Modulation of cell？:？cell junctions is a key event in cutaneous wound repair. In this study we report that activation of the epidermal growth factor (EGF) receptor disrupts cell？:？cell adhesion, but with different kinetics and fates for the desmosomal cadherin desmoglein and for E-cadherin. Downregulation of desmoglein preceded that of E-cadherin in vivo and in an EGF-stimulated in vitro wound reepithelialization model. Dual immunofluorescence staining revealed that neither E-cadherin nor desmoglein-2 internalized with the EGF receptor, or with one another. In response to EGF, desmoglein-2 entered a recycling compartment based on predominant colocalization with the recycling marker Rab11. In contrast, E-cadherin downregulation was accompanied by cleavage of the extracellular domain. A broad-spectrum matrix metalloproteinase inhibitor protected E-cadherin but not the desmosomal cadherin, desmoglein-2, from EGF-stimulated disruption. These findings demonstrate that although activation of the EGF receptor regulates adherens junction and desmosomal components, this stimulus downregulates associated cadherins through different mechanisms. 1. Introduction During cutaneous wound repair, epidermal cells at the wound margin undergo phenotypic and functional changes including increased proliferation, migration, and a partial epithelial-to-mesenchymal transition (EMT) characterized by disruption of cell？:？cell junctions, changes in cell？:？substrate adhesion, and retraction and reorganization of the cytoskeleton [1–3]. Kalluri and Weinberg proposed three sub-classifications of EMT with type 2 EMT associated with wound healing, tissue regeneration, and organ fibrosis [4]. An essential aspect of type 2 EMT is that once repair is achieved epithelial phenotype and tissue integrity is restored. A hallmark of successful wound repair is the reestablishment of cell？:？cell junctions and barrier function, thereby illustrating dynamic modulation of adherens junctions and desmosomes during wound reepithelialization. In mouse epidermis, a decrease in E-cadherin is evident 3 days after wounding in full-thickness incisional or excisional wound models with subsequent protein restoration upon wound closure [5]. Blocking E-cadherin function with antibody caused uneven wound margins and disruption of the reorganizing actin cytoskeleton in mouse epidermis [6], demonstrating the importance of E-cadherin in wound repair. Similarly, the dissolution of hemidesmosomes, which connect the cell to the extracellular matrix, and desmosomes responsible for cell？:？cell contacts occurs during
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