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首页> 外文期刊>Nature >Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity
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Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity

机译：幽门螺杆菌CagA靶向PAR1 / MARK激酶，破坏上皮细胞极性

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摘要

Helicobacter pylori cagA-positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma. CagA is delivered into gastric epithelial cells and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein, thereby inducing the formation of an elongated cell shape known as the 'hummingbird' phenotype. In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical-basolateral polarity. We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity. Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C (aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane, collectively causing junctional and polarity defects. Because of the multimeric nature of PAR1 (ref. 14), PAR1 also promotes CagA multimerization, which stabilizes the CagA-SHP2 interaction. Furthermore, induction of the hummingbird phenotype by CagA-activated SHP2 requires simultaneous inhibition of PAR1 kinase activity by CagA. Thus, the CagA-PAR1 interaction not only elicits the junctional and polarity defects but also promotes the morphogenetic activity of CagA. Our findings revealed that PAR1 is a key target of H. pylori CagA in the disorganization of gastric epithelial architecture underlying mucosal damage, inflammation and carcinogenesis.
机译：幽门螺杆菌cagA阳性菌株与胃炎，溃疡和胃腺癌有关。 CagA被递送到胃上皮细胞中，并在酪氨酸磷酸化后特异性结合并激活SHP2癌蛋白，从而诱导形成细长的细胞形状，称为“蜂鸟”表型。在极化的上皮细胞中，CagA也会破坏紧密连接并导致根尖-基底外侧极性的丧失。我们在这里显示幽门螺杆菌CagA专门与PAR1 / MARK激酶相互作用，这在上皮细胞极性中具有重要作用。 CagA协会抑制PAR1激酶活性，并防止非典型蛋白激酶C（aPKC）介导的PAR1磷酸化，这使PAR1从膜上解离，共同导致连接和极性缺陷。由于PAR1的多聚体性质（参考文献14），PAR1还促进CagA多聚化，从而稳定了CagA-SHP2的相互作用。此外，CagA激活的SHP2诱导蜂鸟表型需要CagA同时抑制PAR1激酶活性。因此，CagA-PAR1相互作用不仅引起连接缺陷和极性缺陷，而且促进了CagA的形态发生活性。我们的研究结果表明，PAR1是幽门螺杆菌CagA在胃粘膜损害，炎症和致癌作用的胃上皮结构紊乱中的关键靶标。

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