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Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response.

Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M - J. Cell Biol. (2003)

Bottom Line: The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response.CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2.The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke-University, Leipziger Strasse 44, 39120 Magdeburg, Germany.

ABSTRACT
Infection with the human microbial pathogen Helicobacter pylori is assumed to lead to invasive gastric cancer. We find that H. pylori activates the hepatocyte growth factor/scatter factor receptor c-Met, which is involved in invasive growth of tumor cells. The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response. CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2. The H. pylori-induced motogenic response is suppressed and blocked by the inhibition of PLCgamma and of MAPK, respectively. Thus, upon translocation, CagA modulates cellular functions by deregulating c-Met receptor signaling. The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.

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H. pylori activates c-Met receptor tyrosine kinase and induces the motogenic response. (A) H. pylori infection induces motility of AGS and MDCK cells. AGS and MDCK cells were infected with H. pylori, or MDCK cells were treated with 50 U/ml HGF. Phase-contrast microscopy was performed at the indicated time points. (B) H. pylori activates the c-Met receptor in AGS cells. AGS cells were infected with H. pylori or treated with HGF. c-Met was immunoprecipitated from lysates prepared at the indicated time points. Immunoprecipitates (IP) were subjected to SDS-PAGE and immunoblot (IB) analysis with antiphosphotyrosine (top) or anti–c-Met (bottom) antibodies. (C) H. pylori infection activates HER2/Neu. AGS cells were pretreated with or without AG1478 and AG825, and either infected with H. pylori for 90 min or treated with 10 ng/ml EGF for 5 min. Cell lysates were prepared, and HER2/Neu was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (D) AG1478 and AG825 have no effect on c-Met activation. AGS cells were pretreated with or without AG1478 and AG825 and infected with H. pylori for 180 min, and c-Met was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (E) The inhibitors of EGFR and HER2/Neu had no effect on the motility of AGS cells. AGS cells were treated with the inhibitors of EGFR (AG1478) and HER2/Neu (AG825) and infected with H. pylori. Phase-contrast microscopy was performed 4 h after infection.
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fig1: H. pylori activates c-Met receptor tyrosine kinase and induces the motogenic response. (A) H. pylori infection induces motility of AGS and MDCK cells. AGS and MDCK cells were infected with H. pylori, or MDCK cells were treated with 50 U/ml HGF. Phase-contrast microscopy was performed at the indicated time points. (B) H. pylori activates the c-Met receptor in AGS cells. AGS cells were infected with H. pylori or treated with HGF. c-Met was immunoprecipitated from lysates prepared at the indicated time points. Immunoprecipitates (IP) were subjected to SDS-PAGE and immunoblot (IB) analysis with antiphosphotyrosine (top) or anti–c-Met (bottom) antibodies. (C) H. pylori infection activates HER2/Neu. AGS cells were pretreated with or without AG1478 and AG825, and either infected with H. pylori for 90 min or treated with 10 ng/ml EGF for 5 min. Cell lysates were prepared, and HER2/Neu was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (D) AG1478 and AG825 have no effect on c-Met activation. AGS cells were pretreated with or without AG1478 and AG825 and infected with H. pylori for 180 min, and c-Met was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (E) The inhibitors of EGFR and HER2/Neu had no effect on the motility of AGS cells. AGS cells were treated with the inhibitors of EGFR (AG1478) and HER2/Neu (AG825) and infected with H. pylori. Phase-contrast microscopy was performed 4 h after infection.

Mentions: In vitro, HGF promotes epithelial cell growth and survival, as well as epithelial–mesenchymal transition, where it stimulates the dissociation and dispersal of colonies of epithelial cells and the acquisition of a fibroblastic morphology. This results in increased cellular motility and invasiveness (Thiery, 2002). Hence, we tested whether epithelial cell clusters become migratory after infection with H. pylori. Comparison of the same AGS cell colony before and 4 h after H. pylori infection demonstrated the strong stimulation of AGS cell motility (Fig. 1 A) but HGF does not induce motility in AGS cells (not depicted). H. pylori could also stimulate the motility of MDCK cells, which was similar in HGF-treated cells (Fig. 1 A).


Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response.

