Medici, DamianHay, Elizabeth D.Olsen, Bjorn R.2019-10-032008Medici, Damian, Elizabeth D. Hay, and Bjorn R. Olsen. 2008. “Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-Dependent Expression of Transforming Growth Factor-β3.” Edited by Marianne Bronner-Fraser. Molecular Biology of the Cell 19 (11): 4875–87. https://doi.org/10.1091/mbc.e08-05-0506.1059-15241939-4586http://nrs.harvard.edu/urn-3:HUL.InstRepos:41467449Members 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.en-USJournal Article2019-10-0310.1091/mbc.E08-05-0506