MECHANISMS OF SIGNAL TRANSDUCTION
The PDZ Domains of Zonula Occludens-1 Induce an Epithelial to Mesenchymal Transition of Madin-Darby Canine Kidney I Cells: EVIDENCE FOR A ROLE OF β-CATENIN/Tcf/Lef SIGNALING*

https://doi.org/10.1074/jbc.275.13.9492Get rights and content
Under a Creative Commons license
open access

The integrity of cell-cell contacts such as adherens junctions (AJ) and tight junctions (TJ) is essential for the function of epithelia. During carcinogenesis, the increased motility and invasiveness of tumor cells reflect the loss of characteristic epithelial features, including cell adhesion. While β-catenin, a component of AJ, plays a well characterized dual role in cell adhesion and signal transduction leading to epithelial cell transformation, little is known about possible roles of tight junction components in signaling processes. Here we show that mutants of the TJ protein zonula occludens protein-1 (ZO-1), which encode the PDZ domains (ZO-1 PDZ) but no longer localize at the plasma membrane, induce a dramatic epithelial to mesenchymal transition (EMT) of Madin-Darby canine kidney I (MDCKI) cells. The observed EMT of these MDCK-PDZ cells is characterized by a repression of epithelial marker genes, a restricted differentiation potential and a significantly induced tumorigenicity. Intriguingly, the β-catenin signaling pathway is activated in the cells expressing the ZO-1 PDZ protein. Ectopic expression of the adenomatous polyposis coli tumor suppressor gene, known to down-regulate activated β-catenin signaling, reverts the transformed fibroblastoid phenotype of MDCK-PDZ cells. Thus, cytoplasmic localization of the ZO-1 PDZ domains induces an EMT in MDCKI cells, most likely by modulating β-catenin signaling.

Cited by (0)

*

This work was supported by grants from the Swiss Cancer League and the Swiss National Science Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

These authors contributed equally to this work.

To whom correspondence may be addressed. E-mail: manuela. [email protected].

**

Present address: Aventis, Cambridge Genomics Center, Cell Biology and Genetics, Cambridge, MA 02139.

To whom correspondence may be addressed. Present address: Inst. of Molecular and Cell Biology, 30 Medical Dr., Singapore 117609, Republic of Singapore. E-mail: [email protected].