cag plus Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells
cag plus Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells
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DOI：
10.1074/jbc.m107630200
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发表时间：
2001-12-21
影响因子：
4.8
通讯作者：
Kelly, CP
中科院分区：
文献类型：
--
作者：
Keates, S;Sougioultzis, S;Kelly, CP
已知胃病原体幽门螺杆菌激活上皮细胞信号传导途径，调节许多炎症反应基因。本研究的目的是阐明细胞外信号调节激酶（ERK）1/2磷酸化的途径。幽门感染的AGS胃上皮细胞。我们发现H.幽门螺杆菌通过表皮生长因子（EGF）受体的激活激活小GTP结合蛋白Ras，其反过来介导ERK 1/2磷酸化。cag+菌株; pylori菌株比cag-菌株能够诱导更强的EGF受体活化，对同基因突变体的研究表明，这种作用需要完整的IV型细菌分泌系统。使用酪氨酸磷酸化抑制剂AG 1478阻断EGF受体活化可防止H. pylori介导的Ras活化，抑制ERK 1/2磷酸化，并显著降低白细胞介素-8基因表达和蛋白质产生。用肝素（一种金属蛋白酶抑制剂）和中和抗体对EGF受体激活机制的研究表明，H。幽门螺杆菌通过激活内源性配体肝素结合EGF样生长因子反式激活EGF受体。胃上皮细胞EGF受体的反式激活可能在调节cag+ H诱导的增殖和炎症反应中起重要作用。幽门感染
The gastric pathogen Helicobacter pylori is known to activate epithelial cell signaling pathways that regulate numerous inflammatory response genes. The aim of this study was to elucidate the pathway leading to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in H. pylori-infected AGS gastric epithelial cells. We find that H. pylori, via activation of the epidermal growth factor (EGF) receptor activates the small GTP-binding protein Ras, which in turn, mediates ERK1/2 phosphorylation. cag+ strains of H. pylori are able to induce greater EGF receptor activation than cag- strains, and studies with isogenic mutants indicate that an intact type IV bacterial secretion system is required for this effect. Blockade of EGF receptor activation using tyrphostin AG1478 prevents H. pylori-mediated Ras activation, inhibits ERK1/2 phosphorylation, and substantially decreases interleukin-8 gene expression and protein production. Investigations into the mechanism of EGF receptor activation, using heparin, a metalloproteinase inhibitor and neutralizing antibodies reveal that H. pylori transactivates the EGF receptor via activation of the endogenous ligand heparin-binding EGF-like growth factor. Transactivation of gastric epithelial cell EGF receptors may be instrumental in regulating both proliferative and inflammatory responses induced by cag+ H. pylori infection.