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MBC in Press, published online ahead of print March 28, 2007
Mol. Biol. Cell 10.1091/mbc.E06-04-0348

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Submitted on April 24, 2006
Revised on March 6, 2007
Accepted on March 20, 2007

E-Cadherin Homophilic Ligation Inhibits Cell Growth and Epidermal Growth Factor Receptor Signaling Independent of Other Cell Interactions

Michaël Perrais,*{dagger}{ddagger} Xiao Chen,* Mirna Perez-Moreno,{sect} 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; {sect}The Rockfeller University, New York, NY 10021

Monitoring Editor: Jean Schwarzbauer

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 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/TCF 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, are required for growth inhibition. E-cadherin ligation also inhibits EGF receptor mediated growth signaling by a {beta}-catenin dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but inhibits transphosphorylation of Tyr845 and activation of STAT5. 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.

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




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