Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with Helicobacter pylori CagA
Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with Helicobacter pylori CagA
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DOI：
10.1128/mcb.26.1.261-276.2006
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发表时间：
2006-01
影响因子：
5.3
通讯作者：
Ryouhei Tsutsumi;A. Takahashi;T. Azuma;H. Higashi;M. Hatakeyama
中科院分区：
文献类型：
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作者：
Ryouhei Tsutsumi;A. Takahashi;T. Azuma;H. Higashi;M. Hatakeyama
摘要cagA阳性幽门螺杆菌感染与萎缩性胃炎、消化性溃疡和胃腺癌有关。CagA基因产物CagA由幽门螺杆菌转位到胃上皮细胞，并通过Src家族激酶(SFKs)进行酪氨酸磷酸化。酪氨酸磷酸化的CagA结合并激活SHP-2磷酸酶和C-末端的Src激酶(CSK)，同时诱导一种被称为“蜂鸟表型”的细长细胞形状。在这里，我们发现CagA降低了胃上皮细胞粘着斑激酶(FAK)酪氨酸磷酸化水平。磷酸化FAK的减少是由于SHP-2介导的FAK在激活的磷酸化位点去磷酸化，而不是由于CSK依赖的对使FAK磷酸化的SFK的抑制。成分活性FAK和CagA的共表达抑制了蜂鸟表型的诱导，而显性-阴性FAK的表达诱导了具有蜂鸟表型特征的拉长的细胞形状。这些结果表明，SHP-2对FAK的抑制在CagA的形态发生活性中起着至关重要的作用。CagA引起的细胞黏附功能受损和运动能力增强可能参与了cagA阳性Hp感染相关胃部病变的发生。
ABSTRACT Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with atrophic gastritis, peptic ulcer, and gastric adenocarcinoma. The cagA gene product CagA is translocated from H. pylori into gastric epithelial cells and undergoes tyrosine phosphorylation by Src family kinases (SFKs). Tyrosine-phosphorylated CagA binds and activates SHP-2 phosphatase and the C-terminal Src kinase (Csk) while inducing an elongated cell shape termed the “hummingbird phenotype.” Here we show that CagA reduces the level of focal adhesion kinase (FAK) tyrosine phosphorylation in gastric epithelial cells. The decrease in phosphorylated FAK is due to SHP-2-mediated dephosphorylation of FAK at the activating phosphorylation sites, not due to Csk-dependent inhibition of SFKs, which phosphorylate FAK. Coexpression of constitutively active FAK with CagA inhibits induction of the hummingbird phenotype, whereas expression of dominant-negative FAK elicits an elongated cell shape characteristic of the hummingbird phenotype. These results indicate that inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA. Impaired cell adhesion and increased motility by CagA may be involved in the development of gastric lesions associated with cagA-positive H. pylori infection.