title: 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.
  
  
  RESULTS
  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
  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.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
authors.forename: Maya
authors.initials: M
authors.lastname: Huguenin
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
authors.forename: Sandra
authors.initials: S
authors.lastname: Trachsel-Rösmann
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oneda
authors.forename: Daniel
authors.initials: D
authors.lastname: Ambort
authors.forename: Erwin E
authors.initials: EE
authors.lastname: Sterchi
authors.forename: Daniel
authors.initials: D
authors.lastname: Lottaz
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; D011994:Recombinant Proteins; D008666:Metalloendopeptidases; C095663:meprin B