Biological Function of Matriptase, a Novel Trypsin-Like Protease, in Human Breast Cancer
Abstract
Matriptase is an epithelial-derived, type 2, integral membrane, serine protease. It contains an N-terminal putative transmembrane sequence, followed by multiple LDL and CUB repeats, and the C-terminal protease domain. To further understand its role in breast cancer, I have investigated its substrate specificity and its interaction with inhibitors. I showed in this report that matriptase specifically cleaves synthetic peptide after an Arg or Lys residue, and prefers small side-chain amino acid, such as Ala and Gly, at P2 site. A 3-D structure of the protease domain of matriptase was built by the homology modeling. This modeled structure was used in a structure-based screening of inhibitors. Two bis-benzamindine derivatives were developed to be both potent and selective inhibitor of matriptase. In addition, a naturally occurring trypsin inhibitor from sunflower seed was found to inhibit matriptase as well as HAI1; this inhibitor had little inhibition to thrombin and uPA. I have also shown that matriptase can activate HGF and pro-uPA. These results further support the hypothesis that matriptase acts as an upstream activator in metastasis and cancer invasion by interacting with and recruiting various factors to the site of contact between cancer and stromal cells; and by degrading or processing a broad range of substrates.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396440
Entities
People
- Sheau-ling Lee
Organizations
- Georgetown University