Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites
Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites
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DOI：
10.1073/pnas.222375399
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发表时间：
2002-10-29
影响因子：
11.1
通讯作者：
Hatakeyama, M
中科院分区：
文献类型：
--
作者：
Higashi, H;Tsutsumi, R;Hatakeyama, M
幽门螺杆菌是胃炎和消化性溃疡的病原体。cagA（+）H. pylori菌株比cagA（-）菌株毒力更强，并且与胃癌有关。cagA基因产物CagA被细菌注射到胃上皮细胞中，随后经历酪氨酸磷酸化。磷酸化的CagA特异性结合SHP-2磷酸酶，激活磷酸酶活性，从而诱导细胞的形态转化。大多数Western H.幽门螺杆菌分离物具有在不同菌株中重复的34个氨基酸序列。在这里，我们表明，重复序列包含一个酪氨酸磷酸化位点。发现具有更多重复序列的CagA蛋白经历更大的酪氨酸磷酸化，表现出增加的SHP-2结合，并诱导更大的形态学变化。与此相反，H.在胃癌流行的东亚分离的pylori菌株在对应于Western CagA重复序列的区域具有独特的酪氨酸磷酸化序列。这东亚特定的序列赋予更强的SHP-2结合和形态转化活动，西方CagA。最后，一个关键的氨基酸残基，决定SHP-2不同的CagA蛋白之间的结合活性进行了鉴定。我们的研究结果表明，个别CagA干扰宿主细胞功能的潜力是由SHP-2的结合活性，这反过来又取决于酪氨酸磷酸化位点的数量和序列的程度。在西方和东亚H.幽门螺杆菌分离株可能是这两个地区胃癌发病率显著不同的原因。
Helicobacter pylori is a causative agent of gastritis and peptic ulcer. cagA(+) H. pylori strains are more virulent than cagA(-) strains and are associated with gastric carcinoma. The cagA gene product, CagA, is injected by the bacterium into gastric epithelial cells and subsequently undergoes tyrosine phosphorylation. The phosphorylated CagA specifically binds SHP-2 phosphatase, activates the phosphatase activity, and thereby induces morphological transformation of cells. CagA proteins of most Western H. pylori isolates have a 34-amino acid sequence that variably repeats among different strains. Here, we show that the repeat sequence contains a tyrosine phosphorylation site. CagA proteins having more repeats were found to undergo greater tyrosine phosphorylation, to exhibit increased SHP-2 binding, and to induce greater morphological changes. In contrast, predominant CagA proteins specified by H. pylori strains isolated in East Asia, where gastric carcinoma is prevalent, had a distinct tyrosine phosphorylation sequence at the region corresponding to the repeat sequence of Western CagA. This East Asian-specific sequence conferred stronger SHP-2 binding and morphologically transforming activities to Western CagA. Finally, a critical amino acid residue that determines SHP-2 binding activity among different CagA proteins was identified. Our results indicate that the potential of individual CagA to perturb host-cell functions is determined by the degree of SHP-2 binding activity, which depends in turn on the number and sequences of tyrosine phosphorylation sites. The presence of distinctly structured CagA proteins in Western and East Asian H. pylori isolates may underlie the strikingly different incidences of gastric carcinoma in these two geographic areas.