E-cadherin is a transmembrane protein that mediates calcium-dependent cell–cell adhesion and plays a key role in maintaining the structural integrity of epithelial monolayers. Loss of E-cadherin expression or function contributes to tumor progression, and because cancers are characterized by loss of cellular adhesion and dissemination, the ability of E-cadherin to suppress tumor cell invasion was logically attributed to its adhesive properties. In the June 23 Journal of Cell Biology, Alice S. Wong and Barry M. Gumbiner at the University of Virginia present new evidence that questions this hypothesis and that suggests a different scenario (Journal of Cell Biology, 161:1191-1203, June 23, 2003).

Wong and Gumbiner expressed wildtype E-cadherin and various E-cadherin mutants in two invasive, E-cadherin–negative human cell lines derived from breast and prostate cancers. They observed that the extracellular adhesive domain of E-cadherin is neither necessary nor sufficient for inhibiting cancer progression. The invasion suppressor activity maps to the cytoplasmic domain that interacts with β-catenin, a protein component of the Wnt signal transduction pathway that determines the transcription of the T-cell factor (TCF) responsive target genes. In addition they observed that although the suppression of invasiveness involves β-catenin, it is independent on activation of TCF-regulated genes.

"The most likely explanation is that E-cadherin binds and sequesters β-catenin away from a target protein other than TCF," suggest the authors, launching the quest for another β-catenin–dependent signaling pathway that could regulate invasion.