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Molecular and Cellular Biology, January 2005, p. 389-402, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.389-402.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Lysosomal Targeting of E-Cadherin: a Unique Mechanism for the Down-Regulation of Cell-Cell Adhesion during Epithelial to Mesenchymal Transitions{dagger}

Felipe Palacios,1 Jogender S. Tushir,1 Yasuyuki Fujita,2 and Crislyn D'Souza-Schorey1*

Department of Biological Sciences and Walther Cancer Institute, University of Notre Dame, Notre Dame, Indiana,1 MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom2

Received 14 June 2004/ Returned for modification 19 July 2004/ Accepted 4 October 2004

A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. Here we demonstrate that, upon v-Src expression, a potent trigger of epithelial to mesenchymal transitions, E-cadherin is internalized and then shuttled to the lysosome instead of being recycled back to the lateral membrane. Thus, while E-cadherin internalization facilitates the dissolution of adherens junctions, its subsequent traffic to the lysosome serves as a means to ensure that cells do not reform their cell-cell contacts and remain motile. We also show that ubiquitin tagging of E-cadherin is essential for its sorting to the lysosome. The lysosomal targeting of E-cadherin is mediated by hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and v-Src-induced activation of the Rab5 and Rab7 GTPases. Our studies reveal that the lysosomal targeting of E-cadherin is an important posttranscriptional mechanism to deplete cellular E-cadherin during Src-induced epithelial to mesenchymal transitions.

* Corresponding author. Mailing address: Department of Biological Sciences, University of Notre Dame, Box 369, Galvin Life Sciences Bldg., Notre Dame, IN 46556-0369. Phone: (574) 631-3735. Fax: (574) 631-7413. E-mail: D'Souza-Schorey.1{at}nd.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2005, p. 389-402, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.389-402.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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