beta is widely expressed durin g development and its biological activity has been implicated in epith elial-mesenchymal interactions, e.g., in branching morphogenesis of th e lung, kidney, and mammary gland, and in inductive events between mam mary epithelium and stroma. In the present study, we investigated the effects of TGF beta on mouse mammary epithelial cells in vitro. TGF be ta reversibly induced an alteration in the differentiation of normal m ammary epithelial NMuMG cells from epithelial to fibroblastic phenotyp e. The change in cell morphology correlated with (a) decreased express ion of the epithelial markers E-cadherin, ZO-1, and desmoplakin I and II; (b) increased expression of mesenchymal markers, such as fibronect in; and (c) a fibroblast-like reorganization of actin fibers. This phe notypic differentiation displays the hallmarks of an epithelial to mes enchymal transdifferentiation event. Since NMuMG cells make high level s of the type I TGF beta receptor Tsk7L, yet lack expression of the AL K-5/R4 type I receptor which has been reported to mediate TGF-beta res ponsiveness, we evaluated the role of the Tsk7L receptor in TGF beta-m ediated transdifferentiation. We generated NMuMG cells that stably ove rexpress a truncated Tsk7L type I receptor that lacks most of the cyto plasmic kinase domain, thus function as a dominant negative mutant. Th ese transfected cells no longer underwent epithelial to mesenchymal mo rphological change upon exposure to TGF beta, yet still displayed some TGF beta-mediated responses. We conclude that TGF beta has the abilit y to modulate E-cadherin expression and induce a reversible epithelial to mesenchymal transdifferentiation in epithelial cells. Unlike other transdifferentiating growth factors, such as bFGF and HGF, these chan ges are accompanied by growth inhibition. Our results also implicate t he Tsk7L type I receptor as mediating the TGF beta-induced epithelial to mesenchymal transition.