Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori (original) (raw)

Nature Genetics volume 33, pages 375–381 (2003)Cite this article

A Corrigendum to this article was published on 01 April 2003

This article has been updated

Abstract

The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive cellular vacuolation in vitro1,2,3 and gastric tissue damage in vivo, leading to gastric ulcers, when administered intragastrically4. Here we report that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz, also called PTP-ζ or RPTP-β, encoded by Ptprz) do not show mucosal damage by VacA, although VacA is incorporated into the gastric epithelial cells to the same extent as in wild-type mice. Primary cultures of gastric epithelial cells from Ptprz+/+ and Ptprz −/− mice also showed similar incorporation of VacA, cellular vacuolation and reduction in cellular proliferation, but only Ptprz+/+ cells showed marked detachment from a reconstituted basement membrane 24 h after treatment with VacA. VacA bound to Ptprz, and the levels of tyrosine phosphorylation of the G protein–coupled receptor kinase–interactor 1 (Git1), a Ptprz substrate, were higher after treatment with VacA, indicating that VacA behaves as a ligand for Ptprz. Furthermore, pleiotrophin (PTN), an endogenous ligand of Ptprz, also induced gastritis specifically in Ptprz+/+ mice when administered orally. Taken together, these data indicate that erroneous Ptprz signaling induces gastric ulcers.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Change history

Added the revised supplementary info (all six pieces were replaced)

References

  1. Tee, W., Lambert, J.R. & Dwyer, B. Cytotoxin production by Helicobacter pylori from patients with upper gastrointestinal tract diseases. J. Clin. Microbiol. 33, 1203–1205 (1995).
    CAS PubMed PubMed Central Google Scholar
  2. Cover, T.L. & Blaser, M.J. Purification and characterization of the vacuolating toxin from Helicobacter pylori. J. Biol. Chem. 267, 10570–10575 (1992).
    CAS PubMed Google Scholar
  3. Yahiro, K. et al. Helicobacter pylori vacuolating cytotoxin binds to the 140-kDa protein in human gastric cancer cell lines, AZ-521 and AGS. Biochem. Biophys. Res. Commun. 238, 629–632 (1997).
    Article CAS PubMed Google Scholar
  4. Telford, J.L. et al. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J. Exp. Med. 179, 1653–1658 (1994).
    Article CAS PubMed Google Scholar
  5. Warren, J.R. & Marshall, B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1, 1273–1275 (1983).
    CAS PubMed Google Scholar
  6. Blaser, M.J. & Parsonnet, J. Parasitism by the 'slow' bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J. Clin. Invest. 94, 4–8 (1994).
    Article CAS PubMed PubMed Central Google Scholar
  7. Zarrilli, R., Ricci, V. & Romano, M. Molecular response of gastric epithelial cells to _Helicobacter pylori_-induced cell damage. Cell Microbiol. 1, 93–99 (1999).
    Article CAS PubMed Google Scholar
  8. Massari, P. et al. Binding of the Helicobacter pylori vacuolating cytotoxin to target cells. Infect. Immun. 66, 3981–3984 (1998).
    CAS PubMed PubMed Central Google Scholar
  9. Yahiro, K. et al. Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyrosine phosphatase β. J. Biol. Chem. 274, 36693–36699 (1999).
    Article CAS PubMed Google Scholar
  10. Seto, K., Hayashi-Kuwabara, Y., Yoneta, T., Suda, H. & Tamaki, H. Vacuolation induced by cytotoxin from Helicobacter pylori is mediated by the EGF receptor in HeLa cells. FEBS Lett. 431, 347–350 (1998).
    Article CAS PubMed Google Scholar
  11. Garner, J.A. & Cover, T.L. Binding and internalization of Helicobacter pylori vacuolating cytotoxin by epithelial cells. Infect. Immun. 64, 4197–4203 (1996).
    CAS PubMed PubMed Central Google Scholar
  12. Ricci, V. et al. Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J. Pathol. 183, 453–459 (1997).
    Article CAS PubMed Google Scholar
  13. Padilla, P.I. et al. Morphologic differentiation of HL-60 cells is associated with appearance of RPTPβ and induction of Helicobacter pylori VacA sensitivity. J. Biol. Chem. 275, 15200–15206 (2000).
    Article CAS PubMed Google Scholar
  14. Shintani, T., Watanabe, E., Maeda, N. & Noda, M. Neurons as well as astrocytes express proteoglycan-type protein tyrosine phosphatase ζ: analysis of mice in which the PTPζ/RPTPβ gene was replaced with the LacZ gene. Neurosci. Lett. 247, 135–138 (1998).
    Article CAS PubMed Google Scholar
  15. Nishiwaki, T., Maeda, N. & Noda, M. Characterization and developmental regulation of proteoglycan-type protein tyrosine phosphatase ζ/RPTPβ isoforms. J. Biochem. 123, 458–467 (1998).
    Article CAS PubMed Google Scholar
  16. Kawachi, H., Fujikawa, A., Maeda, N. & Noda, M. Identification of GIT1/Cat-1 as a substrate molecule of protein tyrosine phosphatase ζ/RPTPβ by the yeast substrate-trapping system. Proc. Natl. Acad. Sci. USA 98, 6593–6598 (2001).
    Article CAS PubMed PubMed Central Google Scholar
  17. Ghiara, P. et al. Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease. Infect Immun. 63, 4154–4160 (1995).
    CAS PubMed PubMed Central Google Scholar
  18. Wallace, J.L. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. Gastroenterology 112, 1000–1016 (1997).
    Article CAS PubMed Google Scholar
  19. Glavin, G.B. & Szabo, S. Experimental gastric mucosal injury: laboratory models reveal mechanisms of pathogenesis and new therapeutic strategies. FASEB J. 6, 825–831 (1992).
    Article CAS PubMed Google Scholar
  20. Maeda, N. & Noda, M. Involvement of receptor-like protein tyrosine phosphatase ζ/RPTPβ and its ligand pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) in neuronal migration. J. Cell Biol. 142, 203–216 (1998).
    Article CAS PubMed PubMed Central Google Scholar
  21. Qi, M. et al. Haptotactic migration induced by midkine. Involvment of protein-tyrosine phosphatase ζ, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. J. Biol. Chem. 276, 15868–15875 (2001).
    Article CAS PubMed Google Scholar
  22. Tominaga, K. et al. Rapid expression and specific localization of teneasscin in gastric ulcer healing in rats. Digestion 58, 120–128 (1997).
    Article CAS PubMed Google Scholar
  23. Ricci, V. et al. Effect of Helicobacter pylori on gastric epithelial cell migration and proliferation in vitro: role of VacA and CagA. Infect. Immun. 64, 2829–2833 (1996).
    CAS PubMed PubMed Central Google Scholar
  24. Manabe R.I., Kovalenko, M., Webb, D.J. & Horwitz, A.R. GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration. J. Cell Sci. 115, 1497–1510 (2002).
    CAS PubMed Google Scholar
  25. Turner, C.E., West, K.A. & Brown, M.C. Paxillin-ARF GAP signaling and the cytoskeleton. Curr. Opin. Cell Biol. 13, 593–599 (2001).
    Article CAS PubMed Google Scholar
  26. Bagrodia, S. et al. A tyrosine-phosphorylated protein that binds to an important regulatory region on the cool family of p21-activated kinase-binding proteins. J. Biol. Chem. 274, 22393–22400 (1999).
    Article CAS PubMed Google Scholar
  27. Zhao, Z.S., Manser, E., Loo, T.H. & Lim, L. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol. Cell. Biol. 20, 6354–6363 (2000).
    Article CAS PubMed PubMed Central Google Scholar
  28. Pai, R., Cover, T.L. & Tarnawski, A.S. Helicobacter pylori vacuolating cytotoxin (VacA) disorganizes the cytoskeletal architecture of gastric epithelial cells. Biochem. Biophys. Res. Commun. 262, 245–250 (1999).
    Article CAS PubMed Google Scholar
  29. Fukamachi, H. et al. Fetal rat glandular stomach epithelial cells differentiate into surface mucous cells which express cathepsin E in the absence of mesenchymal cells in primary culture. Differentiation 56, 83–89 (1994).
    Article CAS PubMed Google Scholar

