I completed my doctorate in Biochemistry at Rice University and postdoctoral training in cell biology at Baylor College of Medicine, Houston Texas. I began my research into serine protease inhibitors and the plasminogen activation system when I took a position at a biotechnology company in Sydney Australia. In 1988, I joined the Oncology Program at the Queensland Institute of Medical Research, in Brisbane Australia where my interest in membrane anchored serine proteases evolved. I returned to the United States in 2001 to join the Vascular Biology research program at the Holland Laboratory of the American Red Cross in Rockville Maryland. In 2004, I joined the faculty of the University of Maryland, School of Medicine as Professor of Physiology and Associate Director of the Center for Vascular and Inflammatory Diseases. My research programs have been continuously funded and I have been supported by the Lance Armstrong Foundation and the National Institutes of Health. I am active in post-graduate training and am director of the Molecular and Cellular Cancer Biology track in the Molecular Medicine Graduate Program. I am currently associated with training grants in Transfusion Medicine and Membrane Biology from the National Institutes of Health. I am a member of the Publications Committee of the American Society for Biochemistry and Molecular Biology, and a member of the Editorial Board of the Journal of Biological Chemistry. My research programs have been continuously funded and I have been supported by the National Institutes of Health, the Department of Defense, the Lance Armstrong Foundation, and the Mary Kay Ash Foundation. I am active in post-graduate training and am Director of the Molecular Medicine Program in the Graduate Program in Life Sciences. I am currently co-director of a T32 Training Program in Cancer Biology supported by National Institutes of Health and associated with several other T32 training programs at the University of Maryland. I currently serve as Treasurer of the American Society for Biochemistry and Molecular Biology (ASBMB), have previously served as served as Chair of the Publications Committee of the ASBMB, and am a member of the Editorial Boards of the Journal of Biological Chemistry and the Biochemical Journal.
Our research is focused on signaling mechanisms involved in vascular disease and cancer. 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 vascular 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 signaling 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:
Physiological roles of membrane anchored serine proteases in cell biology, cancer and angiogenesis. A focus is the function of Testisin during sperm maturation and angiogenesis and its contribution to ovarian cancer malignancy.
Mechanisms associated with protease-activated receptor signaling during inflammation and in the control of membrane barrier function.
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.
Lab Techniques and EquipmentWe generate and make extensive use of knockout and transgenic mouse models for determining essential gene functions, as well as incorporate both microarray and proteomics approaches for differential molecular analyses. We also employ a range of mouse models for the study of tumor growth and metastasis, analysis of new blood vessel formation (angiogenesis) and sperm function. Recombinant DNA techniques, including cloning, mutagenesis and heterologous expression are used routinely and are coupled with state-of-the-art cell biological analyses such as confocal fluorescence microscopy. We produce recombinant proteases using insect cells for analyses of their biochemical and enzymatic properties. We also utilize molecular approaches such as immunoblotting, immunoprecipitation and reporter gene assays to study cellular signaling pathways involved in cell growth regulation and differentiation.
Laboratory Personnel :
Marguerite Buzza (C. J. Martin Fellow, Australia); Research Associate
The biology of serine proteases and serpins
Ekemini Udofa: Molecular Medicine graduate student
Kathryn Hodge Driesbaugh: Molecular Medicine graduate student
Erik Martin: Molecular Medicine graduate student
Antalis, T.M., Lin, M.L., Donnan, K., Mateo, L.,
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., and 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.
Hooper, J.D., Scarman, A.L., Clarke, B., Normyle, J.F., and Antalis, T.M. (2000) The mosaic transmembrane serine protease corin is expressed in heart myocytes. Eur. J. Biochem. 267(23), 6931-6937.
Hooper, J.D., Clements, J.A., Quigley, J.P., and Antalis, T.M. (2000) Type II Transmembrane Serine Proteases - Insights into an emerging class of cell surface proteolytic enzymes. Mini Review, J Biol Chem. 276(2), 857-860.
Aimes, R.T., Zijlstra, A., Hooper, J.D., Ogbourne, S., Sit, M.-L., Fuchs, S., Gotley, D.C., Quigley, J.P., and Antalis, T.M. (2003) Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. Thrombosis and Haemostasis. 89(3):561-572.
Netzel-Arnett, S, Hooper, J.D., Szabo, R.,
Darnell, G.A., Antalis, T.M., Johnstone, R.W., Stringer, B.W., Ogbourne, S.M., Harrich, D., and 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.
Hobson, J.P., Netzel-Arnett, S., Szabo, R., Rehault, S.M., Church, F.C., Strickland, D.K., Lawrence, D.A., Antalis, T.M., and Bugge, T.H. (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.
Manton, K.J., Douglas, M.L., Netzel-Arnett, S., Fitzpatrick, D.R., Nicol, D.L., Boyd, A.W., Clements, J.A., and Antalis, T.M. (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.
Darnell, G.A., Antalis, T.M., Rose, B.R., and Suhrbier, A. (2005) Silencing of integrated human papillomavirus type 18 oncogene transcription in cells expressing SerpinB2. J Virol. 79(7):4246-56.
Szabo, R., Netzel-Arnett, S., Hobson, J.P., Antalis, T.M., and Bugge, T.H. (2005) Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity. Biochem J. 390:231-42.
Darnell, G.A., Schroder, W.A., Gardner, J., Harrich, D., Yu, H., Medcalf, R.L., Warrilow, D., Antalis, T.M., Sonza, S., and Suhrbier, A. (2006) Serpinb2 is an inducible host factor involved in enhancing HIV-1 transcription and replication. J Biol Chem. 281(42):31348-58.
