Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion.
Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion.
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DOI：
10.1084/jem.20051027
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发表时间：
2005-11-07
期刊：
影响因子：
--
通讯作者：
Sasakawa C
中科院分区：
文献类型：
--
作者：
Suzuki M;Mimuro H;Suzuki T;Park M;Yamamoto T;Sasakawa C
CagA 蛋白是幽门螺杆菌的主要毒力因子，可被递送至胃上皮细胞并引发生长因子样反应。一旦进入细胞内，CagA 就会被 Src 家族激酶酪氨酸磷酸化，并靶向诱导细胞反应所需的宿主蛋白。我们发现磷酸化的 CagA 与 Crk 衔接蛋白（Crk-II、Crk-I 和 Crk-L）结合，并且这种相互作用对于幽门螺杆菌感染期间 CagA 介导的宿主反应非常重要。显性失活 Crk 的过表达和 RNA 干扰介导的内源性 Crk 敲低可阻断培养物中幽门螺杆菌诱导的胃上皮细胞分散。胃上皮的幽门螺杆菌感染引起含有 E-钙粘蛋白/连环蛋白的粘附连接的破坏，这也依赖于 CagA/Crk 信号传导。此外，抑制 SoS1/H-Ras/Raf1、C3G/Rap1/B-Raf 或 Dock180/Rac1/Wiskott-Aldrich 综合征蛋白家族 verprolin 同源蛋白通路（所有这些通路都涉及 Crk 接头的下游），大大减弱了 CagA 相关的宿主反应。因此，CagA 靶向 Crk 在诱导多效性细胞对幽门螺杆菌感染的反应中发挥着核心作用，幽门螺杆菌感染可导致多种胃部疾病，包括胃癌。
CagA protein is a major virulence factor of Helicobacter pylori, which is delivered into gastric epithelial cells and elicits growth factor–like responses. Once within the cells, CagA is tyrosine phosphorylated by Src family kinases and targets host proteins required to induce the cell responses. We show that the phosphorylated CagA binds Crk adaptor proteins (Crk-II, Crk-I, and Crk-L) and that the interaction is important for the CagA-mediated host responses during H. pylori infection. H. pylori–induced scattering of gastric epithelial cells in culture was blocked by overexpression of dominant-negative Crk and by RNA interference–mediated knockdown of endogenous Crk. H. pylori infection of the gastric epithelium induced disruption of E-cadherin/catenin–containing adherens junctions, which was also dependent on CagA/Crk signaling. Furthermore, inhibition of the SoS1/H-Ras/Raf1, C3G/Rap1/B-Raf, or Dock180/Rac1/Wiskott-Aldrich syndrome protein family verprolin homologous protein pathway, all of which are involved downstream of Crk adaptors, greatly diminished the CagA-associated host responses. Thus, CagA targeting of Crk plays a central role in inducing the pleiotropic cell responses to H. pylori infection that cause several gastric diseases, including gastric cancer.
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