Helicobacter pylori Protein HP0175 Transactivates Epidermal Growth Factor Receptor through TLR4 in Gastric Epithelial Cells*
- Sanchita Basu,
- Sushil Kumar Pathak1,
- Gargi Chatterjee,
- Shresh Pathak,
- Joyoti Basu and
- Manikuntala Kundu2
- 2 To whom correspondence should be addressed. Tel.: 913323506619; Fax: 913323506790; E-mail: manikuntala{at}vsnl.net.
Abstract
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 β-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.
Footnotes
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↵3 The abbreviations used are: EGFR, EGF receptor; EGF, epidermal growth factor; GPCR, G protein-coupled receptor; HB-EGF, heparin-binding EGF; MBCD, methyl-β-cyclodextrin; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor; siRNA, small interfering RNA.
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↵4 S. Basu, S. K. Pathak, G. Chatterjee, S. Pathak, J. Basu, and M. Kundu, unpublished observations.
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↵* This work was supported in part by grants from the Department of Atomic Energy, Government of India, and the Indian Council of Medical Research (to M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S5.
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↵1 Supported by a fellowship from the Council of Scientific and Industrial Research, Government of India.
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- Received July 2, 2008.
- Revision received August 20, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
