Molecular biology of angiogenesis and cancer; membrane serine proteases and their inhibitors; regulation of transcription factors by serpins; plasminogen activation and extracellular matrix remodeling in vascular biology
The long term goal of our research is to better understand the biology of serine proteases and their inhibitors (serpins) and to investigate their potential as targets for diagnostic applications or rational drug-based therapies for cancer and other diseases. Proteases are powerful hydrolytic enzymes that mediate cleavage, activation and degradation of many cellular proteins, and therefore play fundamental roles in virtually every aspect of cell behavior, including survival, growth, differentiation, and malignant transformation. Inappropriate proteolysis can significantly impact disease progression, thus proteases represent attractive targets for intervention in a number of disorders and diseases. The serine proteases are one of the largest and most highly conserved multigene families. These proteases are distinguished by the fact that a serine residue plays a critical role in the catalytic process.
Members of the serine protease family are well recognized to initiate and control complex biological systems, such as blood coagulation, wound healing, digestion, immune responses, reproduction and development. Recently, through genomics and database mining approaches, the existence of membrane anchored serine proteases, a unique group of molecules that contain serine protease domains in addition to multiple other structural domains, and which include hydrophobic membrane-anchoring sequences has been recognized. We currently know very little about these enzymes and their activities. Disruption or mutation of several of the genes encoding these proteases are directly associated with inherited genetic diseases, and while many of the membrane anchored serine proteases show restricted tissue distribution in normal cells, their expression is widely dysregulated during tumor growth and progression. A detailed understanding of these proteases and how they interact with other proteases and cell associated signalling molecules is necessary for our understanding of cell growth and regulation as it relates to cancer, angiogenesis and other diseases.
Our current research interests include:
- the physiological roles of membrane anchored serine proteases in cell biology, cancer and angiogenesis. A particular focus is the function of Testisin during sperm maturation and angiogenesis and its contribution to ovarian cancer malignancy.
- the activity of the serine protease inhibitor, plasminogen activator inhibitor type-2 (PAI-2) as a protector of the retinoblastoma (Rb) protein and its impact on cell growth arrest, cell survival and differentiation.
1. Szabo R, Netzel-Arnett S, Hobson JP, Antalis TM, Bugge TH. (2005) Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 390(Pt 1):231-42.
2. Darnell GA, Antalis TM, Rose BR, Suhrbier A. (2005) Silencing of integrated human papillomavirus type 18 oncogene transcription in cells expressing SerpinB2. J Virol. 79(7):4246-56.
3. Manton KJ, Douglas ML, Netzel-Arnett S, Fitzpatrick DR, Nicol DL, Boyd AW, Clements JA, Antalis TM. (2005) Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. Br J Cancer 92(4):760-9.
4. Hobson JP, Netzel-Arnett S, Szabo R, Rehault SM, Church FC, Strickland DK, Lawrence DA, Antalis TM, Bugge TH. (2004) Mouse DESC1 is located within a cluster of seven DESC1-like genes and encodes a type II transmembrane serine protease that forms serpin inhibitory complexes. J Biol Chem. 279(45):46981-94.
5. Darnell, G.A., Antalis, T.M., Johnstone, R.W., Stringer, B.W., Ogbourne, S.M., Harrich, D., Suhrbier A. (2003) Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif. Mol Cell Biol. 23(18):6520-6532.
6. Netzel-Arnett, S, Hooper, J.D., Szabo, R., Madison, E.L., Quigley, J.P., Bugge, T.H. and Antalis, T.M. (2003) Membrane Associated Serine Proteases: A rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer, Cancer and Metastasis Reviews 22:237-258.
7. Aimes, R.T., Zijlstra, A., Hooper, J.D., Ogbourne, S., Sit, M.-L., Fuchs, S., Gotley, D.C., Quigley, J.P., Antalis, T.M..(2003) Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thrombosis and Haemostasis 89(3):561-72.
8. Ogbourne SM, Antalis TM (2001) Characterisation of PAUSE-1, a powerful silencer in the human plasminogen activator inhibitor type 2 gene promoter. Nucleic Acids Res. 2001 Oct 1;29(19):3919-27.
9. Hooper, J.D., Clements, J.A., Quigley, J.P., Antalis, T.M. (2000) Type II Transmembrane Serine Proteases - Insights into an emerging class of cell surface proteolytic enzymes. Mini Review, J. Biol. Chemistry, J Biol Chem. 276(2), 857-860.
10. Hooper, J.D., Scarman, A.L., Clarke, B., Normyle, J.F., Antalis, T.M. (2000) The mosaic transmembrane serine protease corin is expressed in heart myocytes. Eur. J. Biochem. 267(23), 6931-6937.
11. Hooper, J.D., Nicol, D.L., Dickinson, J.L., Eyre, H.J., Scarman, A.L., Normyle, J.F., Stuttgen, M.A., Douglas, M., Loveland, K.A.L., Sutherland, G.R., Antalis. T.M. (1999) Testisin, a new human serine protease expressed by premeiotic testicular germ cells and lost in testicular germ cell tumors. Cancer Research 59(13): 3199-31205.
12. Antalis, T.M., Lin, M.L., Donnan, K., Mateo, L., Gardner, J., Dickinson, J.L., Buttigieg, K., Suhrbier, A. (1998) The serpin plasminogen activator inhibitor type 2 (PAI-2) protects against viral cytopathic effects: evidence for a PAI-2 mediated influence on the interferon alpha/beta signaling pathway. Journal of Experimental Medicine 187: 1799-1811.
13. Ogbourne SM, Antalis TM (1998) Transcriptional control and the role of silencers in transcriptional regulation in eukaryotes. Biochem J. 1998 Apr 1;331 ( Pt 1):1-14. Review.
14. Dickinson JL, Bates EJ, Ferrante A, Antalis TM. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem. 1995 Nov 17;270(46):27894-904.