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. We found that mice deficient in protein tyrosine phosphatase receptor type Z(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 showed similar cellular vacuolation, but only Ptprz+/+ cells showed marked detachment from a reconstituted basement membrane from 24 h after treatment with VacA. VacA bound to Ptprz, and the tyrosine-phosphorylation level of Git1, a Ptprz substrate, was elevated by VacA, indicating that VacA behaves as a ligand for Ptprz. These data indicate that erroneous Ptprz signaling by VacA, but not cellular vacuolation, induces gastric ulcers.