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Vol. 17, Issue 4, 1871-1879, April 2006
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1-induced Epithelial-Mesenchymal Transition
Department of Cell Biology, Harvard Medical School, Boston, MA 02115
Submitted August 16, 2005;
Revised January 17, 2006;
Accepted January 31, 2006
Monitoring Editor: Asma Nusrat
Transforming growth factor beta 1 (TGF-
1) has been shown to induce epithelial-mesenchymal transition (EMT) during various stages of embryogenesis and progressive disease. This alteration in cellular morphology is typically characterized by changes in cell polarity and loss of adhesion proteins such as E-cadherin. Here we demonstrate that EMT is associated with loss of claudin-1, claudin-2, occludin, and E-cadherin expression within 72 h of exposure to TGF-1 in MDCKII cells. It has been suggested that this expression loss occurs through TGF-1 in a Smad-independent mechanism, involving MEK and PI3K pathways, which have previously been shown to induce expression of the Snail (SNAI-1) gene. Here we show that these pathways are responsible for loss of tight junctions and a partial loss of E-cadherin. However, our results also demonstrate that a complete loss of E-cadherin and transformation to the mesenchymal phenotype are dependent on Smad signaling, which subsequently stimulates formation of -catenin/LEF-1 complexes that induce EMT.
Abbreviation used: DN, dominant negative; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-related kinase; GSK-3, glycogen synthase kinase-3 beta; ILK, integrin linked kinase; LEF-1, lymphoid enhancer factor-1; PI3K, phosphoinositide-3-kinase; TR, transforming growth factor-beta receptor; TGF-, transforming growth factor-beta.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
Address correspondence to: Daniel A. Goodenough (daniel_goodenough{at}hms.harvard.edu).
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