The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion.

Abstract

BACKGROUND:

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.

• Authors: Maya Huguenin, Eliane J Müller, Sandra Trachsel-Rösmann, Beatrice Oneda, Daniel Ambort, Erwin E Sterchi, Daniel Lottaz
• Journal: PloS one (PLoS One) Vol. 3 Issue 5 Pg. e2153 (May 14 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 18478055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Recombinant Proteins
• Metalloendopeptidases
• meprin B

Topics

• Animals
• Caco-2 Cells
• Cadherins (metabolism)
• Cell Adhesion (physiology)
• Cell Line
• Dogs
• Epithelial Cells (enzymology, metabolism)
• Humans
• Metalloendopeptidases (metabolism, physiology)
• Recombinant Proteins (metabolism)