Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy

TY - JOUR

T1 - Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor

T2 - a potential target for anti-invasive cancer therapy

AU - Ploug, M

AU - Gårdsvoll, H

AU - Jørgensen, T J D

AU - Lønborg Hansen, L

AU - Danø, K

PY - 2002/4

Y1 - 2002/4

N2 - 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%.

AB - 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%.

KW - Amino Acid Sequence

KW - Animals

KW - Humans

KW - In Vitro Techniques

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Molecular Structure

KW - Neoplasm Invasiveness

KW - Neoplasms

KW - Oligopeptides

KW - Receptors, Cell Surface

KW - Receptors, Urokinase Plasminogen Activator

KW - Urokinase-Type Plasminogen Activator

KW - Journal Article

KW - Review

U2 - 10.1042/

DO - 10.1042/

M3 - Review

C2 - 12023847

SN - 0300-5127

VL - 30

SP - 177

EP - 183

JO - Biochemical Society Transactions

JF - Biochemical Society Transactions

IS - 2

ER -