期刊
INTERNATIONAL JOURNAL OF CANCER
卷 122, 期 4, 页码 823-831出版社
WILEY
DOI: 10.1002/ijc.23190
关键词
Helicobacter pylori CagA; beta-catenin signal; EPIYA motif; gastric adenocarcinoma
类别
Infection with Helicobacter pylori cagA-positive strains causes gastritis and peptic ulceration and is associated with gastric adenocarcinoma. The cagA gene product CagA is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases at the C-terminal EPIYA-repeat region. Tyrosine-phosphorylated CagA specifically binds and activates SHP-2 tyrosine phosphatase, causing cell morphological transformation known as the hummingbird phenotype. CagA also destabilizes the E-cadherin/beta-catenin complex to elicit aberrant activation of the beta-catenin signal that underlies intestinal metaplasia. Here we show that translocalization of membranous beta-catenin and subsequent activation of the beta-catenin signal by CagA requires the EPIYA-repeat region, which is characterized by structural variation between CagA of H. pylori isolated in Western countries (Western CagA) and that of East Asian H. pylori isolates (East Asian CagA), but is independent of CagA tyrosine phosphorylation. Detailed analysis using a series of Western and East Asian CagA mutants revealed that deregulation of beta-catenin requires residues 10091086 and residues 908-1012 of ABCCC Western CagA and ABD East Asian CagA, respectively, and is mediated by the 16-aminoacid CagA multimerization sequence that is conserved between the 2 geographically distinct H. pylori CagA species. Our results indicate that aberrant activation of the P-catenin signal, which promotes precancerous intestinal metaplasia, is an inherent and fundamental CagA activity that is independent of the structural polymorphism of CagA. (C) 2007 Wiley-Liss, Inc.
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