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Mol. Biol. Cell 18 (6): 2013-2025

Copyright © 2007 by The American Society for Cell Biology.

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independently of Other Cell InteractionsFormula

Michaël Perrais*,{dagger},{ddagger}, Xiao Chen*, Mirna Perez-Moreno§, and Barry M. Gumbiner*

*Department of Cell Biology, University of Virginia, Charlottesville, VA 22908-0732; {dagger}Institut National de la Santé et de la Recherche Médicale, U837, 59045 Lille, France; {ddagger}Université Lille 2, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Jean-Pierre Aubert Research Center, 59045 Lille, France; and §The Rockefeller University, New York, NY 10021

Received for publication April 24, 2006. Revision received March 6, 2007. Accepted for publication March 20, 2007.

Monitoring Editor: Jean Schwarzbauer

Abstract: E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to beta-catenin is required for cell growth inhibition, but beta-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor beta-catenin binding to {alpha}-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a beta-catenin–dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a beta-catenin–dependent mechanism that inhibits selective signaling functions of growth factor receptors.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0348) on March 28, 2007.

Formula The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Barry M. Gumbiner (gumbiner{at}virginia.edu).

Abbreviations: BrdU, 5-bromodeoxyuridine • EGF, epidermal growth factor • EGFR, epidermal growth factor receptor • ERK, extracellular signal-regulated kinase • Fc-hE, Fc-hE–cadherin • FL, full length • LEF, leukocyte enhancer factor • siRNA, small interfering RNA • STAT, signal transducers and activators of transcription • TCF, T cell factor.

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