The Metalloprotease Meprinβ Processes E-Cadherin and Weakens Intercellular Adhesion

摘要: BACKGROUND: Meprin (EC 3.4.24.18), an astacin-like metalloprotease, is expressed in the epithelium of intestine and kidney tubules has been related to cancer, but mechanistic links are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We used MDCK Caco-2 cells stably transfected with meprin alpha or beta establish models renal intestinal epithelial expressing this protease at physiological levels. In both E-cadherin was cleaved, producing a cell-associated 97-kDa fragment, which enhanced upon activation zymogen reduced presence inhibitor. The cleavage site localized extracellular domain adjacent plasma membrane. vitro assays purified components showed that fragment specifically generated by beta, not ADAM-10 MMP-7. Concomitantly degradation cytoplasmic tail, plaque proteins beta-catenin plakoglobin were processed intracellular protease, whereas alpha-catenin, does bind directly E-cadherin, remained intact. Using confocal microscopy, we observed partial colocalization lateral membranes incompletely polarized preconfluent early confluent stages. beta-expressing displayed strength cell-cell contacts significantly lower tendency form multicellular aggregates. CONCLUSIONS/SIGNIFICANCE: By identifying as substrate for cellular context, study reveals novel biological role cells. Our results suggest crucial control adhesiveness via potential implications wide range processes including barrier function cancer progression.