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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.

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Examples illustrating the translation of the stoichiometric EGFR model into a logical description.The examples are taken from the stoichiometric map of Oda et al [14]. A The activation level of MKK7 is only influenced by one upstream molecule (active MEKK1). B c-Jun and c-Fos form the transcription factor AP-1. Accordingly, both species are combined with an AND gate (denoted by “·” in the logical equations). C Gab1 can bind directly to EGFR homodimers or via receptor-bound Grb2. For the activation of downstream elements, the activation mechanism of Gab2 does not make a difference what results in a logical OR connection represented by two (independent) activation arrows: Grb2→Gab1 OR EGFR→Gab1. D In this example, we cannot immediately decide whether both Raf-1 and MEKK1 are necessary for the activation of MKK1 (in the model description we use the synonym MEK1) or if the activation of one of these two kinases suffices. Further information is required or an ITT gate can be used (in model M1 we used an OR based on facts published in the literature).
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pcbi-1000438-g002: Examples illustrating the translation of the stoichiometric EGFR model into a logical description.The examples are taken from the stoichiometric map of Oda et al [14]. A The activation level of MKK7 is only influenced by one upstream molecule (active MEKK1). B c-Jun and c-Fos form the transcription factor AP-1. Accordingly, both species are combined with an AND gate (denoted by “·” in the logical equations). C Gab1 can bind directly to EGFR homodimers or via receptor-bound Grb2. For the activation of downstream elements, the activation mechanism of Gab2 does not make a difference what results in a logical OR connection represented by two (independent) activation arrows: Grb2→Gab1 OR EGFR→Gab1. D In this example, we cannot immediately decide whether both Raf-1 and MEKK1 are necessary for the activation of MKK1 (in the model description we use the synonym MEK1) or if the activation of one of these two kinases suffices. Further information is required or an ITT gate can be used (in model M1 we used an OR based on facts published in the literature).

Mentions: Translating a stoichiometric model into a logical model is not a trivial task and requires additional information. Whenever a species is only influenced by one upstream molecule, the interpretation as a Boolean function is straightforward: the downstream species is active (state 1) if and only if the state of the upstream species is 1 (vice versa if the influence is negative) (see Figure 2A). In some other cases it is clear how to code the dependency in a logical function – for example, the formation of a complex (e.g. the heterodimerization of c-Jun and c-Fos to the transcription factor AP-1 (see Figure 2B) or binding of a ligand to a receptor), where all involved proteins have to be present to trigger downstream events and are thus connected with an AND gate. Furthermore, we use an OR gate whenever a protein can be recruited through different receptors or adapter proteins (see Figure 2C).


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)

Examples illustrating the translation of the stoichiometric EGFR model into a logical description.The examples are taken from the stoichiometric map of Oda et al [14]. A The activation level of MKK7 is only influenced by one upstream molecule (active MEKK1). B c-Jun and c-Fos form the transcription factor AP-1. Accordingly, both species are combined with an AND gate (denoted by “·” in the logical equations). C Gab1 can bind directly to EGFR homodimers or via receptor-bound Grb2. For the activation of downstream elements, the activation mechanism of Gab2 does not make a difference what results in a logical OR connection represented by two (independent) activation arrows: Grb2→Gab1 OR EGFR→Gab1. D In this example, we cannot immediately decide whether both Raf-1 and MEKK1 are necessary for the activation of MKK1 (in the model description we use the synonym MEK1) or if the activation of one of these two kinases suffices. Further information is required or an ITT gate can be used (in model M1 we used an OR based on facts published in the literature).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2710522&req=5

pcbi-1000438-g002: Examples illustrating the translation of the stoichiometric EGFR model into a logical description.The examples are taken from the stoichiometric map of Oda et al [14]. A The activation level of MKK7 is only influenced by one upstream molecule (active MEKK1). B c-Jun and c-Fos form the transcription factor AP-1. Accordingly, both species are combined with an AND gate (denoted by “·” in the logical equations). C Gab1 can bind directly to EGFR homodimers or via receptor-bound Grb2. For the activation of downstream elements, the activation mechanism of Gab2 does not make a difference what results in a logical OR connection represented by two (independent) activation arrows: Grb2→Gab1 OR EGFR→Gab1. D In this example, we cannot immediately decide whether both Raf-1 and MEKK1 are necessary for the activation of MKK1 (in the model description we use the synonym MEK1) or if the activation of one of these two kinases suffices. Further information is required or an ITT gate can be used (in model M1 we used an OR based on facts published in the literature).
Mentions: Translating a stoichiometric model into a logical model is not a trivial task and requires additional information. Whenever a species is only influenced by one upstream molecule, the interpretation as a Boolean function is straightforward: the downstream species is active (state 1) if and only if the state of the upstream species is 1 (vice versa if the influence is negative) (see Figure 2A). In some other cases it is clear how to code the dependency in a logical function – for example, the formation of a complex (e.g. the heterodimerization of c-Jun and c-Fos to the transcription factor AP-1 (see Figure 2B) or binding of a ligand to a receptor), where all involved proteins have to be present to trigger downstream events and are thus connected with an AND gate. Furthermore, we use an OR gate whenever a protein can be recruited through different receptors or adapter proteins (see Figure 2C).

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