The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion

Huguenin, Maya; Müller, Eliane J; Trachsel-Rösmann, Sandra; Oneda, Beatrice; Ambort, Daniel; Sterchi, Erwin E; Lottaz, Daniel (2008). The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion. PLoS ONE, 3(5), e2153. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0002153

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology

UniBE Contributor:

Sterchi, Erwin-Ernst and Lottaz, Daniel

ISSN:

1932-6203

ISBN:

18478055

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:03

Last Modified:

16 Nov 2015 14:47

Publisher DOI:

10.1371/journal.pone.0002153

PubMed ID:

18478055

Web of Science ID:

000262172800018

BORIS DOI:

10.7892/boris.27328

URI:

https://boris.unibe.ch/id/eprint/27328 (FactScience: 106047)

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