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