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.
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.
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Tobias
T
Pasqualon
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Jessica
J
Pruessmeyer
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Sarah
S
Weidenfeld
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Aaron
A
Babendreyer
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Esther
E
Groth
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Julian
J
Schumacher
Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany.
Nicole
N
Schwarz
Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany.
Bernd
B
Denecke
Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany.
Holger
H
Jahr
Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France.|Department of Human Genetics, KU Leuven, 3000, Louvain, Belgium.
Pascale
P
Zimmermann
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Daniela
D
Dreymueller
Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. aludwig@ukaachen.de.
Andreas
A
Ludwig
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008168:Lung / Q000166:cytology*; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D053668:Syndecan-1 / Q000737:chemistry / Q000378:metabolism*
D017931:DNA Primers; D053668:Syndecan-1; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
Lung metastasis formation; Shedding; Syndecan-1; Tumor cell migration