Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells.
The pathophysiology of Helicobacter pylori-associated gastroduodenal diseases, ulcerogenesis, and carcinogenesis is intimately linked to activation of epidermal growth factor receptor (EGFR) and production of vascular endothelial growth factor (VEGF). Extracellular virulence factors, such as CagA and VacA, have been proposed to regulate EGFR activation and VEGF production in gastric epithelial cells. We demonstrate that the H. pylori secretory protein, HP0175, by virtue of its ability to bind TLR4, transactivates EGFR and stimulates EGFR-dependent VEGF production in the gastric cancer cell line AGS. Knock-out of the hp0175 gene attenuates the ability of the resultant H. pylori strain to activate EGFR or to induce VEGF production. HP0175-induced activation of EGFR is preceded by translocation of TLR4 into lipid rafts. In lipid rafts, the Src kinase family member Lyn interacts with TLR4, leading to tyrosine phosphorylation of TLR4. Knockdown of Lyn prevents HP0175-induced activation of EGFR and VEGF production. Tyrosine-phosphorylated TLR4 interacts with EGFR. This interaction is necessary for the activation of EGFR. Disruption of lipid rafts with methyl beta-cyclodextrin prevents HP0175-induced tyrosine phosphorylation of TLR4 and activation of EGFR. This mechanism of transactivation of EGFR is novel and distinct from that of metalloprotease-dependent shedding of EGF-like ligands, leading to autocrine activation of EGFR. It provides new insight into our understanding of the receptor cross-talk network.
Basu
Sanchita
S
Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla Chandra Road, Kolkata 700009, India.
Pathak
Sushil Kumar
SK
Chatterjee
Gargi
G
Pathak
Shresh
S
Basu
Joyoti
J
Kundu
Manikuntala
M
D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry; D008954:Models, Biological; D010766:Phosphorylation; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D014443:Tyrosine / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics
D001426:Bacterial Proteins; C534393:HP0175 protein, Helicobacter pylori; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D066246:ErbB Receptors; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases