β-Catenin Serves as a Clutch between Low and High Intercellular E-Cadherin Bond Strengths

A wide range of invasive pathological outcomes originate from the loss of epithelial phenotype and involve either loss of function or downregulation of transmembrane adhesive receptor complexes, including Ecadherin (Ecad) and binding partners beta-catenin and alpha-catenin at adherens junctions. Cellular pathways regulating wild-type beta-catenin level, or direct mutations in beta-catenin that affect the turnover of the protein have been shown to contribute to cancer development, through induction of uncontrolled proliferation of transformed tumor cells, particularly in colon cancer. Using single-molecule force spectroscopy, we show that depletion of beta-catenin or the prominent cancer-related S45 deletion mutation in beta-catenin present in human colon cancers both weaken tumor intercellular Ecad/Ecad bond strength and diminishes the capacity of specific extracellular matrix proteins including collagen I, collagen IV, and laminin V to modulate intercellular Ecad/Ecad bond strength through alpha-catenin and the kinase activity of glycogen synthase kinase 3 (GSK-3 beta). Thus, in addition to regulating tumor cell proliferation, cancer-related mutations in beta-catenin can influence tumor progression by weakening the adhesion of tumor cells to one another through reduced individual Ecad/Ecad bond strength and cellular adhesion to specific components of the extracellular matrix and the basement membrane.