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Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn

Oncogene volume 25, pages 4595–4604 (2006)Cite this article

Abstract

Cadherin cell–cell adhesion proteins play an important role in modulating the behavior of tumor cells. E-cadherin serves as a suppressor of tumor cell invasion, and when tumor cells turn on the expression of a non-epithelial cadherin, they often express less E-cadherin, enhancing the tumorigenic phenotype of the cells. Here, we show that when A431 cells are forced to express R-cadherin, they dramatically downregulate the expression of endogenous E- and P-cadherin. In addition, we show that this downregulation is owing to increased turnover of the endogenous cadherins via clathrin-dependent endocytosis. p120ctn binds to the juxtamembrane domain of classical cadherins and has been proposed to regulate cadherin adhesive activity. One way p120ctn may accomplish this is to serve as a rheostat to regulate the levels of cadherin. Here, we show that the degradation of E-cadherin in response to expression of R-cadherin is owing to competition for p120ctn.

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Acknowledgements

We thank Drs Masatoshi Takeichi and Kathleen Green for antibodies and Dr Takeichi for the R-cadherin cDNA. This work was supported by R01-DE12308, R01-GM51188 and P20-RR018759 from the NIH, by 0460001z from American Heart Association (to SC) and by National Cancer Institute Cancer Center Support Grant P30 CA36727 (to the Eppley Institute). MM was supported by a postdoctoral fellowship from the Eppley Breast Cancer Training Program (DAMD 17-00-1-0361) from the Department of Defense and by a research fellowship from the Uehara Memorial Foundation. KRL was supported by NIH training grant T32 CA09746 (to the Eppley Institute). SAK was supported by a Widaman fellowship from University of Nebraska Medical Center.

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  1. M Maeda, E Johnson and S H Mandal: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oral Biology, University of Nebraska Medical Center, Omaha, NE, USA

    M Maeda, E Johnson, K R Lawson, R A Svoboda, J K Wahl III, M J Wheelock & K R Johnson

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    S H Mandal, S Caplan, M J Wheelock & K R Johnson

  3. Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    K R Lawson, S Caplan, M J Wheelock & K R Johnson

  4. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    S A Keim, J K Wahl III, M J Wheelock & K R Johnson

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  1. M Maeda
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Correspondence to M J Wheelock.

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Maeda, M., Johnson, E., Mandal, S. et al. Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn. Oncogene 25, 4595–4604 (2006). https://doi.org/10.1038/sj.onc.1209396

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