Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA
Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA
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DOI：
10.1111/j.1349-7006.2008.00950.x
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发表时间：
2008-10-01
期刊：
影响因子：
5.7
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Lu, Huai-Sheng;Saito, Yasuhiro;Hatakeyama, Masanori
幽门螺杆菌caga阳性菌株与胃炎、消化性溃疡和胃腺癌有关。在进入胃上皮细胞后，CagA编码的CagA蛋白特异性结合并以依赖于CagA酪氨酸磷酸化的方式异常激活SHP-2癌蛋白。然后，caga失调的SHP-2引发异常的Erk激活，同时导致被称为蜂鸟表型的细长细胞形状。在极化上皮细胞中，CagA还结合PAR1b/MARK2并抑制PAR1b激酶活性，从而破坏紧密连接和上皮细胞极性，而不依赖于CagA酪氨酸磷酸化。我们在这里表明，介导CagA与PAR1b相互作用的CagA- multimization （CM）序列不仅对CagA触发的连接缺陷至关重要，而且通过增强CagA- shp -2复合物的形成，在诱导蜂鸟表型中起着重要作用。我们还发现，从东亚幽门螺杆菌中分离的CagA的CM序列（称为E-CM序列）比从西方幽门螺杆菌中分离的CagA（称为W-CM序列）更强地结合PAR1b。在西方的CagA物种中，结合PAR1b的能力与W-CM序列的数量成正比。此外，CagA的par1b结合活性水平与连接缺陷的大小和蜂鸟表型诱导的程度相关。我们的研究结果表明，CM序列的结构多样性是CagA（一种与胃癌发生相关的细菌癌蛋白）毒力程度的重要决定因素。（癌症科学2008；99:2004-2011）
Helicobacter pylori (H. pylori) cagA-positive strains are associated with gastritis, peptic ulcerations, and gastric adenocarcinoma. Upon delivery into gastric epithelial cells, the cagA-encoded CagA protein specifically binds and aberrantly activates SHP-2 oncoprotein in a manner that is dependent on CagA tyrosine phosphorylation. CagA-deregulated SHP-2 then elicits aberrant Erk activation while causing an elongated cell shape known as the hummingbird phenotype. In polarized epithelial cells, CagA also binds to PAR1b/MARK2 and inhibits the PAR1b kinase activity, thereby disrupting tight junctions and epithelial cell polarity independent of CagA tyrosine phosphorylation. We show here that the CagA-multimerization (CM) sequence that mediates interaction of CagA with PAR1b is not only essential for the CagA-triggered junctional defects but also plays an important role in induction of the hummingbird phenotype by potentiating CagA-SHP-2 complex formation. We also show that the CM sequence of CagA isolated from East Asian H. pylori (referred to as the E-CM sequence) binds PAR1b more strongly than that of CagA isolated from Western H. pylori (referred to as the W-CM sequence). Within Western CagA species, the ability to bind PAR1b is proportional to the number of W-CM sequences. Furthermore, the level of PAR1b-binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction. Our findings reveal that structural diversity in the CM sequence is an important determinant for the degree of virulence of CagA, a bacterial oncoprotein that is associated with gastric carcinogenesis. (Cancer Sci 2008; 99: 2004-2011)