Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA

Naito, Masanori; Yamazaki, Takeshi; Tsutsumi, Ryouhei; Higashi, Hideaki; Onoe, Kazunori; Yamazaki, Shiho; Azuma, Takeshi; Hatakeyama, Masanori

Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA

Naito, Masanori; Yamazaki, Takeshi; Tsutsumi, Ryouhei et al.

Gastroenterology, 2006, 130(4), 1181-1190

Permalink : https://hdl.handle.net/2115/10527

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アクセス権	open access
URI	https://hdl.handle.net/2115/10527
タイトル	Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA
著者	Naito, Masanori ; Yamazaki, Takeshi ; Tsutsumi, Ryouhei ; Higashi, Hideaki ; Onoe, Kazunori ; Yamazaki, Shiho ; Azuma, Takeshi ; Hatakeyama, Masanori
著者名 Naito, Masanori
著者名 Yamazaki, Takeshi
著者名 Tsutsumi, Ryouhei
著者名 Higashi, Hideaki
著者名 Onoe, Kazunori
著者名 Yamazaki, Shiho
著者名 Azuma, Takeshi
著者名 Hatakeyama, Masanori
言語	英語
キーワード	gastric epithelial-cells
	virulence factor CagA
	tyrosine phosphorylation
	pathogenicity island
	duodenal-ulcer
	increased risk
	IV secretion
	protein
	infection
	kinase
発行日	2006-03
出版者	W B SAUNDERS CO-ELSEVIER
収録物名	Gastroenterology
巻(号)	130(4)
ページ	1181-1190
抄録	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
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Copyright2006 by American Gastroenterological Association Institute
PISSN	0016-5085
関連情報	PMID 16618412
関連情報	URI http://www.sciencedirect.com/science/journal/00165085
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1053/j.gastro.2005.12.038