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Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein–Barr virus

Nature Microbiology volume 1, Article number: 16026 (2016) Cite this article

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Abstract

Most if not all gastric cancers are associated with chronic infection of the stomach mucosa with Helicobacter pylori cagA-positive strains1–4. Approximately 10% of gastric cancers also harbour Epstein–Barr virus (EBV) in the cancer cells5,6. Following delivery into gastric epithelial cells via type IV secretion7,8, the cagA-encoded CagA protein undergoes tyrosine phosphorylation on the Glu–Pro–Ile–Tyr–Ala (EPIYA) motifs initially by Src family kinases (SFKs) and then by c-Abl9,10. Tyrosine-phosphorylated CagA binds to the pro-oncogenic protein tyrosine phosphatase SHP2 and thereby deregulates the phosphatase activity11,12, which has been considered to play an important role in gastric carcinogenesis13. Here we show that the SHP2 homologue SHP1 interacts with CagA independently of the EPIYA motif. The interaction potentiates the phosphatase activity of SHP1 that dampens the oncogenic action of CagA by dephosphorylating the CagA EPIYA motifs. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic downregulation of SHP1 expression. Clinical specimens of EBV-positive gastric cancers also exhibit SHP1 hypermethylation with reduced SHP1 expression. The results reveal that SHP1 is the long-sought phosphatase that can antagonize CagA. Augmented H. pylori CagA activity, via SHP1 inhibition, might also contribute to the development of EBV-positive gastric cancer.

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Figure 1: CagA associates with SHP1 in a tyrosine phosphorylation-independent manner.
Figure 2: Dephosphorylation of CagA by SHP1.
Figure 3: SHP1 counteracts phosphorylation-dependent CagA activity.
Figure 4: Hypermethylation of SHP1 by EBV in gastric epithelial cells.

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Acknowledgements

We thank Takashi Matozaki for SHP1 cDNA. We also thank Ping-Ning Hsu for BJAB cells. This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, and Technology (MEXT) of Japan (M.H.), and by the Core Research for Evolutional Science and Technology (CREST) program of the Japan Agency for Medical Research and Development (A.K.).

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Authors and Affiliations

  1. Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

    Priya Saju, Naoko Murata-Kamiya, Takeru Hayashi, Yoshie Senda, Lisa Nagase, Saori Noda & Masanori Hatakeyama

  2. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-0022, Japan

    Saori Noda

  3. Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

    Keisuke Matsusaka, Sayaka Funata, Masayuki Urabe & Atsushi Kaneda

  4. Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan

    Sayaka Funata, Akiko Kunita, Masayuki Urabe & Masashi Fukayama

  5. Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

    Masayuki Urabe & Yasuyuki Seto

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Contributions

P.S., A.Ka., and M.H. designed the experiments. P.S., N.M-K., Y.S., L.N., S.N., K.M., S.F., A.Ku., and T.H. performed the experiments. P.S., N.M-K., T.H., Y.S., S.N., K.M., S.F. and A.Ka. analysed data. L.N., M.U., Y.S., A.Ka. and M.F. provided materials. P.S., A.Ka., and M.H. wrote the paper.

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Correspondence to Masanori Hatakeyama.

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Saju, P., Murata-Kamiya, N., Hayashi, T. et al. Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein–Barr virus. Nat Microbiol 1, 16026 (2016). https://doi.org/10.1038/nmicrobiol.2016.26

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