Download references

Acknowledgements

We thank T. Etoh, M. Mizoguchi, K. Yamada and M. Gotoh for technical assistance and A. Kodama for secretarial assistance. The BIAcore system was used at the NIBB Center for Analytical Instruments. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and from Yamanouchi Foundation for Research on Metabolic Disorders and by Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation.

Author information

Authors and Affiliations

  1. Division of Molecular Neurobiology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki, 444-8585, Japan
    Akihiro Fujikawa, Daisuke Shirasaka, Shoichi Yamamoto, Masahide Fukada, Takafumi Shintani & Masaharu Noda
  2. Department of Endoscopy and Division of Diabetes, Department of Clinical Molecular Medicine, Digestive and Kidney Diseases, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
    Daisuke Shirasaka & Nobuo Aoyama
  3. Discovery Research Laboratories, Shionogi & Co., 5-12-4 Sagisu, Fukushima-ku, Osaka, 553-0002, Japan
    Shoichi Yamamoto
  4. Department of Biomedical Laboratory Sciences, School of Health Sciences, School of Medicine, Shinshu University, 1-1 Asahi 3-chome, Matsumoto, 390-8621, Japan
    Hiroyoshi Ota
  5. Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
    Kinnosuke Yahiro, Akihiro Wada & Toshiya Hirayama
  6. Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
    Hiroshi Fukamachi

Authors

  1. Akihiro Fujikawa
  2. Daisuke Shirasaka
  3. Shoichi Yamamoto
  4. Hiroyoshi Ota
  5. Kinnosuke Yahiro
  6. Masahide Fukada
  7. Takafumi Shintani
  8. Akihiro Wada
  9. Nobuo Aoyama
  10. Toshiya Hirayama
  11. Hiroshi Fukamachi
  12. Masaharu Noda

Corresponding author

Correspondence toMasaharu Noda.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Fujikawa, A., Shirasaka, D., Yamamoto, S. et al. Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori.Nat Genet 33, 375–381 (2003). https://doi.org/10.1038/ng1112

Download citation

This article is cited by

Associated content