| RRC ID |
51671
|
| 著者 |
Saju P, Murata-Kamiya N, Hayashi T, Senda Y, Nagase L, Noda S, Matsusaka K, Funata S, Kunita A, Urabe M, Seto Y, Fukayama M, Kaneda A, Hatakeyama M.
|
| タイトル |
Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein-Barr virus.
|
| ジャーナル |
Nat Microbiol
|
| 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.
|
| 巻・号 |
1
|
| ページ |
16026
|
| 公開日 |
2016-3-14
|
| DOI |
10.1038/nmicrobiol.2016.26
|
| PII |
nmicrobiol201626
|
| PMID |
27572445
|
| MeSH |
Antigens, Bacterial / metabolism*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism*
Carcinogenesis
Cell Line, Tumor
DNA Methylation
Epithelial Cells / microbiology
Epithelial Cells / virology
Helicobacter pylori / pathogenicity*
Herpesvirus 4, Human / growth & development*
Host-Pathogen Interactions*
Humans
Phosphorylation
Promoter Regions, Genetic
Protein Binding
Protein Interaction Mapping
Protein Processing, Post-Translational
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
|
| IF |
15.54
|
| 引用数 |
38
|
| リソース情報 |
| ヒト・動物細胞 |
MKN7(RCB0999)
MKN74(RCB1002) |
