caa a22 4500 606174850 CHVBK 20210128100740.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s00018-015-1912-4 doi (NATIONALLICENCE)springer-10.1007/s00018-015-1912-4 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 [Elektronische Daten] [Tobias Pasqualon, Jessica Pruessmeyer, Sarah Weidenfeld, Aaron Babendreyer, Esther Groth, Julian Schumacher, Nicole Schwarz, Bernd Denecke, Holger Jahr, Pascale Zimmermann, Daniela Dreymueller, Andreas Ludwig] 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. Springer Basel, 2015 Syndecan-1 nationallicence Shedding nationallicence Tumor cell migration nationallicence Lung metastasis formation nationallicence Pasqualon Tobias Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Pruessmeyer Jessica Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Weidenfeld Sarah Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Babendreyer Aaron Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Groth Esther Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Schumacher Julian Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Schwarz Nicole Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany aut Denecke Bernd Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany aut Jahr Holger Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany aut Zimmermann Pascale Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France aut Dreymueller Daniela Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Ludwig Andreas Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut Cellular and Molecular Life Sciences Springer Basel 72/19(2015-10-01), 3783-3801 1420-682X 72:19<3783 2015 72 18 https://doi.org/10.1007/s00018-015-1912-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-015-1912-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Pasqualon Tobias Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Pruessmeyer Jessica Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Weidenfeld Sarah Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Babendreyer Aaron Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Groth Esther Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Schumacher Julian Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Schwarz Nicole Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany aut NATIONALLICENCE 700 1- Denecke Bernd Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany aut NATIONALLICENCE 700 1- Jahr Holger Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany aut NATIONALLICENCE 700 1- Zimmermann Pascale Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France aut NATIONALLICENCE 700 1- Dreymueller Daniela Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 700 1- Ludwig Andreas Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/19(2015-10-01), 3783-3801 1420-682X 72:19<3783 2015 72 18