Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF

被引:114
作者
Wallasch, C
Crabtree, JE
Bevec, D
Robinson, PA
Wagner, H
Ullrich, A
机构
[1] Axxima Pharmaceut AG, D-81252 Martinsried, Germany
[2] St James Univ Hosp, Mol Med Unit, Leeds LS9 7TF, W Yorkshire, England
[3] Tech Univ Munich, Inst Med Microbiol Immunol & Hyg, D-81675 Munich, Germany
[4] Max Planck Inst Biochem, Dept Mol Biol, D-81252 Martinsried, Germany
关键词
Helicobacter pylori; EGFR; transactivation; gastric cancer; triple membrane passing signal; HB-EGF; metalloprotease;
D O I
10.1016/S0006-291X(02)00740-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Helicobacter pylori has a major aetiological role in human gastric carcinogenesis but the cellular and molecular pathways by which infection promotes transformation remain to be resolved. This study demonstrates that H. pylori exposure to MKN-1, ST42, and MKN-28 gastric epithelial tumour cells results in the activation of HB-EGF gene expression and EGFR tyrosine phosphorylation. These cell responses are induced by both cagPAI positive and cagPAI negative H. pylori strains and are dependent on cell surface expression of the HB-EGF precursor. The induction of HB-EGF gene transcription by H. pylori requires metalloprotease-, EGFR-, and Mek1-activities, indicating the involvement of the "triple membrane passing signal" (TMPS) for EGFR transactivation. Moreover, the release of the inflammatory cytokine IL-8 by cells exposed to H. pylori is significantly impaired by inhibitors of TMPS pathway elements. Our findings support a model in which H. pylori triggers constitutive EGFR signal activation, which enhances IL-8 production, and initiates neoplastic transformation of gastric epithelial cells. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:695 / 701
页数:7
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