Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori.
The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive cellular vacuolation in vitro and gastric tissue damage in vivo, leading to gastric ulcers, when administered intragastrically. Here we report that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz, also called PTP-zeta or RPTP-beta, 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.
Fujikawa
Akihiro
A
Division of Molecular Neurobiology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji-cho, Okazaki 444-8585, Japan.
Shirasaka
Daisuke
D
Yamamoto
Shoichi
S
Ota
Hiroyoshi
H
Yahiro
Kinnosuke
K
Fukada
Masahide
M
Shintani
Takafumi
T
Wada
Akihiro
A
Aoyama
Nobuo
N
Hirayama
Toshiya
T
Fukamachi
Hiroshi
H
Noda
Masaharu
M
D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology* / Q000633:toxicity; D018797:Cell Cycle Proteins; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005756:Gastritis / Q000209:etiology / Q000473:pathology; D016481:Helicobacter Infections / Q000209:etiology* / Q000473:pathology; D016480:Helicobacter pylori / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D013276:Stomach Ulcer / Q000209:etiology* / Q000473:pathology; D014774:Virulence
D001426:Bacterial Proteins; D018797:Cell Cycle Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D010750:Phosphoproteins; C074689:VacA protein, Helicobacter pylori; D017027:Protein Tyrosine Phosphatases