Toni M. Antalis, PhD

Antalis, T.M., Lin, M.L., Donnan, K., Mateo, L., Gardner, J., Dickinson, J.L., Buttigieg, K., and 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. J. Exp. Med. 187: 1799-1811.

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., 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.

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, 8(3): Epub 2013 Mar 5. PMCID: PMC3589482.

Zhao, A., Yang, Z, Sun, R., Grinchuk, V., Netzel-Arnett, S., Anglin, I.E., Driesbaugh, K.H., Notari, L., Bohl, J.A., Madden, K.B., Urban, J.F. Jr., Antalis, T.M., Shea-Donohue, T. (2013) SerpinB2 is critical to Th2 immunity against enteric nematode infection. J Immunol. Jun 1;190(11):5779-87. PMID: 23630350.

Udofa, E.A., Stringer, B.W., Gade, P., Mahony, D., Buzza, M.S., Kalvakolanu, D.V., Antalis, T.M. (2013) The transcription factor C/EBP-β mediates constitutive and LPS-inducible transcription of murine SerpinB2. PLoS One. 8(3):e57855. PMCID: PMC3589482.

Buzza, M.S., Martin, E.W., Driesbaugh, K.H., Désilets, A., Leduc, R., Antalis, T.M. (2013) Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. J Biol Chem. Apr 12;288(15):10328-37. PMCID: PMC3624416.

Book Chapter:  Bradley, S.G., Antalis, T.M., Bond, J.S.. Chapter 11: Proteases in the Mammalian Digestive System In: K. Brix and W. Stöcker (eds.), Proteases: Structure and Function, Springer-Verlag Wien 2013 DOI 10.1007/978-3-7091-0885-7_11.

Alaish, S.M., Timmons, J., Smith, A., Buzza, M.S., Murphy, E., Zhao, A., Sun, Y., Turner, D.J., Shea-Donahue, T., Antalis, T.M., Cross, A., Dorsey, S.G. Candidate genes for limiting Cholestatic intestinal injury identified by gene expression profiling. Physiol Rep. 2013 Sep;1(4). doi: 10.1002/phy2.73. PMCID: PMC3808870.

Shea-Donohue, T., Zhao, A., Antalis, T.M. SerpinB2 mediated regulation of macrophage function during enteric infection.Gut Microbes. 2014 Mar 1;5(2):254-8. PMCID: PMC4063854.

Siefert, S.A., Chabasse, C., Mukhopadhyay, S., Hoofnagle, M.H., Strickland, D.K., Sarkar, R., Antalis, T.M. Enhanced Venous Thrombus Resolution in Plasminogen Activator Inhibitor Type-2 Deficient Mice. J Thromb Haemost. 2014 Jul 10. PMCID: PMC4194171

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 vascular 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 in angiogenesis and its contribution to ovarian cancer malignancy.
• Mechanisms associated with protease-activated receptor signaling during inflammation and in endothelial and epithelial barrier functions.
• Activity of the plasminogen activation cascade in clot dissolution and particularly the role of the serine protease inhibitor, plasminogen activator inhibitor type-2 (PAI-2) as a transcriptional modulator and pro-survival factor for macrophages and tumor cells, and function in deep vein thrombosis.

Patent
Provisional Patent TA-2016-015. Engineered Anthrax Protective Antigen Proteins for Cancer Therapy. PCT filed 08-19-2016. Inventors: T.M. Antalis, E Martin

• Appointed Associate Director, Training and Education, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore MD
• Chair, ASBMB Special Symposia on Membrane Anchored Proteases, September, 2015
• Invited Speaker and session chair, XVth International Workshop on the Molecular and Cellular Biology of Plasminogen Activation, Rome Italy September, 2015
• Invited Speaker, Gordon Conference on Plasminogen Activation and Extracellular Proteolysis, Ventura, CA, February 2016
• Festival of Science, ‘Training and Education at the UMGCCC’, November 10, 2016
• Invited Speaker, ‘Potent Anti-Tumor Activity of Membrane-anchored Serine Protease-Activated Engineered Toxins’ 8^th International Symposium on Serpins and Proteases in Health and Disease, March 23-27, 2017 Shanghai, China.

We 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.

• Marguerite Buzza, PhD, (C. J. Martin Fellow, Australia); Research Associate
• Subhradip Mukhopadhyay, PhD, Senior Postdoctoral Fellow
• Erik Martin, Molecular Medicine Graduate Student, GPILS
• Gregory Conway, Molecular Medicine Graduate Student, GPILS
• Tierra Johnson, Molecular Medicine Graduate Student, GPILS

• Kathryn Hodge, PhD (May 2014)
• Ekemini Udofa, PhD (May 2014)