Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

Bedau, Tillmann, Peters, Florian, Prox, Johannes, Arnold, Philipp, Schmidt, Frederike, Finkernagel, Malin, Köllmann, Sandra, Wichert, Rielana, Otte, Anna, Ohler, Anke, Stirnberg, Marit, Lucius, Ralph, Koudelka, Tomas, Tholey, Andreas, Biasin, Valentina, Pietrzik, Claus U., Kwapiszewska, Grazyna and Becker-Pauly, Christoph (2016) Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration The FASEB Journal, 31 (3). pp. 1226-1237. DOI 10.1096/fj.201601113R.

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Abstract

The adhesion molecule CD99 is essential for the transendothelial migration of leukocytes. In this study, we used biochemical and cellular assays to show that CD99 undergoes ectodomain shedding by the metalloprotease meprin β and subsequent intramembrane proteolysis by γ-secretase. The cleavage site in CD99 was identified by mass spectrometry within an acidic region highly conserved through different vertebrate species. This finding fits perfectly to the unique cleavage specificity of meprin β with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin β would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin β induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin β in Mep1b-/- mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin β could serve as a therapeutic target, given that in a proof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin β inhibitor-treated mice.-Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Köllmann, S., Wichert, R., Otte, A., Ohler, A., Stirnberg, M., Lucius, R., Koudelka, T., Tholey, A., Biasin, V., Pietrzik, C. U., Kwapiszewska, G., Becker-Pauly, C. Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration.

Document Type: Article
Keywords: TEM; adhesion molecule; inflammation; proteolysis
Research affiliation: Kiel University > Kiel Marine Science
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
DOI etc.: 10.1096/fj.201601113R
ISSN: 0892-6638
Date Deposited: 08 Jan 2018 11:21
Last Modified: 01 Feb 2018 12:07
URI: http://eprints.uni-kiel.de/id/eprint/41257

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