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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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CagA interacts with the c-Met tyrosine kinase receptor and enhances the motogenic response of AGS cells to H. pylori infection. (A and B) AGS cells were infected with the wild-type H. pylori strain or isogenic mutant strains cagA and virB11. Phase-contrast microscopy was performed at the indicated time points. (B) Different H. pylori strains activate c-Met. Cells were harvested at the indicated time points after infection. c-Met was immunoprecipitated (IP) with anti–c-Met antibody and analyzed by immunoblotting (IB) using antiphosphotyrosine antibody. (C and D) CagA interacts with the c-Met receptor. AGS cells were infected with H. pylori. Cell lysates were prepared at the indicated time points. c-Met (C) or CagA (D) were immunoprecipitated with the corresponding specific antibodies and subjected to immunoblot analysis using anti-CagA (C) and anti–c-Met (D) antibodies. (E) CagA–c-Met interaction depends on c-Met tyrosine phosphorylation. AGS cells were transiently transfected with plasmids expressing either HA-tagged wild-type CagA (CagA) or HA-tagged phosphorylation-resistant CagA (CagAΔP) and were treated with HGF for 5 min. CagA was precipitated with anti-HA antibody, and immunoprecipitates were analyzed by Western blot analysis using anti–c-Met (top), antiphosphotyrosine (middle) antibodies, and anti–c-Met (bottom) antibodies.
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fig3: CagA interacts with the c-Met tyrosine kinase receptor and enhances the motogenic response of AGS cells to H. pylori infection. (A and B) AGS cells were infected with the wild-type H. pylori strain or isogenic mutant strains cagA and virB11. Phase-contrast microscopy was performed at the indicated time points. (B) Different H. pylori strains activate c-Met. Cells were harvested at the indicated time points after infection. c-Met was immunoprecipitated (IP) with anti–c-Met antibody and analyzed by immunoblotting (IB) using antiphosphotyrosine antibody. (C and D) CagA interacts with the c-Met receptor. AGS cells were infected with H. pylori. Cell lysates were prepared at the indicated time points. c-Met (C) or CagA (D) were immunoprecipitated with the corresponding specific antibodies and subjected to immunoblot analysis using anti-CagA (C) and anti–c-Met (D) antibodies. (E) CagA–c-Met interaction depends on c-Met tyrosine phosphorylation. AGS cells were transiently transfected with plasmids expressing either HA-tagged wild-type CagA (CagA) or HA-tagged phosphorylation-resistant CagA (CagAΔP) and were treated with HGF for 5 min. CagA was precipitated with anti-HA antibody, and immunoprecipitates were analyzed by Western blot analysis using anti–c-Met (top), antiphosphotyrosine (middle) antibodies, and anti–c-Met (bottom) antibodies.

Mentions: We have previously shown that the H. pylori mutant strain PAI failed to stimulate AGS cell motility, in contrast to the isogenic wild-type H. pylori strain (Churin et al., 2001). Therefore, we examined in more detail whether the induction of the motogenic response and c-Met activation depended on the CagA protein and a functional type IV secretion system. Compared with the wild-type strain, the isogenic H. pylori cagA mutant strain induced only a weak motogenic response in AGS cells. The virB11 mutant strain lacking the functional type IV secretion system failed to promote the motogenic response (Fig. 3 A). Furthermore, overexpression of CagA in AGS cells did not induce motility, indicating that H. pylori infection and translocation of the CagA protein are required for the motogenic response (unpublished data).


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)

CagA interacts with the c-Met tyrosine kinase receptor and enhances the motogenic response of AGS cells to H. pylori infection. (A and B) AGS cells were infected with the wild-type H. pylori strain or isogenic mutant strains cagA and virB11. Phase-contrast microscopy was performed at the indicated time points. (B) Different H. pylori strains activate c-Met. Cells were harvested at the indicated time points after infection. c-Met was immunoprecipitated (IP) with anti–c-Met antibody and analyzed by immunoblotting (IB) using antiphosphotyrosine antibody. (C and D) CagA interacts with the c-Met receptor. AGS cells were infected with H. pylori. Cell lysates were prepared at the indicated time points. c-Met (C) or CagA (D) were immunoprecipitated with the corresponding specific antibodies and subjected to immunoblot analysis using anti-CagA (C) and anti–c-Met (D) antibodies. (E) CagA–c-Met interaction depends on c-Met tyrosine phosphorylation. AGS cells were transiently transfected with plasmids expressing either HA-tagged wild-type CagA (CagA) or HA-tagged phosphorylation-resistant CagA (CagAΔP) and were treated with HGF for 5 min. CagA was precipitated with anti-HA antibody, and immunoprecipitates were analyzed by Western blot analysis using anti–c-Met (top), antiphosphotyrosine (middle) antibodies, and anti–c-Met (bottom) antibodies.
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Related In: Results  -  Collection

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fig3: CagA interacts with the c-Met tyrosine kinase receptor and enhances the motogenic response of AGS cells to H. pylori infection. (A and B) AGS cells were infected with the wild-type H. pylori strain or isogenic mutant strains cagA and virB11. Phase-contrast microscopy was performed at the indicated time points. (B) Different H. pylori strains activate c-Met. Cells were harvested at the indicated time points after infection. c-Met was immunoprecipitated (IP) with anti–c-Met antibody and analyzed by immunoblotting (IB) using antiphosphotyrosine antibody. (C and D) CagA interacts with the c-Met receptor. AGS cells were infected with H. pylori. Cell lysates were prepared at the indicated time points. c-Met (C) or CagA (D) were immunoprecipitated with the corresponding specific antibodies and subjected to immunoblot analysis using anti-CagA (C) and anti–c-Met (D) antibodies. (E) CagA–c-Met interaction depends on c-Met tyrosine phosphorylation. AGS cells were transiently transfected with plasmids expressing either HA-tagged wild-type CagA (CagA) or HA-tagged phosphorylation-resistant CagA (CagAΔP) and were treated with HGF for 5 min. CagA was precipitated with anti-HA antibody, and immunoprecipitates were analyzed by Western blot analysis using anti–c-Met (top), antiphosphotyrosine (middle) antibodies, and anti–c-Met (bottom) antibodies.
Mentions: We have previously shown that the H. pylori mutant strain PAI failed to stimulate AGS cell motility, in contrast to the isogenic wild-type H. pylori strain (Churin et al., 2001). Therefore, we examined in more detail whether the induction of the motogenic response and c-Met activation depended on the CagA protein and a functional type IV secretion system. Compared with the wild-type strain, the isogenic H. pylori cagA mutant strain induced only a weak motogenic response in AGS cells. The virB11 mutant strain lacking the functional type IV secretion system failed to promote the motogenic response (Fig. 3 A). Furthermore, overexpression of CagA in AGS cells did not induce motility, indicating that H. pylori infection and translocation of the CagA protein are required for the motogenic response (unpublished data).

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