Differential binding of urokinase and peptide antagonists to the urokinasereceptor: Evidence from characterization of the receptor in four primate species

Citation
Lh. Engelholm et N. Behrendt, Differential binding of urokinase and peptide antagonists to the urokinasereceptor: Evidence from characterization of the receptor in four primate species, BIOL CHEM, 382(3), 2001, pp. 435-442
Citations number
32
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOLOGICAL CHEMISTRY
ISSN journal
14316730 → ACNP
Volume
382
Issue
3
Year of publication
2001
Pages
435 - 442
Database
ISI
SICI code
1431-6730(200103)382:3<435:DBOUAP>2.0.ZU;2-B
Abstract
The urokinase plasminogen activator receptor (uPAR) is a membrane protein a ctive in localizing the plasminogen activation cascade system on the cell s urface. The resulting pericellular proteolytic activity is responsible for degradation reactions in the extracellular matrix that are needed for the i nvasion of cancer cells, thus making uPAR a potential target far anti-invas ive therapy based on binding antagonists. A remarkable property of the uPA- uPAR system is a pronounced species specificity in ligand recognition. We h ave now cloned and studied uPAR from four primate species and show that eve n though these sequences contain very few substitutions relative to the hum an uPAR, the receptor protein products differ markedly in terms of ligand s electivity. Thus, a well described competitive peptide antagonist directed against the human uPAR reacts with only one of the monkey receptors (chimpa nzee uPAR), in spite of the fact that uPAR from all of the four species cro ss-reacts with human uPA. Notably uPAR from African green monkey, which is completely devoid of reactivity with the peptide, contains only three subst itutions relative to chimpanzee uPAR in the molecular regions critical for binding. these findings aid the elucidation of the structure/function relat ionship of uPAR and, unexpectedly, identify a structural distinction govern ing the binding of uPA and a very similar peptide antagonist.