Protease Pathways in the Gastrointestinal Tract

Summary

Principal Investigator: Toni Antalis
Abstract: The serine proteases are the pivotal regulators of a variety of cellular processes critical for normal homeostasis. In the gut, host intestinal serine proteases not only control digestion, but their misregulated activities contribute to the pathogenesis of GI inflammatory, autoimmune, and neoplastic diseases. Recent evidence suggests that the intestinal paracellular pathway with its tight junctions (tj), plays a key role in modulating gut functions in healthy indiividuals. We recently found that the type II transmembrane serine protease, matriptase, is localized at intercellular apical junctional complexes in polarized intestinal epithelial cells and that loss of matriptase compromises barrier integrity. Depletion of matriptase by RNA interference enhances paracellular permeability in polarized Caco-2 monolayers cultured in vitro. In mice, matriptase depletion compromises epithelial barrier function, measured by transepithelial resistance of ex vivo epithelial tissue segments, and dramatically enhances susceptibility to experimental colitis induced by dextran sodium sulfate (DSS). Matriptase activates several inactive protease zymogens, including urokinase plasminogen activator (uPA) and prostasin, and also activates pro-hepatocyte growth factor (HGF), which serves as a ligand for c-met, a receptor tyrosine kinase involved in gastrointestinal repair. We expect that matriptase misregulation could contribute to barrier dysfunction underlying the pathogenesis of multiple microbial, autoimmune and inflammatory bowel diseases. The proposed studies will test the hypothesis that matriptase participates in the formation and maintenance of the GI mucosal barrier, and protects against exacerbated inflammatory and autoimmune responses. These hypotheses will be tested in the following specific aims: (1) to investigate junctional complex assembly underlying the paracellular permeability defect in matriptase hypomorph mice;(2) to investigate molecular pathways involved in the coupling of matriptase to tight junction assembly and the paracellular pathway and (3) to investigate the role of matriptase in the restoration of mucosal barrier function after DSS-induced acute injury. At the completion of these aims, we will have obtained molecular insight into the intestinal paracellular permeability defect caused by matriptase deficiency and will have a better understanding of the role of matriptase in maintaining intestinal epithelial barrier integrity after acute injury.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3
    Karen M Lammers
    Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Gastroenterology 135:194-204.e3. 2008
  2. pmc SerpinB2 is critical to Th2 immunity against enteric nematode infection
    Aiping Zhao
    Department of Medicine, Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Immunol 190:5779-87. 2013
  3. pmc SerpinB2 mediated regulation of macrophage function during enteric infection
    Terez Shea-Donohue
    Department of Radiation Oncology University of Maryland School of Medicine Baltimore, MD USA Department of Medicine University of Maryland School of Medicine Baltimore, MD USA Department of Physiology University of Maryland School of Medicine Baltimore, MD USA
    Gut Microbes 5:254-8. 2014
  4. pmc The glycosylphosphatidylinositol-anchored serine protease PRSS21 (testisin) imparts murine epididymal sperm cell maturation and fertilizing ability
    Sarah Netzel-Arnett
    Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Biol Reprod 81:921-32. 2009
  5. pmc Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2
    Amit Tripathi
    Mucosal Biology Research Center, Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA
    Proc Natl Acad Sci U S A 106:16799-804. 2009
  6. pmc Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo
    Q M Nhu
    Department of Microbiology and Immunology, University of Maryland, Baltimore UMB, School of Medicine, Baltimore, Maryland, USA
    Mucosal Immunol 3:29-39. 2010
  7. pmc Type II transmembrane serine proteases
    Thomas H Bugge
    Proteases and Tissue Remodeling Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 284:23177-81. 2009
  8. pmc 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
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201, USA
    Am J Pathol 176:2986-96. 2010
  9. pmc The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment
    Toni M Antalis
    Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Biochem J 428:325-46. 2010
  10. pmc Membrane-anchored serine proteases in health and disease
    Toni M Antalis
    Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Prog Mol Biol Transl Sci 99:1-50. 2011

