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Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA
| Title: | Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA |
| Authors: | Naito, Masanori Browse this author | | Yamazaki, Takeshi Browse this author | | Tsutsumi, Ryouhei Browse this author | | Higashi, Hideaki Browse this author | | Onoe, Kazunori Browse this author | | Yamazaki, Shiho Browse this author | | Azuma, Takeshi Browse this author | | Hatakeyama, Masanori Browse this author |
| Keywords: | gastric epithelial-cells | | virulence factor CagA | | tyrosine phosphorylation | | pathogenicity island | | duodenal-ulcer | | increased risk | | IV secretion | | protein | | infection | | kinase |
| Issue Date: | Mar-2006 |
| Publisher: | W B SAUNDERS CO-ELSEVIER |
| Journal Title: | Gastroenterology |
| Volume: | 130 |
| Issue: | 4 |
| Start Page: | 1181 |
| End Page: | 1190 |
| Publisher DOI: | 10.1053/j.gastro.2005.12.038 |
| PMID: | 16618412 |
| Abstract: | Background & Aims: Helicobacter pylori CagA-positive strain is associated with gastric adenocarcinoma. CagA is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation at the EPIYA sites by Src family kinases (SFKs). Owing to homologous recombination within the 3'-region of the cagA gene, 4 distinct EPIYA sites, each of which is defined by surrounding sequences, are variably assembled in both number and order among CagA proteins from different clinical H pylori isolates. Tyrosine-phosphorylated CagA specifically binds and deregulates SHP-2 via the Western CagA-specific EPIYA-C or East Asian CagA-specific EPIYA-D site, and C-terminal Src kinase (Csk) via the EPIYA-A or EPIYA-B site. Here we investigated the influence of EPIYA-repeat polymorphism on the CagA activity. Methods: A series of EPIYA-repeat variants of CagA were expressed in AGS gastric epithelial cells and the ability of individual CagA to bind SHP-2 or Csk was determined by the sequential immunoprecipitation and immunoblotting method. Results: CagA proteins carrying multiple EPIYA-C or EPIYA-D sites bound and deregulated SHP-2 more strongly than those having a single EPIYA-C or EPIYA-D. Furthermore, the ability of CagA to bind Csk was correlated with the number of EPIYA-A and EPIYA-B sites. Because Csk inhibits SFK, CagA with greater Csk-binding activity more strongly inhibited Src-dependent CagA phosphorylation and more effectively attenuated induction of cell elongation caused by CagA-SHP-2 interaction. Conclusions: EFIYA-repeat polymorphism of CagA greatly influences the magnitude and duration of phosphorylation-dependent CagA activity, which may determine the potential of individual CagA as a bacterial virulence factor that directs gastric carcinogenesis |
| Rights: | Copyright2006 by American Gastroenterological Association Institute |
| Relation: | http://www.sciencedirect.com/science/journal/00165085 |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/10527 |
| Appears in Collections: | 遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 畠山 昌則
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