Attenuation of Helicobacter pylori CagA·SHP-2 signaling by interaction between CagA and C-terminal Src kinase

Ryouhei Tsutsumi, Hideaki Higashi, Megumi Higuchi, Masato Okada, Masanori Hatakeyama

研究成果: Article査読

236 被引用数 (Scopus)

抄録

Helicobacter pylori (H. pylori) is a causative agent of gastric diseases ranging from gastritis to cancer. The CagA protein is the product of the caga gene carried among virulent H. pylori strains and is associated with severe disease outcomes, most notably gastric carcinoma. CagA is injected from the attached H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation. The phosphorylated CagA binds and activates SHP-2 phosphatase and thereby induces a growth factor-like morphological change termed the "hummingbird phenotype." In this work, we demonstrate that CagA is also capable of interacting with C-terminal Src kinase (Csk). As is the case with SHP-2, Csk selectively binds tyrosine-phosphorylated CagA via its SH2 domain. Upon complex formation, CagA stimulates Csk, which in turn inactivates the Src family of protein-tyrosine kinases. Because Src family kinases are responsible for CagA phosphorylation, an essential prerequisite of CagA·SHP-2 complex formation and subsequent induction of the hummingbird phenotype, our results indicate that CagA-Csk interaction down-regulates CagA·SHP-2 signaling by both competitively inhibiting CagA·SHP-2 complex formation and reducing levels of CagA phosphorylation. We further demonstrate that CagA·SHP-2 signaling eventually induces apoptosis in AGS cells. Our results thus indicate that CagA-Csk interaction prevents excess cell damage caused by deregulated activation of SHP-2. Attenuation of CagA activity by Csk may enable cagA-positive H. pylori to persistently infect the human stomach for decades while avoiding excess CagA toxicity to the host.

本文言語English
ページ(範囲)3664-3670
ページ数7
ジャーナルJournal of Biological Chemistry
278
6
DOI
出版ステータスPublished - 2003 2 7
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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