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ADHESION MOLECULES AS MEDIATORS OF CELL SIGNALING: PROTEOLYTIC PROCESSING OF DESMOGLEIN 2 IN CELL GROWTH AND SURVIVAL DM Brennan and MG Mahoney Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA.
Desmogleins are the transmembrane components of the desmosomal adhesion complex. The role of desmogleins in cell-cell adhesion has been well characterized. However, recent evidence suggests that desmogleins have more complex and diverse roles as mediators of cell signaling pathways relevant to cell growth and survival, potentially through the proteolytic processing of desmoglein 2 (Dsg2). The goal of this study is to assess the proteolytic processing of Dsg2 in a transgenic (Tg) mouse model that overexpresses Dsg2 in the epidermis, and elucidate cell growth and survival pathways relevant to the processing of Dsg2. A panel of Dsg2 antibodies were characterized to determine antigenic sites and used in all aspects of this study. In vitro cell culture assays were used to assess the fate of Dsg2 in response to inhibitors of cell growth and survival assays, and in response to chemical-induced apoptosis. In vivo, Dsg2 processing was assessed via immunoblotting and immunohistochemical analysis of Dsg2 Tg mouse skin and tumors. In vitro results indicate differential regulation of Dsg2 processing by a variety of cell growth and survival pathways; furthermore, Dsg2 ectodomain shedding was increased in response to apoptosis. Immunoanalysis demonstrate complex processing of Dsg2, particularly in tumors from Dsg2 Tg mice. Finally, we demonstrate a correlation between Dsg2 ectodomain shedding and EGF receptor phosphorylation, further elucidating the mechanism by which Dsg2 activates cell signaling pathways. Taken together this evidence increases our understanding of the complex roles of desmogleins, particularly Dsg2, as mediators of cell signaling.
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