Cell Growth E-Cadherin Inhibits the Growth of Single Cells

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

E-cadherin is found at the junctions of epithelial cells. Besides mediating cell-cell adhesion through homophilic interactions (E-cadherin from one cell binding to E-cadherin on an adjacent cell), E-cadherin mediates contact inhibition of cell growth, and loss of E-cadherin is associated with tumorigenesis. As a result of the many molecular interactions that occur between cells at junctions, it has been unclear whether E-cadherin alone can inhibit cell growth in the absence of cell contact. Perrais et al. devised an experimental system designed to monitor the effects of ligation of E-cadherin on the growth of single cells. The authors exposed single epithelial cells, attached to fibronectin-coated coverslips, to microspheres coated with chimeric proteins of the extracellular domain of E-cadherin fused to the immunoglobulin Fc domain (Fc-hE). Exposure of single cells to Fc-hE-microspheres resulted in decreased BrdU incorporation (a marker of DNA replication), as measured by immunofluorescence microscopy, compared with that in cells exposed to control microspheres, which indicates that ligation of E-cadherin on these cells resulted in decreased cellular proliferation. Cadherins mediate cell-cell adhesion in part through interactions of their cytoplasmic domains with catenins. Through the use of mutated forms of E-cadherin in epithelial cell lines, the authors found that the -catenin binding domain of E-cadherin was necessary for the inhibition of cellular proliferation. Knockdown of -catenin by siRNA eliminated E-cadherin-mediated inhibition of cell growth, resulting in increased cellular proliferation. E-cadherin-mediated inhibition of cell growth, however, was not dependent on -catenin-dependent transcriptional activation. Ligation of E-cadherin by Fc-hE-microspheres inhibited cell growth stimulated by epidermal growth factor (EGF) in epithelial cell lines. This effect of E-cadherin was also dependent on the presence of -catenin. Whereas E-cadherin ligation did not inhibit either the autophosphorylation of the EGF receptor (EGFR) or EGFR-mediated activation of extracellular signal-regulated kinase (ERK), it did inhibit the transphosphorylation of the Tyr845 residue of EGFR and the subsequent activation of signal transducer and activator of transcription 5 (STAT5). Together these data suggest that homophilic ligation of E-cadherin can inhibit cell growth and EGFR signaling independently of cell-cell contact.

M. Perrais, X. Chen, M. Perez-Moreno, B. M. Gumbiner, E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Mol. Biol. Cell 18, 2013-2025 (2007). [Abstract] [Full Text]

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