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Cell to Cell Adhesion Disassembly During EMT

In addition to E-Cadherin transcriptional repression, the disassembly and removal of existing cell to cell adhesion complexes is required during epithelial to mesenchymal transition (EMT). Adherens junctions and tight junctions are disassembled and internalized via Clathrin-dependent and -independent mechanisms. For instance, Clathrin-dependent endocytosis is initiated by Src-mediated tyrosine phosphorylation of E-Cadherin. Following phosphorylation, the Ubiquitin ligase (E3), Hakai, mediates E-Cadherin complex ubiquitination. Ubiquitin modification triggers a series of events that include Clathrin recruitment, Clathrin-coated vesicle assembly and budding, and trafficking through the endocytic pathway to the lysosome. In addition to internalization, E-Cadherin is proteolytically processed by MMPs and ADAM protein family members, which facilitates E-Cadherin ectodomain shedding to further destabilize junctions. Other cell adhesion complexes, such as tight junctions, can be internalized via Caveolin-mediated endocytosis following Actin depolymerization.