Journal
FASEB JOURNAL
Volume 31, Issue 3, Pages 1226-+Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201601113R
Keywords
proteolysis; inflammation; TEM; adhesion molecule
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB877]
- Proteolysis as a Regulatory Event in Pathophysiology [PI379/6-1, PI379/5-2, BE4086/2-1, BE4086/5-1]
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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 beta and subsequent intramembrane proteolysis by gamma-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 beta with a strong preference for aspartate residues and suggests coevolution of protease and substrate. We hypothesized that limited CD99 cleavage by meprin beta would alter cellular transendothelial migration (TEM) behavior in tissue remodeling processes, such as inflammation and cancer. Indeed, meprin beta induced cell migration of Lewis lung carcinoma cells in an in vitro TEM assay. Accordingly, deficiency of meprin beta in Mep1b(-/-) mice resulted in significantly increased CD99 protein levels in the lung. Therefore, meprin beta could serve as a therapeutic target, given that in aproof-of-concept approach we showed accumulation of CD99 protein in lungs of meprin beta inhibitortreated mice.- Bedau, T., Peters, F., Prox, J., Arnold, P., Schmidt, F., Finkernagel, M., Kollmann, 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 b and promotes transendothelial cell migration.
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