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The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data.

Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S - PLoS Comput. Biol. (2009)

Bottom Line: By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions.Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2.Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.

ABSTRACT
The epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential; however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.

Show MeSH
Species participation in the feedback loops.The darker a species is colored, the more loops it participates in. Colorless species are not part of feedback loops. All colored species build up one strongly connected component in the underlying interaction graph.
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pcbi-1000438-g003: Species participation in the feedback loops.The darker a species is colored, the more loops it participates in. Colorless species are not part of feedback loops. All colored species build up one strongly connected component in the underlying interaction graph.

Mentions: Figure 3 shows the participation of the different species in the feedback loops. Remarkably, the small G protein Ras is included in 98% of the loops, underlining its central role in the regulation of this network. Ras is a key regulator of cell fate [36] and a known oncogene in many human cancers [37]. However, the high number of feedbacks containing Ras in our model can also reflect the fact that Ras is one of the best studied proteins and therefore the feedback mechanisms of Ras are possibly better known than those of other proteins.


The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data.

Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S - PLoS Comput. Biol. (2009)

Species participation in the feedback loops.The darker a species is colored, the more loops it participates in. Colorless species are not part of feedback loops. All colored species build up one strongly connected component in the underlying interaction graph.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2710522&req=5

pcbi-1000438-g003: Species participation in the feedback loops.The darker a species is colored, the more loops it participates in. Colorless species are not part of feedback loops. All colored species build up one strongly connected component in the underlying interaction graph.
Mentions: Figure 3 shows the participation of the different species in the feedback loops. Remarkably, the small G protein Ras is included in 98% of the loops, underlining its central role in the regulation of this network. Ras is a key regulator of cell fate [36] and a known oncogene in many human cancers [37]. However, the high number of feedbacks containing Ras in our model can also reflect the fact that Ras is one of the best studied proteins and therefore the feedback mechanisms of Ras are possibly better known than those of other proteins.

Bottom Line: By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions.Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2.Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany.

ABSTRACT
The epidermal growth factor receptor (EGFR) signaling pathway is probably the best-studied receptor system in mammalian cells, and it also has become a popular example for employing mathematical modeling to cellular signaling networks. Dynamic models have the highest explanatory and predictive potential; however, the lack of kinetic information restricts current models of EGFR signaling to smaller sub-networks. This work aims to provide a large-scale qualitative model that comprises the main and also the side routes of EGFR/ErbB signaling and that still enables one to derive important functional properties and predictions. Using a recently introduced logical modeling framework, we first examined general topological properties and the qualitative stimulus-response behavior of the network. With species equivalence classes, we introduce a new technique for logical networks that reveals sets of nodes strongly coupled in their behavior. We also analyzed a model variant which explicitly accounts for uncertainties regarding the logical combination of signals in the model. The predictive power of this model is still high, indicating highly redundant sub-structures in the network. Finally, one key advance of this work is the introduction of new techniques for assessing high-throughput data with logical models (and their underlying interaction graph). By employing these techniques for phospho-proteomic data from primary hepatocytes and the HepG2 cell line, we demonstrate that our approach enables one to uncover inconsistencies between experimental results and our current qualitative knowledge and to generate new hypotheses and conclusions. Our results strongly suggest that the Rac/Cdc42 induced p38 and JNK cascades are independent of PI3K in both primary hepatocytes and HepG2. Furthermore, we detected that the activation of JNK in response to neuregulin follows a PI3K-dependent signaling pathway.

Show MeSH