卡加
蛋白质酪氨酸磷酸酶
幽门螺杆菌
生物
磷酸化
磷酸酶
下调和上调
癌症研究
酪氨酸磷酸化
癌变
分泌物
癌症
分子生物学
细胞生物学
生物化学
毒力
基因
遗传学
作者
Priya Saju,Naoko Murata‐Kamiya,Tetsuhito Hayashi,Yoshie Senda,Lisa Nagase,Saori Noda,Keisuke Matsusaka,Sayaka Funata,Akiko Kunita,Masayuki Urabe,Yasuyuki Seto,Masashi Fukayama,Atsushi Kaneda,Masanori Hatakeyama
出处
期刊:Nature microbiology
日期:2016-03-14
卷期号:1 (4)
被引量:81
标识
DOI:10.1038/nmicrobiol.2016.26
摘要
Most if not all gastric cancers are associated with chronic infection of the stomach mucosa with Helicobacter pylori cagA-positive strains(1-4). Approximately 10% of gastric cancers also harbour Epstein-Barr virus (EBV) in the cancer cells(5,6). Following delivery into gastric epithelial cells via type IV secretion(7,8), the cagA-encoded CagA protein undergoes tyrosine phosphorylation on the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs initially by Src family kinases (SFKs) and then by c-Abl(9,10). Tyrosine-phosphorylated CagA binds to the pro-oncogenic protein tyrosine phosphatase SHP2 and thereby deregulates the phosphatase activity(11,12), which has been considered to play an important role in gastric carcinogenesis(13). Here we show that the SHP2 homologue SHP1 interacts with CagA independently of the EPIYA motif. The interaction potentiates the phosphatase activity of SHP1 that dampens the oncogenic action of CagA by dephosphorylating the CagA EPIYA motifs. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic downregulation of SHP1 expression. Clinical specimens of EBV-positive gastric cancers also exhibit SHP1 hypermethylation with reduced SHP1 expression. The results reveal that SHP1 is the long-sought phosphatase that can antagonize CagA. Augmented H. pylori CagA activity, via SHP1 inhibition, might also contribute to the development of EBV-positive gastric cancer.
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