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Published online 17 November 2003. doi:10.1083/jcb.200308162
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© The Rockefeller University Press, 0021-9525/2003/11/847 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 847-857

Article

 Autoregulation of E-cadherin expression by cadherin–cadherin interactions : the roles of ß-catenin signaling, Slug, and MAPK



Maralice Conacci-Sorrell1, Inbal Simcha1, Tamar Ben-Yedidia1, Janna Blechman1, Pierre Savagner2 and Avri Ben-Ze'ev1

1 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
2 EMI 0229 Institut National de la Santé de la Recherche Médicale, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, Cedex 5, France

Address correspondence to Avri Ben-Ze'ev, Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: (972)-8-934-2422. Fax: (972)-8-946-5261. email: avri.ben-zeev{at}weizmann.ac.il

Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin–ß-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated ß-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by ß-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and ß-catenin in adherens junctions. In such cells, ß-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin–mediated contacts resulted in nuclear localization and signaling by ß-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell–cell adhesion involving Slug, ß-catenin and ERK could be important in tumorigenesis.

Key Words: cell adhesion; ß-catenin; slug; ERK; tumorigenesis

Abbreviations used in this paper: EMT, epithelial to mesenchymal transition; RTK, receptor tyrosine kinases; WT, wild-type.


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