Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF.
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.
Wallasch
C
C
Axxima Pharmaceuticals AG, Am Klopferspitz 19, 82152 Martinsried, Germany. wallasch@axxima.com
Crabtree
J E
JE
Bevec
D
D
Robinson
P A
PA
Wagner
H
H
Ullrich
A
A
D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism*; D004848:Epithelium / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000201:enzymology; D013997:Time Factors; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D012333:RNA, Messenger; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D008666:Metalloendopeptidases