Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity
Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity
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DOI：
10.1038/nature05765
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发表时间：
2007-05-17
期刊：
影响因子：
64.8
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Saadat, Iraj;Higashi, Hideaki;Hatakeyama, Masanori
幽门螺杆菌cagA阳性菌株与胃炎、溃疡和胃腺癌相关（1）。CagA被递送到胃上皮细胞（2）中，并且在酪氨酸磷酸化时，特异性结合并激活SHP 2癌蛋白（3-7），从而诱导被称为“蜂鸟”表型的细长细胞形状的形成（2，3）。在极化的上皮细胞中，CagA也破坏紧密连接并导致顶端基底外侧极性的丧失（8，9）。我们在这里表明，H。幽门螺杆菌CagA特异性地与PAR 1/MARK激酶相互作用，PAR 1/MARK激酶在上皮细胞极性中具有重要作用（10，11）。CagA的结合抑制PAR 1激酶活性并阻止非典型蛋白激酶C（aPKC）介导的PAR 1磷酸化，其使PAR 1从膜上解离（12，13），共同引起连接和极性缺陷。由于PAR 1的多聚体性质（参考文献14），PAR 1还促进CagA多聚化，从而稳定CagA-SHP 2相互作用（15）。此外，通过CagA激活的SHP 2诱导蜂鸟表型需要同时通过CagA抑制PAR 1激酶活性。因此，CagA-PAR 1相互作用不仅消除了连接和极性缺陷，而且促进了CagA的形态发生活性。我们的研究结果表明PAR 1是H.幽门螺杆菌CagA在胃粘膜损伤、炎症和癌变基础的胃上皮结构紊乱中的作用。
Helicobacter pylori cagA-positive strains are associated with gastritis, ulcerations and gastric adenocarcinoma(1). CagA is delivered into gastric epithelial cells(2) and, on tyrosine phosphorylation, specifically binds and activates the SHP2 oncoprotein(3-7), thereby inducing the formation of an elongated cell shape known as the 'hummingbird' phenotype(2,3). In polarized epithelial cells, CagA also disrupts the tight junction and causes loss of apical basolateral polarity(8,9). We show here that H. pylori CagA specifically interacts with PAR1/MARK kinase, which has an essential role in epithelial cell polarity(10,11). Association of CagA inhibits PAR1 kinase activity and prevents atypical protein kinase C ( aPKC)-mediated PAR1 phosphorylation, which dissociates PAR1 from the membrane(12,13), 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(15). 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.