A cytoplasmic C-terminal fragment of syndecan-1 is generated by sequential proteolysis and antagonizes syndecan-1 dependent lung tumor cell migration
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Tobias Pasqualon1, Jessica Pruessmeyer1, Vera Jankowski2, Aaron Babendreyer1, Esther Groth1, Julian Schumacher1, Andrea Koenen1, Sarah Weidenfeld1, Nicole Schwarz3, Bernd Denecke4, Holger Jahr5, Daniela Dreymueller1, Joachim Jankowski2, Andreas Ludwig1
1Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany
2Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
3Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany
4Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany
5Department of Orthopaedic Surgery, RWTH Aachen University, Aachen, Germany
Andreas Ludwig, e-mail: email@example.com
Keywords: lung cancer, migration, adhesion, proteoglycan, proteolysis
Received: May 29, 2015 Accepted: August 20, 2015 Published: September 03, 2015
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.
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