Netzel-Arnett, S., Currie, B.M., Szabo, R., Lin, C.Y., Chen, L.M., Chai, K.X., Antalis, T.M., Bugge, T.H., List, K. Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J Biol Chem. 2006,281:32941-5.
Antalis, T.M., Shea-Donohue, T., Vogel, S.N., Sears, C., Fasano, A. Mechanisms of disease: protease functions in intestinal mucosal pathobiology. Nat Clin Pract Gastroenterol Hepatol. 2007 Jul;4(7):393-402. Review. PMCID: PMC3049113
Darnell, G.A., Schroder, W.A., Antalis, T.M., Lambley, E., Major, L., Gardner, J., Birrell, G., Cid-Arregui, A., Suhrbier, A. Human papillomavirus E7 requires the protease calpain to degrade the retinoblastoma protein. J Biol Chem. 2007, 282 (52): 37492-500.
Lammers, K.M., Lu, R., Brownley, J., Lu, B., Gerard, C., Thomas, K. Rallabhandi, P., Shea-Donohue, T., Tamiz, A., Alkan, S., Netzel-Arnett, S., Antalis T.M., Vogel, S.N., Fasano, A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008, 135(1): 194-204. PMCID: PMC2653457
Tonnetti L., Netzel-Arnett, S., Darnell, G., Hayes, T., Buzza, M.S., Anglin, I.E., Suhrbier, A. and Antalis, T. SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival. Cancer Research 68 (14): 2008 Jul 15;68(14):5648-57. PMCID: PMC2561898
Antalis, T.M., Bugge, T.H. Methods in molecular biology. Proteases and cancer. Methods and protocols. Preface. Methods Mol Biol. 2009;539:v-vii.
Netzel-Arnett, S., Bugge, T.H., Hess, R.A., Carnes, K., Stringer, B.W., Scarman, A.L., Hooper, J.D., Tonks, I.D., Kay, G.F., and Antalis, T.M. The glycosylphosphatidylinositol (GPI)-anchored serine protease Testisin imparts epididymal sperm cell maturation and fertilizing ability. Biol of Reprod. 2009; 81(5):921-32. PMCID: PMC2770021
Bugge, T.H., Antalis, T.M., Wu, Q. Type II Transmembrane Serine Proteases. J. Biol Chem 2009; 284: 23177-81. PMCID: PMC2749090
Tripathi, A., Lammers, K.M., Goldblum, S., Shea-Donohue, T., Netzel-Arnett, S., Buzza, M.S., Antalis, T.M., Vogel, S.N., Zhao, A., Yang, S., Arrietta, M-C., Meddings, J.B., Fasano, A. Identification of Human Zonulin, a Physiologic Modulator of Tight Junctions, as Pre-Haptoglobin-2. 2009; Proc Natl. Acad. 106(39):16799-804. PMCID: PMC2744629
Nhu, Q.M., Shirey, K., Teijaro, J.R., Farber, D.L., Netzel-Arnett, S., Antalis, T.M., Fasano, A., Vogel, S.N. Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol. 2010; 3(1):29-39. PMCID: PMC2851245
Buzza, M.S., Netzel-Arnett, S., Shea-Donohue, T., Zhao, A., Lin, C.Y., List, K., Szabo, R., Fasano, A., Bugge, T.H., Antalis, T.M. Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine. Proc Natl Acad Sci U S A. 2010 107(9):4200-5. PMCID: PMC2840089
Chen, Y.W., Lee, M.S., Lucht, A., Chou, F.P., Huang, W., Havighurst, T.C., Kim, K., Wang, J.K., Antalis, T.M., Johnson, M.D., Lin, C.Y. 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. 2010 Jun;176(6):2986-96. PMCID: PMC2877858
Cao, C., Gao, Y., Li, Y., Antalis, T.M., Castellino, F.J., Zhang, L. The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b. J Clin Invest. 2010 Jun 1;120(6):1971-80. PMCID: PMC2877939
Antalis, T.M., Buzza, M., Hodge, K., Hooper, J.D., Netzel-Arnett, S. Cutting Edge: Membrane anchored Serine Protease Activites in the Pericellular Environment. Biochemical Journal, 2010; 428:325-46.
Antalis, T.M., Bugge, T.H., Wu, Q. Membrane-anchored serine proteases in health and disease. Prog Mol Biol Transl Sci. 2011;99:1-50.
Strickland, D.K., Muratoglu, S.C., Antalis, T.M. Serpin-Enzyme Receptors LDL Receptor-Related Protein 1. Methods Enzymol. 2011; 499:17-31. PMCID: PMC3189627.
Netzel-Arnett, S., Buzza, M.S., Shea-Donohue, T., Désilets, A., Leduc, R., Fasano, A., Bugge, T.H., Antalis, T.M. Matriptase protects against experimental colitis and promotes intestinal barrier recovery. Inflamm Bowel Dis. 2012 Jul;18(7):1303-14. PMCID: PMC3288858.
Stringer, B., Udofa, E.A., Antalis, T.M. Regulation of the human plasminogen activator inhibitor type 2 gene: cooperation of an upstream silencer and transactivator. J Biol Chem. 2012 Mar 23;287(13):10579-89. PMCID: PMC3322994.
Udofa, E.A., Stringer, B.W., Gade, P., Mahony, D., Buzza, M.S. Kalvakolanu, D.V., Antalis, T.M. The transcription factor C/EBP-β mediates constitutive and LPS-inducible transcription of murine SerpinB2. PLoS One, in press.