Dynamic modulation of intercellular adhesion mediated by matriptase-EPCAM/Trop-2 axes is critical for cell extrusion, division, and collective migration

Epithelial dynamics require rapid remodeling of cell adhesion during extrusion, division, and migration. We identify a matriptase-dependent mechanism regulating the Ca2+- independent adhesion molecules EpCAM and Trop-2. Matriptase activation cleaves these CAMs into two-chain forms, promoting internalization and degradation, followed by replenishment through new synthesis. This turnover enables rapid adaptation of adhesion to environmental cues. Loss of matriptase disrupts this cycle, impairing epithelial integrity, extrusion, mitosis, and collective migration. Matriptase activity is tightly controlled by zymogen activation and inhibition by HAI-1, restricting CAM cleavage. Environmental factors, including pH, redox state, and chloride levels, modulate activation, linking external stimuli to adhesion remodeling. This protease-driven pathway provides a rapid, adaptable system for epithelial adhesion control.