Abstract
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/alpha-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 (K(d)< 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%.
| Original language | English |
|---|---|
| Journal | Biochemical Society Transactions |
| Volume | 30 |
| Issue number | 2 |
| Pages (from-to) | 177-83 |
| Number of pages | 7 |
| ISSN | 0300-5127 |
| DOIs | |
| Publication status | Published - Apr 2002 |
| Externally published | Yes |
Keywords
- Amino Acid Sequence
- Animals
- Humans
- In Vitro Techniques
- Models, Molecular
- Molecular Sequence Data
- Molecular Structure
- Neoplasm Invasiveness
- Neoplasms
- Oligopeptides
- Receptors, Cell Surface
- Receptors, Urokinase Plasminogen Activator
- Urokinase-Type Plasminogen Activator
- Journal Article
- Review
