E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation

beta-catenin is a multifunctional protein found in three cell compartments: the plasma membrane, the cytoplasm and the nucleus. The cell has developed elaborate ways of regulating the level and localization of beta-catenin to assure its specific function in each compartment. One aspect of this regul ation is inherent in the structural organization of beta-catenin itself; mo st of its protein-interacting motifs overlap so that interaction with one p artner can block binding of another at the same time. Using recombinant pro teins, we found that E-cadherin and lymphocyte-enhancer factor-1 (LEF-1) fo rm mutually exclusive complexes with beta-catenin; the association of beta- catenin with LEF-1 was competed out by the E-cadherin cytoplasmic domain. S imilarly, LEF-1 and adenomatous polyposis coli (APC) formed separate, mutua lly exclusive complexes with beta-catenin, In Wnt-1-transfected C57MG cells , free beta-catenin accumulated and was able to associate with LEF-1. The a bsence of E-cadherin in E-cadherin-/- embryonic stem (ES) cells also led to an accumulation of free beta-catenin and its association with LEF-1, there by mimicking Wnt signaling. beta-catenin/LEF-1-mediated transactivation in these cells was antagonized by transient expression of wildtype E-cadherin, but not of E-cadherin lacking the beta-catenin binding site. The potent ab ility of E-cadherin to recruit beta-catenin to the cell membrane and preven t its nuclear localization and transactivation was also demonstrated using SW480 colon carcinoma cells.