Scientific Experts

  • Thomas H Bugge
  • Toni Antalis
  • Terez Shea-Donohue
  • Sarah Netzel-Arnett
  • Aiping Zhao
  • Marguerite S Buzza
  • Alessio Fasano
  • Karen M Lammers
  • Dudley K Strickland
  • Chen Yong Lin
  • Q M Nhu
  • Ya Wen Chen
  • Amit Tripathi
  • Stefanie N Vogel
  • Zhonghan Yang
  • Kathryn Hodge Driesbaugh
  • Jennifer A Bohl
  • Rex Sun
  • Luigi Notari
  • Viktoryia Grinchuk
  • Joseph F Urban
  • Kathleen B Madden
  • Ian E Anglin
  • Selen Catania Muratoglu
  • J R Teijaro
  • Thomas C Havighurst
  • Karin List
  • D L Farber
  • Michael D Johnson
  • Ming Shyue Lee
  • Amanda Lucht
  • Roman Szabo
  • A Fasano
  • Wei Huang
  • Kyungmann Kim
  • S Netzel-Arnett
  • K Shirey
  • S N Vogel
  • Feng Pai Chou
  • Jehng Kang Wang
  • Rex A Hess
  • Jon B Meddings
  • ShiQi Yang
  • John D Hooper
  • Kay Carnes
  • Anthony L Scarman
  • Brett W Stringer
  • Simeon Goldblum
  • Ian D Tonks
  • Marie Claire Arrietta
  • Graham F Kay
  • Ruliang Lu
  • Amir Tamiz
  • Julie Brownley
  • Sefik Alkan
  • Karen Thomas
  • Craig Gerard
  • Bao Lu
  • Prasad Rallabhandi

Detail Information

Publications13

  1. pmc Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3
    Karen M Lammers
    Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Gastroenterology 135:194-204.e3. 2008
    ..We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment...
  2. pmc SerpinB2 is critical to Th2 immunity against enteric nematode infection
    Aiping Zhao
    Department of Medicine, Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    J Immunol 190:5779-87. 2013
    ....
  3. pmc SerpinB2 mediated regulation of macrophage function during enteric infection
    Terez Shea-Donohue
    Department of Radiation Oncology University of Maryland School of Medicine Baltimore, MD USA Department of Medicine University of Maryland School of Medicine Baltimore, MD USA Department of Physiology University of Maryland School of Medicine Baltimore, MD USA
    Gut Microbes 5:254-8. 2014
    ..Thus, serpinB2 represents an immune regulated factor that has multiple roles in the intestinal mucosa. ..
  4. pmc The glycosylphosphatidylinositol-anchored serine protease PRSS21 (testisin) imparts murine epididymal sperm cell maturation and fertilizing ability
    Sarah Netzel-Arnett
    Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Biol Reprod 81:921-32. 2009
    ..These data suggest that aberrant regulation of PRSS21 may underlie certain secondary male infertility syndromes, such as "easily decapitated" spermatozoa in humans...
  5. pmc Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2
    Amit Tripathi
    Mucosal Biology Research Center, Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 20201, USA
    Proc Natl Acad Sci U S A 106:16799-804. 2009
    ..Our results therefore characterize zonulin as a previously undescribed ligand that engages a key signalosome involved in the pathogenesis of human immune-mediated diseases that can be targeted for therapeutic interventions...
  6. pmc Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo
    Q M Nhu
    Department of Microbiology and Immunology, University of Maryland, Baltimore UMB, School of Medicine, Baltimore, Maryland, USA
    Mucosal Immunol 3:29-39. 2010
    ..These data support and extend our recently described, novel model of PAR(2)-TLR4 "receptor cooperativity" and highlight the complexity of signaling integration between heterologous innate immune biosensors...
  7. pmc Type II transmembrane serine proteases
    Thomas H Bugge
    Proteases and Tissue Remodeling Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Biol Chem 284:23177-81. 2009
    ..Progress has also been made in identifying molecular substrates and endogenous inhibitors. This minireview summarizes the current knowledge of the rapidly advancing TTSP field...
  8. pmc 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
    Ya Wen Chen
    Greenebaum Cancer Center, University of Maryland Baltimore, Baltimore, MD 21201, USA
    Am J Pathol 176:2986-96. 2010
    ..The aberrant cellular localization, and increased expression of the protease seen in cancer, may contribute to prostate tumorigenesis by providing access of the enzyme to nonphysiological substrates and binding-proteins...
  9. pmc The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment
    Toni M Antalis
    Center for Vascular and Inflammatory Diseases and Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Biochem J 428:325-46. 2010
    ..We also discuss the functional consequences of the activities of these proteases on mammalian physiology and disease...
  10. pmc Membrane-anchored serine proteases in health and disease
    Toni M Antalis
    Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Prog Mol Biol Transl Sci 99:1-50. 2011
    ..This chapter reviews our current knowledge of the biological and physiological functions of these proteases, their molecular substrates, and their contributions to disease...
  11. pmc Serpin-Enzyme Receptors LDL Receptor-Related Protein 1
    Dudley K Strickland
    Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Methods Enzymol 499:17-31. 2011
    ..Its identification as a receptor for serpin:enzyme complexes confirms a major role for LRP1 in regulating protease activity...
  12. pmc Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine
    Marguerite S Buzza
    Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Proc Natl Acad Sci U S A 107:4200-5. 2010
    ..These results support a key role for matriptase in regulating intestinal epithelial barrier competence, and suggest an intriguing link between pericellular serine protease activity and tight junction assembly in polarized epithelia...