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Pro-urokinase-type plasminogen activator is a substrate for hepsin
1Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.
The Journal of Biological Chemistry
|August 16, 2006
Summary
Hepsin, a protease overexpressed in prostate cancer, activates pro-urokinase-type plasminogen activator (pro-uPA). This activation initiates proteolytic pathways, potentially causing basement membrane disruption and promoting tumor progression and metastasis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Hepsin, a type II transmembrane serine protease, is significantly upregulated in prostate cancer.
- Hepsin overexpression in mouse models correlates with tumor progression, metastasis, and basement membrane disorganization.
Purpose of the Study:
- To investigate the enzymatic activity of hepsin in initiating the plasminogen/plasmin proteolytic pathway.
- To determine if hepsin's activity is linked to basement membrane defects observed in prostate cancer.
Main Methods:
- Enzymatic assays using recombinant soluble hepsin.
- Analysis of hepsin's interaction with pro-urokinase-type plasminogen activator (pro-uPA) and pro-tissue-type plasminogen activator.
- Assessment of pro-uPA activation by cell surface-expressed hepsin in LnCaP prostate cancer cells.
Main Results:
- Hepsin efficiently converts pro-uPA to active high molecular weight uPA, with catalytic efficiency comparable to plasmin.
- Hepsin does not cleave pro-tissue-type plasminogen activator.
- Hepsin-overexpressing LnCaP cells show a 3-fold higher rate of pro-uPA conversion compared to cells with lower hepsin expression.
Conclusions:
- Hepsin's ability to activate pro-uPA suggests a mechanism for initiating plasmin-mediated proteolytic pathways at the tumor-stroma interface.
- This pathway activation by hepsin may contribute to basement membrane disruption, driving prostate cancer progression and metastasis.
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