Research Papers:

Cancer-associated mutations in the canonical cleavage site do not influence CD99 shedding by the metalloprotease meprin β but alter cell migration in vitro

Tillmann Bedau, Neele Schumacher, Florian Peters, Johannes Prox, Philipp Arnold, Tomas Koudelka, Ole Helm, Frederike Schmidt, Björn Rabe, Marlene Jentzsch, Philip Rosenstiel, Susanne Sebens, Andreas Tholey, Stefan Rose-John and Christoph Becker-Pauly _

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Oncotarget. 2017; 8:54873-54888. https://doi.org/10.18632/oncotarget.18966

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Tillmann Bedau1, Neele Schumacher1, Florian Peters1, Johannes Prox1, Philipp Arnold2, Tomas Koudelka3, Ole Helm4, Frederike Schmidt1, Björn Rabe1, Marlene Jentzsch5, Philip Rosenstiel5, Susanne Sebens4, Andreas Tholey3, Stefan Rose-John1 and Christoph Becker-Pauly1

1Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany

2Anatomical Institute, University of Kiel, 24118 Kiel, Germany

3Institute of Experimental Medicine, University of Kiel, 24118 Kiel, Germany

4Institute for Experimental Tumor Research, University of Kiel, 24118 Kiel, Germany

5Institute of Clinical Molecular Biology, University of Kiel, 24118 Kiel, Germany

Correspondence to:

Christoph Becker-Pauly, email: [email protected]

Keywords: CD99, meprin β, proteolytic shedding, lung cancer, inflammation

Received: January 18, 2017     Accepted: June 17, 2017     Published: July 04, 2017


Transendothelial cell migration (TEM) is crucial for inflammation and metastasis. The adhesion molecule CD99 was shown to be important for correct immune cell extravasation and is highly expressed on certain cancer cells. Recently, we demonstrated that ectodomain shedding of CD99 by the metalloprotease meprin β promotes TEM in vitro.

In this study, we employed an acute inflammation model (air pouch/carrageenan) and found significantly less infiltrated cells in meprin β knock-out animals validating the previously observed pro-inflammatory activity. To further analyze the impact of meprin β on CD99 shedding with regard to cell adhesion and proliferation we characterized two lung cancer associated CD99 variants (D92H, D92Y), carrying point mutations at the main cleavage site. Interestingly, ectodomain shedding of these variants by meprin β was still detectable. However the cleavage site shifted to adjacent positions. Nevertheless, expression of CD99 variants D92H and D92Y revealed partial misfolding and proteasomal degradation. A previously observed influence of CD99 on Src activation and increased proliferation could not be confirmed in this study, independent of wild-type CD99 or the variants D92H and D92Y. However, we identified meprin β as a potent inducer of Src phosphorylation. Importantly, we found significantly increased cell migration when expressing the cancer-associated CD99 variant D92H compared to the wild-type protein.

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