Functional antagonism between
            <i>Helicobacter pylori</i>
            CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells

Yokoyama, Kaoru; Higashi, Hideaki; Ishikawa, Susumu; Fujii, Yasuhiro; Kondo, Satoshi; Kato, Hiroyuki; Azuma, Takeshi; Wada, Akihiro; Hirayama, Toshiya; Aburatani, Hiroyuki; Hatakeyama, Masanori

doi:10.1073/pnas.0502529102

Cited by 127 publications

(126 citation statements)

References 35 publications

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“…Chronic infection with H. pylori cagA-positive strains leads to atrophic gastritis, which is characterized by the continuous loss of gastric glands. We demonstrated that CagA transactivates p21 in gastric epithelial cells at least in part through activation of NFAT as described previously (Yokoyama et al, 2005). The elevated p21 causes G1 cell-cycle arrest.…”

Section: Discussionsupporting

confidence: 86%

“…Notably, detection of CagA at 6 h was almost immediately followed by an increase in p21 WAF1/Cip1 (hereafter designated as p21) (Figure 3a and b). CagA has been recently shown to stimulate the calcineurinnuclear factor of activated T cells (NFAT) pathway, which induces p21, in AGS human gastric epithelial cells (Yokoyama et al, 2005). Consistently, treatment of WT-A10 cells with cyclosporin A, a specific inhibitor of calcineurin, significantly inhibited CagA-mediated p21 accumulation, as was the case in AGS cells ( Figure S2).…”

Section: Resultssupporting

confidence: 69%

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Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and b-catenin, causing cytoplasmic and nuclear accumulation of b-catenin. CagA-deregulated b-catenin then transactivates b-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21 WAF1/Cip1 , again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21 WAF1/Cip1 . These results indicate that perturbation of the E-cadherin/b-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.

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Section: Discussionsupporting

confidence: 86%

Section: Resultssupporting

confidence: 69%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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“…Recent study has shown that CagA activated a transcription factor, NFAT (nuclear factor of activated T-cells) in T lymphocytes, while VacA inhibited NFAT (Yokoyama et al 2005): CagA and VacA are likely to exert opposite cellular effects in some aspects, and hence are related to a variety of H. pylori-dependent diseases. VacA inhibited activation of epidermal growth factor receptor (EGFR) and HER2⁄Neu, and subsequently Erk1⁄2, which are important for cell scattering and elongation (Tegtmeyer et al 2009).…”

Section: Cellular Pathway Affected By Vaca In the Presence Of Cagamentioning

confidence: 99%

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Isomoto

Moss

Hirayama

2010

Tohoku J. Exp. Med.

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“…Therefore, deregulation of SHP-2 by CagA plays an important role in gastric carcinoma development (1). On the other hand, CagA also disturbs cell functions in a tyrosine phosphorylation-independent manner, activating a nuclear factor that induces transcription of several inflammatory genes (11). Furthermore, CagA is also capable of activating NF-κβ, which in turn induces interleukin-8 expression (12) and more recently, it has been reported that this bacterial protein deregulate the β-catenin signaling (13).…”

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confidence: 99%