title: Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein-Barr virus.
abstract: Most if not all gastric cancers are associated with chronic infection of the stomach mucosa with Helicobacter pylori cagA-positive strains(1-4). Approximately 10% of gastric cancers also harbour Epstein-Barr virus (EBV) in the cancer cells(5,6). Following delivery into gastric epithelial cells via type IV secretion(7,8), 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-Abl(9,10). Tyrosine-phosphorylated CagA binds to the pro-oncogenic protein tyrosine phosphatase SHP2 and thereby deregulates the phosphatase activity(11,12), which has been considered to play an important role in gastric carcinogenesis(13). 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.
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Priya
authors: P
authors: Saju
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Naoko
authors: N
authors: Murata-Kamiya
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Takeru
authors: T
authors: Hayashi
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Yoshie
authors: Y
authors: Senda
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Lisa
authors: L
authors: Nagase
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-0022, Japan.
authors: Saori
authors: S
authors: Noda
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Keisuke
authors: K
authors: Matsusaka
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.|Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Sayaka
authors: S
authors: Funata
authors: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Akiko
authors: A
authors: Kunita
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.|Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors: Masayuki
authors: M
authors: Urabe
authors: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors: Yasuyuki
authors: Y
authors: Seto
authors: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Masashi
authors: M
authors: Fukayama
authors: Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Atsushi
authors: A
authors: Kaneda
authors: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors: Masanori
authors: M
authors: Hatakeyama
mesh_terms: D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004847:Epithelial Cells / Q000382:microbiology / Q000821:virology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D004854:Herpesvirus 4, Human / Q000254:growth & development*; D054884:Host-Pathogen Interactions; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6