Churin Y, Al-Ghoul L, Kepp O, Meyer TF, Birchmeier W, Naumann M - J. Cell Biol. (2003)

H. pylori activates c-Met receptor tyrosine kinase and induces the motogenic response. (A) H. pylori infection induces motility of AGS and MDCK cells. AGS and MDCK cells were infected with H. pylori, or MDCK cells were treated with 50 U/ml HGF. Phase-contrast microscopy was performed at the indicated time points. (B) H. pylori activates the c-Met receptor in AGS cells. AGS cells were infected with H. pylori or treated with HGF. c-Met was immunoprecipitated from lysates prepared at the indicated time points. Immunoprecipitates (IP) were subjected to SDS-PAGE and immunoblot (IB) analysis with antiphosphotyrosine (top) or anti–c-Met (bottom) antibodies. (C) H. pylori infection activates HER2/Neu. AGS cells were pretreated with or without AG1478 and AG825, and either infected with H. pylori for 90 min or treated with 10 ng/ml EGF for 5 min. Cell lysates were prepared, and HER2/Neu was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (D) AG1478 and AG825 have no effect on c-Met activation. AGS cells were pretreated with or without AG1478 and AG825 and infected with H. pylori for 180 min, and c-Met was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (E) The inhibitors of EGFR and HER2/Neu had no effect on the motility of AGS cells. AGS cells were treated with the inhibitors of EGFR (AG1478) and HER2/Neu (AG825) and infected with H. pylori. Phase-contrast microscopy was performed 4 h after infection.
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fig1: H. pylori activates c-Met receptor tyrosine kinase and induces the motogenic response. (A) H. pylori infection induces motility of AGS and MDCK cells. AGS and MDCK cells were infected with H. pylori, or MDCK cells were treated with 50 U/ml HGF. Phase-contrast microscopy was performed at the indicated time points. (B) H. pylori activates the c-Met receptor in AGS cells. AGS cells were infected with H. pylori or treated with HGF. c-Met was immunoprecipitated from lysates prepared at the indicated time points. Immunoprecipitates (IP) were subjected to SDS-PAGE and immunoblot (IB) analysis with antiphosphotyrosine (top) or anti–c-Met (bottom) antibodies. (C) H. pylori infection activates HER2/Neu. AGS cells were pretreated with or without AG1478 and AG825, and either infected with H. pylori for 90 min or treated with 10 ng/ml EGF for 5 min. Cell lysates were prepared, and HER2/Neu was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (D) AG1478 and AG825 have no effect on c-Met activation. AGS cells were pretreated with or without AG1478 and AG825 and infected with H. pylori for 180 min, and c-Met was immunoprecipitated and subjected to Western blot analysis using antiphosphotyrosine antibody. (E) The inhibitors of EGFR and HER2/Neu had no effect on the motility of AGS cells. AGS cells were treated with the inhibitors of EGFR (AG1478) and HER2/Neu (AG825) and infected with H. pylori. Phase-contrast microscopy was performed 4 h after infection.
Mentions: In vitro, HGF promotes epithelial cell growth and survival, as well as epithelial–mesenchymal transition, where it stimulates the dissociation and dispersal of colonies of epithelial cells and the acquisition of a fibroblastic morphology. This results in increased cellular motility and invasiveness (Thiery, 2002). Hence, we tested whether epithelial cell clusters become migratory after infection with H. pylori. Comparison of the same AGS cell colony before and 4 h after H. pylori infection demonstrated the strong stimulation of AGS cell motility (Fig. 1 A) but HGF does not induce motility in AGS cells (not depicted). H. pylori could also stimulate the motility of MDCK cells, which was similar in HGF-treated cells (Fig. 1 A).

Bottom Line: The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response.CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2.The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke-University, Leipziger Strasse 44, 39120 Magdeburg, Germany.

ABSTRACT
Infection with the human microbial pathogen Helicobacter pylori is assumed to lead to invasive gastric cancer. We find that H. pylori activates the hepatocyte growth factor/scatter factor receptor c-Met, which is involved in invasive growth of tumor cells. The H. pylori effector protein CagA intracellularly targets the c-Met receptor and promotes cellular processes leading to a forceful motogenic response. CagA could represent a bacterial adaptor protein that associates with phospholipase Cgamma but not Grb2-associated binder 1 or growth factor receptor-bound protein 2. The H. pylori-induced motogenic response is suppressed and blocked by the inhibition of PLCgamma and of MAPK, respectively. Thus, upon translocation, CagA modulates cellular functions by deregulating c-Met receptor signaling. The activation of the motogenic response in H. pylori-infected epithelial cells suggests that CagA could be involved in tumor progression.

Show MeSH
Related in: MedlinePlus