Limits...
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.

Show MeSH

Related in: MedlinePlus

Dependency matrix. The dependency matrix displays network-wide interdependencies in the logical model. The colour of matrix element mij defines the type of the impact of element i on j (green: (strong) activator; red: (strong) inhibitor, yellow: ambivalent factor; black: no effect (see [13])).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2254585&req=5

Figure 2: Dependency matrix. The dependency matrix displays network-wide interdependencies in the logical model. The colour of matrix element mij defines the type of the impact of element i on j (green: (strong) activator; red: (strong) inhibitor, yellow: ambivalent factor; black: no effect (see [13])).

Mentions: The dependency matrix of the interaction graph (computed for time scale 1, Figure 2) displays all functional dependencies between each pair of species. In the following we discuss some of these dependencies. HGF is an activator for the transcription factors STAT3, ATF2, c-Jun and NF-κB, i.e. there are only positive paths from HGF to these nodes which can thus only mediate activating effects. In contrast, HGF is an ambivalent factor for ERK1/2 and its downstream effectors Elk1, c-Myc and ETS1, i.e. there is at least one inhibiting and one activating path emanating from HGF to these species. The reason is that HGF has a positive effect on ERK1/2 via Grb2-Sos1-Ras-Raf1-MEK but does also signal through RasGAP, which has an inhibitory effect on Ras and therefore on the MAP kinase cascade. However, we notice that the activity of RasGAP on the other hand is downregulated by SHP2 so that the above pathway running over Ras is functional. In contrast to HGF, H. pylori is an activator for all seven transcription factors because ERK1/2 cannot be activated via Grb2-Sos1-Ras-Raf1-MEK- and therefore only through the positive pathway PKCα-Raf1-MEK-ERK1/2 (the latter is also functional with HGF). Another example for coexisting positive and negative effects is the α-catenin/β-catenin/E-cadherin-complex, for which both H. pylori and HGF are ambivalent factors, because they signal through Rac1, which has an inhibitory effect on IQGAP-1, and via calmodulin with a positive effect.


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)

Dependency matrix. The dependency matrix displays network-wide interdependencies in the logical model. The colour of matrix element mij defines the type of the impact of element i on j (green: (strong) activator; red: (strong) inhibitor, yellow: ambivalent factor; black: no effect (see [13])).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Dependency matrix. The dependency matrix displays network-wide interdependencies in the logical model. The colour of matrix element mij defines the type of the impact of element i on j (green: (strong) activator; red: (strong) inhibitor, yellow: ambivalent factor; black: no effect (see [13])).
Mentions: The dependency matrix of the interaction graph (computed for time scale 1, Figure 2) displays all functional dependencies between each pair of species. In the following we discuss some of these dependencies. HGF is an activator for the transcription factors STAT3, ATF2, c-Jun and NF-κB, i.e. there are only positive paths from HGF to these nodes which can thus only mediate activating effects. In contrast, HGF is an ambivalent factor for ERK1/2 and its downstream effectors Elk1, c-Myc and ETS1, i.e. there is at least one inhibiting and one activating path emanating from HGF to these species. The reason is that HGF has a positive effect on ERK1/2 via Grb2-Sos1-Ras-Raf1-MEK but does also signal through RasGAP, which has an inhibitory effect on Ras and therefore on the MAP kinase cascade. However, we notice that the activity of RasGAP on the other hand is downregulated by SHP2 so that the above pathway running over Ras is functional. In contrast to HGF, H. pylori is an activator for all seven transcription factors because ERK1/2 cannot be activated via Grb2-Sos1-Ras-Raf1-MEK- and therefore only through the positive pathway PKCα-Raf1-MEK-ERK1/2 (the latter is also functional with HGF). Another example for coexisting positive and negative effects is the α-catenin/β-catenin/E-cadherin-complex, for which both H. pylori and HGF are ambivalent factors, because they signal through Rac1, which has an inhibitory effect on IQGAP-1, and via calmodulin with a positive effect.

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