Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells
Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells
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DOI：
10.1038/sj.onc.1210251
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发表时间：
2007-07-12
期刊：
影响因子：
8
通讯作者：
Hatakeyama, M.
中科院分区：
文献类型：
--
作者：
Murata-Kamiya, N.;Kurashima, Y.;Hatakeyama, M.
幽门螺杆菌cagA阳性菌株感染与胃腺癌相关肠上皮化生是胃的癌前病变，其特征在于胃粘膜向肠表型的转分化。螺杆幽门螺杆菌cagA基因产物CagA被递送到胃上皮细胞中，在那里它通过Src家族激酶进行酪氨酸磷酸化。酪氨酸磷酸化的CagA特异性结合并激活SHP-2磷酸酶，从而诱导细胞形态转化。我们在这里报告，CagA的物理相互作用与E-cadherin独立的CagA酪氨酸磷酸化。CagA/E-cadherin相互作用损害E-cadherin和β-catenin之间的复合物形成，导致β-catenin的细胞质和细胞核积聚。CagA去调节的β-连环蛋白然后反式激活β-连环蛋白依赖性基因，如cdx 1，其编码肠特异性CDX 1转录因子。除了β-连环蛋白信号外，CagA还以磷酸化非依赖性方式反式激活p21（WAF 1/Cip 1）。因此，CagA诱导胃上皮细胞中的胃分化标志物杯状细胞粘蛋白MUC 2的异常表达，所述胃上皮细胞已被p21（WAF 1/Cip 1）阻滞在G1期。这些结果表明H.幽门螺杆菌CagA在肠上皮化生的发展中起着重要作用，肠上皮化生是胃上皮细胞的癌前转分化，胃粘膜型胃腺癌由此产生。
Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and beta-catenin, causing cytoplasmic and nuclear accumulation of beta-catenin. CagA-deregulated beta-catenin then transactivates beta-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21(WAF1/Cip1), again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21(WAF1/Cip1). These results indicate that perturbation of the E-cadherin/beta-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.