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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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c-Met receptor expression is essential for H. pylori– induced motogenic response in epithelial cells. HeLa cells were transfected with siRNA to c-Met or with siRNA to EGFP (as a control for the effect of transfection). After culturing for 72 h, cells were infected with the H. pylori strain P1 for 6 h. The siRNA to c-Met efficiently silenced c-Met receptor expression analyzed in a Western blot (A, top). Silencing of c-Met expression had no effect on EGFR expression (second panel) and phosphorylation (third panel) of translocated CagA protein (bottom). (B) Cells were transfected with c-Met siRNA and infected with the wild-type H. pylori strain P1. Cells are shown by phase-contrast microscopy (top two panels) or stained with immunofluorescence using c-Met antibody. Actin filaments were visualized with rhodamine-conjugated phalloidin. (C) HeLa cells transfected with c-Met siRNA are resistant to the induction of the motogenic response by H. pylori. Phase-contrast of cells transfected with siRNA to c-Met or siRNA to EGFP.
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fig2: c-Met receptor expression is essential for H. pylori– induced motogenic response in epithelial cells. HeLa cells were transfected with siRNA to c-Met or with siRNA to EGFP (as a control for the effect of transfection). After culturing for 72 h, cells were infected with the H. pylori strain P1 for 6 h. The siRNA to c-Met efficiently silenced c-Met receptor expression analyzed in a Western blot (A, top). Silencing of c-Met expression had no effect on EGFR expression (second panel) and phosphorylation (third panel) of translocated CagA protein (bottom). (B) Cells were transfected with c-Met siRNA and infected with the wild-type H. pylori strain P1. Cells are shown by phase-contrast microscopy (top two panels) or stained with immunofluorescence using c-Met antibody. Actin filaments were visualized with rhodamine-conjugated phalloidin. (C) HeLa cells transfected with c-Met siRNA are resistant to the induction of the motogenic response by H. pylori. Phase-contrast of cells transfected with siRNA to c-Met or siRNA to EGFP.

Mentions: To test whether c-Met is directly involved in the stimulation of host cell motogenic response by H. pylori infection, we used small interfering RNA (siRNA) to silence the expression of the c-Met receptor by RNA interference in epithelial cells. An siRNA to c-Met efficiently and specifically silenced c-Met receptor expression, whereas EGFR expression was not affected. Furthermore, the silencing of c-Met receptor expression had no effect on CagA tyrosine phosphorylation (Fig. 2 A). Epithelial cells transfected with siRNA to c-Met did not express c-Met and were resistant to the induction of motility by H. pylori (Fig. 2, B and C). This effect could not be attributed to manipulations required to introduce siRNA into cells because the inhibition of EGFP expression by siRNA had no effect on H. pylori–induced cell motility (Fig. 2 C). Transfection of siRNA, which blocks c-Met expression, also inhibits H. pylori–induced scattering in AGS cells. Experimental data are shown for HeLa cells because these cells were transfectable with high efficiency. We conclude that c-Met expression is necessary for H. pylori–induced motility in epithelial cells.


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)

c-Met receptor expression is essential for H. pylori– induced motogenic response in epithelial cells. HeLa cells were transfected with siRNA to c-Met or with siRNA to EGFP (as a control for the effect of transfection). After culturing for 72 h, cells were infected with the H. pylori strain P1 for 6 h. The siRNA to c-Met efficiently silenced c-Met receptor expression analyzed in a Western blot (A, top). Silencing of c-Met expression had no effect on EGFR expression (second panel) and phosphorylation (third panel) of translocated CagA protein (bottom). (B) Cells were transfected with c-Met siRNA and infected with the wild-type H. pylori strain P1. Cells are shown by phase-contrast microscopy (top two panels) or stained with immunofluorescence using c-Met antibody. Actin filaments were visualized with rhodamine-conjugated phalloidin. (C) HeLa cells transfected with c-Met siRNA are resistant to the induction of the motogenic response by H. pylori. Phase-contrast of cells transfected with siRNA to c-Met or siRNA to EGFP.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172921&req=5

fig2: c-Met receptor expression is essential for H. pylori– induced motogenic response in epithelial cells. HeLa cells were transfected with siRNA to c-Met or with siRNA to EGFP (as a control for the effect of transfection). After culturing for 72 h, cells were infected with the H. pylori strain P1 for 6 h. The siRNA to c-Met efficiently silenced c-Met receptor expression analyzed in a Western blot (A, top). Silencing of c-Met expression had no effect on EGFR expression (second panel) and phosphorylation (third panel) of translocated CagA protein (bottom). (B) Cells were transfected with c-Met siRNA and infected with the wild-type H. pylori strain P1. Cells are shown by phase-contrast microscopy (top two panels) or stained with immunofluorescence using c-Met antibody. Actin filaments were visualized with rhodamine-conjugated phalloidin. (C) HeLa cells transfected with c-Met siRNA are resistant to the induction of the motogenic response by H. pylori. Phase-contrast of cells transfected with siRNA to c-Met or siRNA to EGFP.
Mentions: To test whether c-Met is directly involved in the stimulation of host cell motogenic response by H. pylori infection, we used small interfering RNA (siRNA) to silence the expression of the c-Met receptor by RNA interference in epithelial cells. An siRNA to c-Met efficiently and specifically silenced c-Met receptor expression, whereas EGFR expression was not affected. Furthermore, the silencing of c-Met receptor expression had no effect on CagA tyrosine phosphorylation (Fig. 2 A). Epithelial cells transfected with siRNA to c-Met did not express c-Met and were resistant to the induction of motility by H. pylori (Fig. 2, B and C). This effect could not be attributed to manipulations required to introduce siRNA into cells because the inhibition of EGFP expression by siRNA had no effect on H. pylori–induced cell motility (Fig. 2 C). Transfection of siRNA, which blocks c-Met expression, also inhibits H. pylori–induced scattering in AGS cells. Experimental data are shown for HeLa cells because these cells were transfectable with high efficiency. We conclude that c-Met expression is necessary for H. pylori–induced motility in epithelial cells.

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