Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier

R Kamekura, P Nava, M Feng, M Quiros… - Molecular biology of …, 2015 - Am Soc Cell Biol
R Kamekura, P Nava, M Feng, M Quiros, H Nishio, DA Weber, CA Parkos, A Nusrat
Molecular biology of the cell, 2015Am Soc Cell Biol
Desmosomal cadherins mediate intercellular adhesion and control epithelial homeostasis.
Recent studies show that proteinases play an important role in the pathobiology of cancer by
targeting epithelial intercellular junction proteins such as cadherins. Here we describe the
proinflammatory cytokine-induced activation of matrix metalloproteinase 9 and a disintegrin
and metalloproteinase domain–containing protein 10, which promote the shedding of
desmosomal cadherin desmoglein-2 (Dsg2) ectodomains in intestinal epithelial cells …
Desmosomal cadherins mediate intercellular adhesion and control epithelial homeostasis. Recent studies show that proteinases play an important role in the pathobiology of cancer by targeting epithelial intercellular junction proteins such as cadherins. Here we describe the proinflammatory cytokine-induced activation of matrix metalloproteinase 9 and a disintegrin and metalloproteinase domain–containing protein 10, which promote the shedding of desmosomal cadherin desmoglein-2 (Dsg2) ectodomains in intestinal epithelial cells. Epithelial exposure to Dsg2 ectodomains compromises intercellular adhesion by promoting the relocalization of endogenous Dsg2 and E-cadherin from the plasma membrane while also promoting proliferation by activation of human epidermal growth factor receptor 2/3 signaling. Cadherin ectodomains were detected in the inflamed intestinal mucosa of mice with colitis and patients with ulcerative colitis. Taken together, our findings reveal a novel response pathway in which inflammation-induced modification of columnar epithelial cell cadherins decreases intercellular adhesion while enhancing cellular proliferation, which may serve as a compensatory mechanism to promote repair.
Am Soc Cell Biol