Extracellular cleavage of E-cadherin promotes epithelial cell extrusion

Abstract

Epithelial cell extrusion and subsequent apoptosis is a key mechanism to prevent accumulation of excess cells. Conversely, when driven by oncogene expression, apical cell extrusion is followed by proliferation and represents an initial step of tumorigenesis. E-cadherin (E-cad), the main component of adherens junctions, has been shown to be essential for epithelial cell extrusion, but its mechanistic contribution remains unclear. Here, we provide clear evidence that cell extrusion can be driven by E-cad cleavage, both in a wild type and oncogenic environment. We first show that CDC42 activation in a single epithelial cell results in its efficient MMP-sensitive extrusion through MEK signaling activation and is supported by E-cad cleavage. Second, using an engineered cleavable form of E-cad, we demonstrate that sole extracellular E-cad truncation at the plasma membrane promotes apical extrusion. We propose that extracellular cleavage of E-cad generates a rapid change in cell-cell adhesion sufficient to drive apical cell extrusion. Whereas in normal epithelia, extrusion is followed by apoptosis, when combined to active oncogenic signaling, it is coupled to cell proliferation.