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Toni M. Antalis, PhD

Academic Title:

Professor

Primary Appointment:

Physiology

Secondary Appointment(s):

Surgery

Administrative Title:

Associate Director for Training and Education

Additional Title:

Director, Program in Molecular Medicine, GPILS

Location:

800 West Baltimore St. UMB Biopark Building 1, Rm 220

Phone (Primary):

410-706-8222

Fax:

410-706-8121

Education and Training

  • Rice University, PhD, Biochemistry
  • Baylor College of Medicine, Postdoctoral Training, Cell Biology

Biosketch

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 laboratory is supported by the National Institutes of Health, the Department of Defense, and a Merit Award from the Biomedical Research and Development Service of the Veterans Administration, and I have received past support from the Lance Armstrong Foundation and the Mary Kay Ash Foundation.

I currently serve as Treasurer of the American Society for Biochemistry and Molecular Biology (ASBMB), and have previously served as Chair of the Publications Committee of the ASBMB. I am active in post-graduate training as the Director of the Molecular Medicine Program in the Graduate Program in Life Sciences (GPILS). I am currently co-director of the T32 Training Program in Cancer Biology supported by the National Institutes of Health and I am also a mentor in several other T32 training programs at the University of Maryland School of Medicine.

I serve as a member of the Executive Committee of the Cancer Biology Training Consortium (CABTRAC) and have also served as past President of CABTRAC. I am Director of Education and Training Programs for the Marlene and Stewart Comprehensive Greenebaum Cancer Center and a member of the Hormone Responsive Cancers Program.

Highlighted Publications

Driesbaugh, K.H., Buzza, M.S., Martin, E.W., Conway, G.D., Kao, J.P., Antalis, T.MProteolytic activation of the protease-activated receptor (PAR)-2 by the glycosylphosphatidylinositol-anchored serine protease testisin. J Biol Chem. 2015 Feb 6;290(6):3529-41. PMCID: PMC4319020.

Martin, E.W., Buzza, M.S., Driesbaugh, K.H., Liu, S., Fortenberry, Y.M., Leppla, S.H., Antalis, T.MTargeting the membrane-anchored serine protease testisin with a novel engineered anthrax toxin prodrug to kill tumor cells and reduce tumor burden.  Oncotarget. 2015 Oct 20;6(32):33534-53.  PMCID: PMC4741784.

Manton, K.J., Douglas, M.L., Netzel-Arnett, S., Fitzpatrick, D.R., Nicol, D.L., Boyd, A.W., Clements, J.A., Antalis, T.MHypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesisBr J Cancer. 2015 Dec 1;113(11):1640. PMCID: PMC4705893.

Welch, D.R., Antalis, T.M., Burnstein, K., Vona-Davis, L., Jensen, R.A., Nakshatri, H., Riegel, A.T., Spitz, D.R., Watson, D.K., Weiner, G.J. Cancer Biology Training Consortium. Essential Components of Cancer EducationCancer Res. 2015 Dec 15;75(24):5202-5.  Review. PMCID: PMC4681646.

Antalis, T.M., Conway, G.D., Peroutka, R.J., Buzza, M.S. Membrane-anchored proteases in endothelial cell biologyCurr Opin Hematol. 2016 May;23(3):243-52. PMCID:  PMC4882107.

Antalis, T.MCoagulation signaling to epitheliaBlood. 2016 Jun 23;127(25):3114-6. PMCID:  PMC4920017.

Mukhopadhyay, S., Antalis, T.M., Nguyen, K.P., Hoofnagle, M.H., Sarkar, R. Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice. Blood. 2017 Jun 15;129(24):3245-3255. Epub 2017 Mar 20. PMCID: PMC5472897.

Buzza, M.S., Johnson, T.A., Conway, G.D., Martin, E.W., Mukhopadhyay, S., Shea-Donohue, T., Antalis, T.M. Inflammatory cytokines down-regulate the barrier-protective prostasin-matriptase proteolytic cascade early in experimental colitis. J Biol Chem. 2017 Jun 30;292(26):10801-10812. Epub 2017 May 10. PMCID: PMC5491767.

Kessler, M., Pawar, N.R., Martin, S.S., Antalis, T.M., O’Connor, T.D. Improving the detection and treatment of cancer using plasma tumor DNA obtained via liquid biopsy. Trends in Cancer accepted, Aug. 2018.

Mukhopadhyay, S., Johnson, T.A., Sarkar, R., Antalis, T.M. (2018) Serpins in venous thrombosis and venous thrombus resolution in Serpins: Methods and Protocols; Ed: Alexandra Lucas, MD, FRCP(C); Springer Publishing. In press.

Additional Publication Citations

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 myocytesEur. 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 angiogenesisThrombosis 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 cancerCancer 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 MotifMol 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 complexesJ 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 tumorigenesisBr 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 SerpinB2J 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 reactivityBiochem 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 replicationJ 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 differentiationJ 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 pathobiologyNat 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 proteinJ 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 CXCR3Gastroenterology.  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, TSerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survivalCancer 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 abilityBiol of Reprod. 2009; 81(5):921-32.  PMCID: PMC2770021

Bugge, T.H., Antalis, T.M., Wu, Q. Type II Transmembrane Serine ProteasesJ. 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 vivoMucosal 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 intestineProc 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 cellsAm 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 CD11bJ 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 EnvironmentBiochemical 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 1Methods 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 recoveryInflamm 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 transactivatorJ 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 SerpinB2PLoS 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 infectionJ 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 SerpinB2PLoS 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 pathwayJ 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 profilingPhysiol Rep. 2013 Sep;1(4). doi: 10.1002/phy2.73. PMCID: PMC3808870.

Shea-Donohue, T., Zhao, A., Antalis, T.MSerpinB2 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.MEnhanced Venous Thrombus Resolution in Plasminogen Activator Inhibitor Type-2 Deficient Mice. J Thromb Haemost. 2014 Jul 10. PMCID: PMC4194171

Research Interests

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.

Awards and Affiliations

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

Professional Activity

  • 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’ 8th International Symposium on Serpins and Proteases in Health and Disease, March 23-27, 2017 Shanghai, China.

Lab Techniques and Equipment

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.

Laboratory Personnel

  • 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

Recent Graduates

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