title: A cytoplasmic C-terminal fragment of Syndecan-1 is generated by sequential proteolysis and antagonizes Syndecan-1 dependent lung tumor cell migration.
abstract: Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several tumor types and involved in tumor cell migration and metastasis. Syndecan-1 is shed from the cell surface and the remaining transmembrane fragment undergoes intramembrane proteolysis by γ-secretase. We here show that this generates a cytoplasmic C-terminal fragment (cCTF). In epithelial lung tumor A549 cells the endogenously produced cCTF accumulated when its proteasomal degradation was blocked with bortezomib and this accumulation was prevented by γ-secretase inhibition. Overexpression of the cCTF suppressed migration and invasion of A549 cells. This inhibitory effect was only seen when endogenous Syndecan-1 was present, but not in Syndecan-1 deficient cells. Further, overexpression of Syndecan-1 cCTF increased the basal activation of Src kinase, focal adhesion kinase (FAK) and Rho GTPase. This was associated with increased adhesion to fibronectin and collagen G and an increased recruitment of paxillin to focal adhesions. Moreover, lung tumor formation of A549 cells in mice was reduced by overexpression of Syndecan-1 cCTF. Finally, delivery of a synthetic peptide corresponding to the Syndecan-1 cCTF suppressed A549 cell migration and increased basal phosphorylation of Src and FAK. Our data indicate that the Syndecan-1 cCTF antagonizes Syndecan-1 dependent tumor cell migration in vitro and in vivo by dysregulating proadhesive signaling pathways and suggest that the cCTF can be used as an inhibitory peptide.
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pasqualon
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Pruessmeyer
authors.affiliation: Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Aaron
authors.initials: A
authors.lastname: Babendreyer
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Groth
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Koenen
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weidenfeld
authors.affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schwarz
authors.affiliation: Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahr
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymueller
authors.affiliation: Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D059748:Proteolysis; D015398:Signal Transduction; D053668:Syndecan-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D010446:Peptide Fragments; D053668:Syndecan-1
keywords: adhesion; lung cancer; migration; proteoglycan; proteolysis