While overexpression of some cancer-specific or cancer-associated genes could contribute to the onset and progression of human cancer, malignant tumor cells could also inappropriately express and regulate a preexisting normal cell program, leading to these proteins to be perpetually activated or unrestrained in malignant cells compared with normal counterparts. In this proposal, we present the case of a closely controlled protease (matriptase) at interepithelial junctions that has been constitutively activated and inappropriately distributed to the invading fronts of cancer cells. Matriptase is broadly expressed by almost all human epithelial tissues, suggesting that the physiological role of matriptase may be associated with some rudimentary feature of epithelium, such as interepithelial junctions. Indeed, we have observed that in nontransformed mammary epithelial cells activation of matriptase in response to its physiological, blood-borne activator sphingosine 1-phosphate (S1P) only occurs on intercellular junctions. Furthermore, atypical protein kinase C zeta, a tight junction protein, is likely to be involved in S1P-indcued matriptase activation. In contrast, breast cancer cells constitutively activate matriptase regardless of the presence of S1P, and the activated matriptase is not restricted to cell-cell contacts and has been detected on membrane ruffles and within the cells. Therefore, in breast cancer cells matriptase could serve as membrane activator to recruit and activate urokinase-type plasminogen activator (uPA) and hepatocyte growth factor (HGF), an extracellular matrix-degrading protease system and cell growth/motility factor, respectively. In the current grant proposal, we will carry out four aims. First, we will elucidate physiological role of matriptase by investigating its functional localization and searching for its physiologically relevant substrates and target genes. Second, we will investigate the molecular mechanisms whereby matriptase activity is closely regulated. Third, we will characterize binding proteins of matriptase from matriptase complexes. Finally, we will investigate how matriptase activity, in a model system which matriptase activation can be enhanced or suppressed, affects the phenotypes of breast cancer cells. These studies could lead to new perspectives on the deregulation of this physiological protease in breast cancer and provide new avenues for diagnosis and intervention of the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA104944-01A1
Application #
6827637
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$254,528
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Xu, Han; Xu, Zhenghong; Tseng, I-Chu et al. (2012) Mechanisms for the control of matriptase activity in the absence of sufficient HAI-1. Am J Physiol Cell Physiol 302:C453-62
Chen, Cheng-Jueng; Wu, Bai-Yao; Tsao, Pai-In et al. (2011) Increased matriptase zymogen activation in inflammatory skin disorders. Am J Physiol Cell Physiol 300:C406-15
Chen, Mengqian; Chen, Li-Mei; Lin, Chen-Yong et al. (2010) Hepsin activates prostasin and cleaves the extracellular domain of the epidermal growth factor receptor. Mol Cell Biochem 337:259-66
Tseng, I-Chu; Xu, Han; Chou, Feng-Pai et al. (2010) Matriptase activation, an early cellular response to acidosis. J Biol Chem 285:3261-70
Chen, Ya-Wen; Lee, Ming-Shyue; Lucht, Amanda et al. (2010) TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 176:2986-96
Chen, Ya-Wen; Wang, Jehng-Kang; Chou, Feng-Pai et al. (2010) Regulation of the matriptase-prostasin cell surface proteolytic cascade by hepatocyte growth factor activator inhibitor-1 during epidermal differentiation. J Biol Chem 285:31755-62
Wang, Jehng-Kang; Lee, Ming-Shyue; Tseng, I-Chu et al. (2009) Polarized epithelial cells secrete matriptase as a consequence of zymogen activation and HAI-1-mediated inhibition. Am J Physiol Cell Physiol 297:C459-70
Tseng, I-Chu; Chou, Feng-Pai; Su, Sheng-Feng et al. (2008) Purification from human milk of matriptase complexes with secreted serpins: mechanism for inhibition of matriptase other than HAI-1. Am J Physiol Cell Physiol 295:C423-31
Chen, Mengqian; Chen, Li-Mei; Lin, Chen-Yong et al. (2008) The epidermal growth factor receptor (EGFR) is proteolytically modified by the Matriptase-Prostasin serine protease cascade in cultured epithelial cells. Biochim Biophys Acta 1783:896-903
Chen, Mengqian; Fu, Ya-Yuan; Lin, Chen-Yong et al. (2007) Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. Biochim Biophys Acta 1773:1133-40

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