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A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation

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Abstract

Syndecan-1 is a heparan sulfate proteoglycan expressed by endothelial and epithelial cells and involved in wound healing and tumor growth. Surface-expressed syndecan-1 undergoes proteolytic shedding leading to the release of the soluble N-terminal ectodomain from a transmembrane C-terminal fragment (tCTF). We show that the disintegrin and metalloproteinase (ADAM) 17 generates a syndecan-1 tCTF, which can then undergo further intra-membrane proteolysis by γ-secretase. Scratch-induced wound closure of cultured lung epithelial A549 tumor cells associates with increased syndecan-1 cleavage as evidenced by the release of shed syndecan-1 ectodomain and enhanced generation of the tCTF. Both wound closure and the associated syndecan-1 shedding can be suppressed by inhibition of ADAM family proteases. Cell proliferation, migration and invasion into matrigel as well as several signaling pathways implicated in these responses are suppressed by silencing of syndecan-1. These defects of syndecan-1 deficient cells can be overcome by overexpression of syndecan-1 tCTF or a corresponding tCTF of syndecan-4 but not by overexpression of a tCTF lacking the transmembrane domain. Finally, lung metastasis formation of A549 cells in SCID mice was found to be dependent on syndecan-1, and the presence of syndecan-1 tCTF was sufficient for this activity. Thus, the syndecan-1 tCTF by itself is capable of mediating critical syndecan-1-dependent functions in cell proliferation, migration, invasion and metastasis formation and therefore can replace full length syndecan-1 in the situation of increased syndecan-1 shedding during cell migration and tumor formation.

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Acknowledgments

We thank Tanja Woopen and Melanie Esser for expert technical assistance. We thank Paul Saftig and Karina Reiss (University of Kiel, Germany) for providing Ps1/2-deficient MEFs, Kristin Seré (University Hospital RWTH Aachen, Germany) for SCID mice. J. P. was supported in part by the START-project 155/11 of the Medical Faculty RWTH Aachen. A. L. was supported in part by the Interdisciplinary Center for Clinical Research (IZKF) of the RWH Aachen and by the Deutsche Forschungsgemeinschaft (DFG) project LU869/5-1. P. Z. was supported by the Concerted Actions Program of KU Leuven (GOA/12/016) and l’Institut National du Cancer (INCa subvention 2013-105). T. P. received a RWTH Aachen scholarship for doctoral students.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Tobias Pasqualon, Jessica Pruessmeyer, Sarah Weidenfeld, Aaron Babendreyer, Esther Groth, Julian Schumacher, Daniela Dreymueller & Andreas Ludwig

  2. Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany

    Nicole Schwarz

  3. Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany

    Bernd Denecke

  4. Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany

    Holger Jahr

  5. Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France

    Pascale Zimmermann

  6. Department of Human Genetics, KU Leuven, 3000, Louvain, Belgium

    Pascale Zimmermann

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  1. Tobias Pasqualon
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Correspondence to Andreas Ludwig.

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Pasqualon, T., Pruessmeyer, J., Weidenfeld, S. et al. A transmembrane C-terminal fragment of syndecan-1 is generated by the metalloproteinase ADAM17 and promotes lung epithelial tumor cell migration and lung metastasis formation. Cell. Mol. Life Sci. 72, 3783–3801 (2015). https://doi.org/10.1007/s00018-015-1912-4

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