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Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction.

Franke R, Müller M, Wundrack N, Gilles ED, Klamt S, Kähne T, Naumann M - BMC Syst Biol (2008)

Bottom Line: As another important result, using the formalism of minimal intervention sets, phospholipase Cgamma1 (PLCgamma1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in H. pylori infected cells.The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment.This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCgamma1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str, 44, 39120 Magdeburg, Germany. Raimo.Franke@med.ovgu.de

ABSTRACT

Background: The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen Helicobacter pylori can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The H. pylori effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by H. pylori infection, which might be of importance for tumour development.

Results: A logical model of HGF and H. pylori induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and H. pylori induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cgamma1 (PLCgamma1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in H. pylori infected cells. The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCgamma1. The in silico predictions for the knockout of two other network components were also verified experimentally.

Conclusion: This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an in silico prediction of a relevant target against pathogen infection.

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In silico knockout of PLCγ1 in the HGF stimulated signalling network. A knockout of PLCγ1 does not influence the ERK1/2 pathway in the HGF stimulated network, ERK1/2 is still active. Regarding the text box colors see figure 3.
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Figure 5: In silico knockout of PLCγ1 in the HGF stimulated signalling network. A knockout of PLCγ1 does not influence the ERK1/2 pathway in the HGF stimulated network, ERK1/2 is still active. Regarding the text box colors see figure 3.

Mentions: Figures 5 and 6 show the computed network response for the in silico knockouts of PLCγ1 for H. pylori and HGF stimulation, respectively. In agreement with the computed MISs, ERK1/2 is deactivated in the case of H. pylori stimulation (Figure 6), but is still activated in the case of HGF activation (Figure 5), demonstrating the different response of the network for the two stimuli. Our model shows that the knockout of PLCγ1 can be bypassed via Grb2 – SOS1 – Ras – Raf1 – MEK in the case of HGF stimulation. Next we wanted to verify this prediction experimentally. Apart from PLCγ1, we also selected PI3K (no qualitative effect on ERK1/2 in both scenarios) and MEK (which is, for both cases, a MIS for deactivating ERK1/2) as two further knockout candidates to be tested in experiments.


Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction.

Franke R, Müller M, Wundrack N, Gilles ED, Klamt S, Kähne T, Naumann M - BMC Syst Biol (2008)

In silico knockout of PLCγ1 in the HGF stimulated signalling network. A knockout of PLCγ1 does not influence the ERK1/2 pathway in the HGF stimulated network, ERK1/2 is still active. Regarding the text box colors see figure 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2254585&req=5

Figure 5: In silico knockout of PLCγ1 in the HGF stimulated signalling network. A knockout of PLCγ1 does not influence the ERK1/2 pathway in the HGF stimulated network, ERK1/2 is still active. Regarding the text box colors see figure 3.
Mentions: Figures 5 and 6 show the computed network response for the in silico knockouts of PLCγ1 for H. pylori and HGF stimulation, respectively. In agreement with the computed MISs, ERK1/2 is deactivated in the case of H. pylori stimulation (Figure 6), but is still activated in the case of HGF activation (Figure 5), demonstrating the different response of the network for the two stimuli. Our model shows that the knockout of PLCγ1 can be bypassed via Grb2 – SOS1 – Ras – Raf1 – MEK in the case of HGF stimulation. Next we wanted to verify this prediction experimentally. Apart from PLCγ1, we also selected PI3K (no qualitative effect on ERK1/2 in both scenarios) and MEK (which is, for both cases, a MIS for deactivating ERK1/2) as two further knockout candidates to be tested in experiments.

Bottom Line: As another important result, using the formalism of minimal intervention sets, phospholipase Cgamma1 (PLCgamma1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in H. pylori infected cells.The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment.This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCgamma1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str, 44, 39120 Magdeburg, Germany. Raimo.Franke@med.ovgu.de

ABSTRACT

Background: The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen Helicobacter pylori can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The H. pylori effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by H. pylori infection, which might be of importance for tumour development.

Results: A logical model of HGF and H. pylori induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and H. pylori induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cgamma1 (PLCgamma1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in H. pylori infected cells. The model predicted only an effect on ERK1/2 for the H. pylori stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCgamma1. The in silico predictions for the knockout of two other network components were also verified experimentally.

Conclusion: This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an in silico prediction of a relevant target against pathogen infection.

Show MeSH
Related in: MedlinePlus