Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 11, Pages 4875-4887Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-05-0506
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- National Institutes of Health [R01-DE11142, P01-AR048564]
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Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta 3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta 3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta 1 or TGF-beta 2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta 1- and TGF-beta 2-induced EMT were found to be TGF-beta 3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.
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