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

Affiliations

PMID: 12023847

Review

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

M Ploug et al. Biochem Soc Trans. 2002 Apr.

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%.

PubMed Disclaimer

Cited by

Nanotechnology in cell replacement therapies for type 1 diabetes.
Ernst AU, Bowers DT, Wang LH, Shariati K, Plesser MD, Brown NK, Mehrabyan T, Ma M. Ernst AU, et al. Adv Drug Deliv Rev. 2019 Jan 15;139:116-138. doi: 10.1016/j.addr.2019.01.013. Epub 2019 Feb 2. Adv Drug Deliv Rev. 2019. PMID: 30716349 Free PMC article. Review.
Functional and protein‑protein interaction network analysis of colorectal cancer induced by ulcerative colitis.
Dai Y, Jiang JB, Wang YL, Jin ZT, Hu SY. Dai Y, et al. Mol Med Rep. 2015 Oct;12(4):4947-58. doi: 10.3892/mmr.2015.4102. Epub 2015 Jul 20. Mol Med Rep. 2015. PMID: 26239378 Free PMC article.
Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review).
Wyganowska-Świątkowska M, Tarnowski M, Murtagh D, Skrzypczak-Jankun E, Jankun J. Wyganowska-Świątkowska M, et al. Int J Mol Med. 2019 Jan;43(1):15-25. doi: 10.3892/ijmm.2018.3983. Epub 2018 Nov 7. Int J Mol Med. 2019. PMID: 30431071 Free PMC article. Review.
The urokinase receptor (u-PAR)--a link between tumor cell dormancy and minimal residual disease in bone marrow?
Allgayer H, Aguirre-Ghiso JA. Allgayer H, et al. APMIS. 2008 Jul-Aug;116(7-8):602-14. doi: 10.1111/j.1600-0463.2008.00997.x. APMIS. 2008. PMID: 18834405 Free PMC article. Review.
Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma.
Tincknell G, Piper AK, Aghmesheh M, Becker T, Vine KL, Brungs D, Ranson M. Tincknell G, et al. Cancers (Basel). 2021 Aug 14;13(16):4097. doi: 10.3390/cancers13164097. Cancers (Basel). 2021. PMID: 34439251 Free PMC article. Review.

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