title: The crosstalk between EGF, IGF, and Insulin cell signaling pathways--computational and experimental analysis.
abstract: BACKGROUND
  Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways.
  
  
  RESULTS
  We study the combined signaling network of three major pro-survival signaling pathways: Epidermal Growth Factor Receptor (EGFR), Insulin-like Growth Factor-1 Receptor (IGF-1R), and Insulin Receptor (IR). Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all) trends suggested by the simulations have been confirmed by experiments.
  
  
  CONCLUSIONS
  The simple model implemented in this paper provides a valuable first step in modeling signaling networks. However, to obtain a fully predictive model, a more detailed knowledge regarding parameters of individual interactions might be necessary.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine National Institutes of Health Bethesda, MD, USA. zielinkir@mail.nih.gov
authors.forename: Rafal
authors.initials: R
authors.lastname: Zielinski
authors.forename: Pawel F
authors.initials: PF
authors.lastname: Przytycki
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Przytycka
authors.forename: Jacek
authors.initials: J
authors.lastname: Capala
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D003198:Computer Simulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D007328:Insulin; D013002:Somatomedins; D004815:Epidermal Growth Factor