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Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.

ABSTRACT: Helicobacter pylori VacA toxin contributes to the pathogenesis and severity of gastric injury. We found that incubation of AZ-521 cells with VacA resulted in phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK3beta) through a PI3K-dependent pathway. Following phosphorylation and inhibition of GSK3beta,beta-catenin was released from a GSK3beta/beta-catenin complex, with subsequent nuclear translocation. Methyl-beta-cyclodextrin (MCD) and phosphatidylinositol-specific phospholipase C (PI-PLC), but not 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and bafilomycin A1, inhibited VacA-induced phosphorylation of Akt, indicating that it does not require VacA internalization and is independent of vacuolation. VacA treatment of AZ-521 cells transfected with TOPtkLuciferase reporter plasmid or control FOPtkLucifease reporter plasmid resulted in activation of TOPtkLuciferase, but not FOPtkLucifease. In addition, VacA transactivated the beta-catenin-dependent cyclin D1 promoter in a luciferase reporter assay. Infection of AZ-521 cells by a vacA mutant strain of H. pylori failed to induce phosphorylation of Akt and GSK3beta, or release of beta-catenin from a GSK3beta/beta-catenin complex. Taken together, these results support the conclusion that VacA activates the PI3K/Akt signaling pathway, resulting in phosphorylation and inhibition of GSK3beta, and subsequent translocation ofbeta-catenin to the nucleus, consistent with effects of VacA on beta-catenin-regulated transcriptional activity. These data introduce the possibility that Wnt-dependent signaling might play a role in the pathogenesis of H. pylori infection, including the development of gastric cancer.

SUBMITTER: Nakayama M

PROVIDER: S-EPMC2615499 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.

Nakayama Masaaki M Hisatsune Junzo J Yamasaki Eiki E Isomoto Hajime H Kurazono Hisao H Hatakeyama Masanori M Azuma Takeshi T Yamaoka Yoshio Y Yahiro Kinnosuke K Moss Joel J Hirayama Toshiya T

The Journal of biological chemistry 20081107 3

Helicobacter pylori VacA toxin contributes to the pathogenesis and severity of gastric injury. We found that incubation of AZ-521 cells with VacA resulted in phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK3beta) through a PI3K-dependent pathway. Following phosphorylation and inhibition of GSK3beta,beta-catenin was released from a GSK3beta/beta-catenin complex, with subsequent nuclear translocation. Methyl-beta-cyclodextrin (MCD) and phosphatidylinositol-specific ...[more]

PMID: 18996844

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Dataset Information

Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.

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Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway.

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