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

dc.contributor.author	Samaga, R	en
dc.contributor.author	Saez-Rodriguez, J	en
dc.contributor.author	Alexopoulos, LG	en
dc.contributor.author	Sorger, PK	en
dc.contributor.author	Klamt, S	en
dc.date.accessioned	2014-03-01T01:32:10Z
dc.date.available	2014-03-01T01:32:10Z
dc.date.issued	2009	en
dc.identifier.issn	1553-734X	en
dc.identifier.uri	https://dspace.lib.ntua.gr/xmlui/handle/123456789/20056
dc.subject	High Throughput	en
dc.subject.classification	Biochemical Research Methods	en
dc.subject.classification	Mathematical & Computational Biology	en
dc.subject.other	epidermal growth factor receptor	en
dc.subject.other	mitogen activated protein kinase	en
dc.subject.other	mitogen activated protein kinase p38	en
dc.subject.other	stress activated protein kinase	en
dc.subject.other	analysis	en
dc.subject.other	article	en
dc.subject.other	cell line	en
dc.subject.other	data analysis	en
dc.subject.other	high throughput screening	en
dc.subject.other	information science	en
dc.subject.other	liver cell	en
dc.subject.other	logic	en
dc.subject.other	mammal cell	en
dc.subject.other	mathematical model	en
dc.subject.other	predictive validity	en
dc.subject.other	proteomics	en
dc.subject.other	qualitative analysis	en
dc.subject.other	signal transduction	en
dc.subject.other	stimulus response	en
dc.subject.other	stoichiometry	en
dc.subject.other	Mammalia	en
dc.title	The logic of EGFR/ErbB signaling: Theoretical properties and analysis of high-throughput data	en
heal.type	journalArticle	en
heal.identifier.primary	10.1371/journal.pcbi.1000438	en
heal.identifier.secondary	http://dx.doi.org/10.1371/journal.pcbi.1000438	en
heal.identifier.secondary	e1000438	en
heal.language	English	en
heal.publicationDate	2009	en
heal.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. © 2009 Samaga et al.	en
heal.publisher	PUBLIC LIBRARY SCIENCE	en
heal.journalName	PLoS Computational Biology	en
dc.identifier.doi	10.1371/journal.pcbi.1000438	en
dc.identifier.isi	ISI:000270799700033	en
dc.identifier.volume	5	en
dc.identifier.issue	8	en