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

Akihiro Fujikawa¹, Daisuke Shirasaka^1, 2, Shoichi Yamamoto^1, 3, Hiroyoshi Ota⁴, Kinnosuke Yahiro⁵, Masahide Fukada¹, Takafumi Shintani¹, Akihiro Wada⁵, Nobuo Aoyama², Toshiya Hirayama⁵, Hiroshi Fukamachi⁶ & Masaharu Noda¹

¹  Division of Molecular Neurobiology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki 444-8585, Japan.

²  Department of Endoscopy and Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

³  Discovery Research Laboratories, Shionogi & Co., 5-12-4 Sagisu, Fukushima-ku, Osaka 553-0002, Japan.

⁴  Department of Biomedical Laboratory Sciences, School of Health Sciences, School of Medicine, Shinshu University, 1-1 Asahi 3-chome, Matsumoto 390-8621, Japan.

⁵  Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.

⁶  Department of Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive cellular vacuolation in vitro ^{1, 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- or RPTP-, 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.

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