Deregulation of β-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence
Deregulation of β-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence
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DOI：
10.1002/ijc.23190
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发表时间：
2008-02-15
影响因子：
6.4
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Kurashima, Yo;Murata-Kamiya, Naoko;Hatakeyama, Masanori
幽门螺杆菌 cagA 阳性菌株感染会导致胃炎和消化性溃疡，并与胃腺癌相关。 cagA 基因产物 CagA 被递送到胃上皮细胞中，在胃上皮细胞中 C 末端 EPIYA 重复区域被 Src 家族激酶酪氨酸磷酸化。酪氨酸磷酸化的 CagA 特异性结合并激活 SHP-2 酪氨酸磷酸酶，引起细胞形态转变，称为蜂鸟表型。 CagA 还会破坏 E-钙粘蛋白/β-连环蛋白复合物的稳定性，从而引发肠化生基础上的 β-连环蛋白信号的异常激活。在这里，我们表明膜β-连环蛋白的易位化以及随后CagA激活β-连环蛋白信号需要EPIYA重复区域，其特征在于西方国家分离的幽门螺杆菌CagA（西方CagA）和东亚幽门螺杆菌分离物（东亚CagA）之间的结构变异，但独立于CagA酪氨酸 磷酸化。使用一系列西方和东亚 CagA 突变体的详细分析表明，β-连环蛋白的失调分别需要 ABCCC 西方 CagA 和 ABD 东亚 CagA 的残基 10091086 和残基 908-1012，并且由 16 个氨基酸 CagA 多聚化序列介导，该序列在 2 个地理上不同的幽门螺杆菌 CagA 物种之间保守。我们的结果表明，促进癌前肠化生的 P-连环蛋白信号的异常激活是 CagA 固有的基本活性，与 CagA 的结构多态性无关。 (C) 2007 Wiley-Liss, Inc.
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.