cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells.
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.
Keates
S
S
Division of Gastroenterology and Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. skeates@caregroup.harvard.edu
Sougioultzis
S
S
Keates
A C
AC
Zhao
D
D
Peek
R M
RM
Shaw
L M
LM
Kelly
C P
CP
D000942:Antigens, Bacterial / Q000235:genetics*; D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005753:Gastric Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D016480:Helicobacter pylori / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines; D015533:Transcriptional Activation / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016209:Interleukin-8; D011799:Quinazolines; D020032:Tyrphostins; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; C101044:RTKI cpd; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases