The ability to degrade the extracellular matrix by controlled proteolysis is an important property of malignant cancer cells, which enables them to invade the surrounding tissue and to gain access to the circulation by intravasation. One proteolytic system thought to be involved in these processes is urokinase-mediated plasminogen activation. Expression of a glycolipid-anchored receptor for urokinase-type plasminogen activator (uPA) targets this system to the cell surface. This receptor (uPAR) is composed of three homologous modules belonging to the Ly-6/uPAR/α-neurotoxin protein domain family. Integrity of the three-domain structure of uPAR is required for maintenance of its sub-nanomolar affinity for uPA, but the functional epitope for this interaction is primarily located in uPAR domain I. Using affinity maturation by combinatorial chemistry, we have recently identified a potent 9-mer peptide antagonist of the uPA-uPAR interaction having a high affinity for uPAR (Kd < 1 nM). Photoaffinity labelling suggests that this peptide interacts with a composite binding site in uPAR involving both domains I and III. When tested in a chicken chorioallantoic membrane assay that was developed to quantify intravasation of human cells, this antagonist was able to reduce the intravasation of HEp-3 cancer cells by approx. 60%.
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Conference Article|
April 01 2002
Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy
M. Ploug;
M. Ploug
1
*Finsen Laboratory, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
1To whom correspondence should be addressed (e-mail mploug@finsenlab.dk).
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H. Gårdsvoll;
H. Gårdsvoll
*Finsen Laboratory, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
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T. J. D. Jørgensen;
T. J. D. Jørgensen
*Finsen Laboratory, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
†Department of Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark
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L. Lønborg Hansen;
L. Lønborg Hansen
*Finsen Laboratory, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
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K. Danø
K. Danø
*Finsen Laboratory, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
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Publisher: Portland Press Ltd
Received:
November 21 2001
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2002 Biochemical Society
2002
Biochem Soc Trans (2002) 30 (2): 177–183.
Article history
Received:
November 21 2001
Citation
M. Ploug, H. Gårdsvoll, T. J. D. Jørgensen, L. Lønborg Hansen, K. Danø; Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy. Biochem Soc Trans 1 April 2002; 30 (2): 177–183. doi: https://doi.org/10.1042/bst0300177
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