title: Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration.
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 anin vitroTEM assay. Accordingly, deficiency of meprin β inMep1b-/-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.
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Bedau
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Peters
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Prox
authors.affiliation: Anatomical Institute, University of Kiel, Kiel, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Arnold
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Malin
authors.initials: M
authors.lastname: Finkernagel
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Köllmann
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Rielana
authors.initials: R
authors.lastname: Wichert
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Otte
authors.affiliation: Institute of Pathobiochemistry, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Ohler
authors.affiliation: Pharmaceutical Institute, University of Bonn, Bonn, Germany.
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
authors.affiliation: Anatomical Institute, University of Kiel, Kiel, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Lucius
authors.affiliation: Institute of Experimental Medicine, University of Kiel, Kiel, Germany; and.
authors.forename: Tomas
authors.initials: T
authors.lastname: Koudelka
authors.affiliation: Institute of Experimental Medicine, University of Kiel, Kiel, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tholey
authors.affiliation: Ludwig Boltzmann Institute, Lung Vascular Research, Graz, Austria.
authors.forename: Valentina
authors.initials: V
authors.lastname: Biasin
authors.affiliation: Institute of Pathobiochemistry, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
authors.affiliation: Ludwig Boltzmann Institute, Lung Vascular Research, Graz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, Kiel, Germany; cbeckerpauly@biochem.uni-kiel.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
mesh_terms: D000071443:12E7 Antigen / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D017124:Conserved Sequence; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis; D057705:Transendothelial and Transepithelial Migration
chemical_list: D000071443:12E7 Antigen; D008666:Metalloendopeptidases; C053833:meprin A
keywords: TEM; adhesion molecule; inflammation; proteolysis