p120-catenin is a key component of the cadherin-gamma-secretase supercomplex.

In this work, we show several previously unknown features of p120-catenin in a cadherin-catenin complex that are critical for our understanding of cadherin-based adhesion and signaling. We show that in human epithelial A-431 cells, nearly all p120 molecules engage in high-affinity interaction with E-cadherin-catenin complexes located at the cellular surface. p120 is positioned in proximity to alpha-catenin in the complex with cadherin. These findings suggest a functional cooperation between p120 and alpha-catenin in cadherin-based adhesion. A low level of cadherin-free p120 molecules, in contrast, could facilitate p120-dependent signaling. Finally, we present compelling evidence that p120 is a key linker cementing the E-cadherin-catenin complex with the transmembrane protease gamma-secretase. The cell-cell contact location of this supercomplex makes it an important candidate for conducting different signals that rely on gamma-secretase proteolytic activity.