{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:32:37Z","timestamp":1773660757135,"version":"3.50.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We study the combined signaling network of three major pro-survival signaling pathways: <jats:bold>E<\/jats:bold> pidermal <jats:bold>G<\/jats:bold> rowth <jats:bold>F<\/jats:bold> actor <jats:bold>R<\/jats:bold> eceptor (EGFR), <jats:bold>I<\/jats:bold> nsulin-like <jats:bold>G<\/jats:bold> rowth <jats:bold>F<\/jats:bold> actor-1 <jats:bold>R<\/jats:bold> eceptor (IGF-1R), and <jats:bold>I<\/jats:bold> nsulin <jats:bold>R<\/jats:bold> eceptor (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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-3-88","type":"journal-article","created":{"date-parts":[[2009,9,4]],"date-time":"2009-09-04T18:15:06Z","timestamp":1252088106000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The crosstalk between EGF, IGF, and Insulin cell signaling pathways - computational and experimental analysis"],"prefix":"10.1186","volume":"3","author":[{"given":"Rafal","family":"Zielinski","sequence":"first","affiliation":[]},{"given":"Pawel F","family":"Przytycki","sequence":"additional","affiliation":[]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[]},{"given":"David","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Teresa M","family":"Przytycka","sequence":"additional","affiliation":[]},{"given":"Jacek","family":"Capala","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,9,4]]},"reference":[{"key":"356_CR1","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1146\/annurev.bi.48.070179.004423","volume":"48","author":"EG Krebs","year":"1979","unstructured":"Krebs EG, Beavo JA: Phosphorylation-dephosphorylation of enzymes. Annu Rev Biochem. 1979, 48: 923-59. 10.1146\/annurev.bi.48.070179.004423","journal-title":"Annu Rev Biochem"},{"issue":"1","key":"356_CR2","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0092-8674(00)81688-8","volume":"100","author":"T Hunter","year":"2000","unstructured":"Hunter T: Signaling--2000 and beyond. Cell. 2000, 100 (1): 113-27. 10.1016\/S0092-8674(00)81688-8","journal-title":"Cell"},{"issue":"5618","key":"356_CR3","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1126\/science.1083653","volume":"300","author":"T Pawson","year":"2003","unstructured":"Pawson T, Nash P: Assembly of Cell Regulatory Systems Through Protein Interaction Domains. Science. 2003, 300 (5618): 445-452. 10.1126\/science.1083653","journal-title":"Science"},{"issue":"2","key":"356_CR4","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/0092-8674(95)90402-6","volume":"80","author":"I Herskowitz","year":"1995","unstructured":"Herskowitz I: MAP kinase pathways in yeast: for mating and more. Cell. 1995, 80 (2): 187-97. 10.1016\/0092-8674(95)90402-6","journal-title":"Cell"},{"key":"356_CR5","doi-asserted-by":"crossref","unstructured":"Finkel T, Gutkind JS, : Signal Transduction and Human Disease. Edited by: Hoboken NJ. 2003, Wiley-Liss 488","DOI":"10.1002\/0471482706"},{"issue":"2","key":"356_CR6","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/0092-8674(95)90401-8","volume":"80","author":"CJ Marshall","year":"1995","unstructured":"Marshall CJ: Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995, 80 (2): 179-85. 10.1016\/0092-8674(95)90401-8","journal-title":"Cell"},{"issue":"8","key":"356_CR7","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1002\/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1","volume":"22","author":"G Carpenter","year":"2000","unstructured":"Carpenter G: The EGF receptor: a nexus for trafficking and signaling. Bioessays. 2000, 22 (8): 697-707. 10.1002\/1521-1878(200008)22:8<697::AID-BIES3>3.0.CO;2-1","journal-title":"Bioessays"},{"issue":"4","key":"356_CR8","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1053\/j.seminoncol.2006.04.003","volume":"33","author":"J Mendelsohn","year":"2006","unstructured":"Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006, 33 (4): 369-85. 10.1053\/j.seminoncol.2006.04.003","journal-title":"Semin Oncol"},{"issue":"10","key":"356_CR9","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/labinvest.3700466","volume":"86","author":"BP Rubin","year":"2006","unstructured":"Rubin BP, Duensing A: Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 2006, 86 (10): 981-6. 10.1038\/labinvest.3700466","journal-title":"Lab Invest"},{"issue":"11","key":"356_CR10","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/nrm2042","volume":"7","author":"JG Albeck","year":"2006","unstructured":"Albeck JG, et al.: Collecting and organizing systematic sets of protein data. Nat Rev Mol Cell Biol. 2006, 7 (11): 803-12. 10.1038\/nrm2042","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"11","key":"356_CR11","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1038\/ncb1497","volume":"8","author":"BB Aldridge","year":"2006","unstructured":"Aldridge BB, et al.: Physicochemical modelling of cell signalling pathways. Nat Cell Biol. 2006, 8 (11): 1195-203. 10.1038\/ncb1497","journal-title":"Nat Cell Biol"},{"issue":"5754","key":"356_CR12","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1126\/science.1116598","volume":"310","author":"KA Janes","year":"2005","unstructured":"Janes KA, et al.: A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science. 2005, 310 (5754): 1646-53. 10.1126\/science.1116598","journal-title":"Science"},{"issue":"7","key":"356_CR13","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1074\/mcp.M300045-MCP200","volume":"2","author":"KA Janes","year":"2003","unstructured":"Janes KA, et al.: A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis. Mol Cell Proteomics. 2003, 2 (7): 463-73.","journal-title":"Mol Cell Proteomics"},{"issue":"4","key":"356_CR14","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1089\/cmb.2004.11.544","volume":"11","author":"KA Janes","year":"2004","unstructured":"Janes KA, et al.: Cue-signal-response analysis of TNF-induced apoptosis by partial least squares regression of dynamic multivariate data. J Comput Biol. 2004, 11 (4): 544-61. 10.1089\/cmb.2004.11.544","journal-title":"J Comput Biol"},{"issue":"1","key":"356_CR15","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.cbpa.2005.12.016","volume":"10","author":"KA Janes","year":"2006","unstructured":"Janes KA, Lauffenburger DA: A biological approach to computational models of proteomic networks. Curr Opin Chem Biol. 2006, 10 (1): 73-80. 10.1016\/j.cbpa.2005.12.016","journal-title":"Curr Opin Chem Biol"},{"issue":"6","key":"356_CR16","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1016\/j.cell.2006.01.041","volume":"124","author":"KA Janes","year":"2006","unstructured":"Janes KA, et al.: The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell. 2006, 124 (6): 1225-39. 10.1016\/j.cell.2006.01.041","journal-title":"Cell"},{"issue":"2","key":"356_CR17","first-page":"226","volume":"17","author":"S Tasaki","year":"2006","unstructured":"Tasaki S, et al.: Modeling and estimation of dynamic EGFR pathway by data assimilation approach using time series proteomic data. Genome Inform. 2006, 17 (2): 226-38.","journal-title":"Genome Inform"},{"issue":"6","key":"356_CR18","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/S0167-7799(03)00115-X","volume":"21","author":"T Ideker","year":"2003","unstructured":"Ideker T, Lauffenburger D: Building with a scaffold: emerging strategies for high- to low-level cellular modeling. Trends Biotechnol. 2003, 21 (6): 255-62. 10.1016\/S0167-7799(03)00115-X","journal-title":"Trends Biotechnol"},{"issue":"2","key":"356_CR19","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1093\/bioinformatics\/btm560","volume":"24","author":"S Hardy","year":"2008","unstructured":"Hardy S, Robillard PN: Petri net-based method for the analysis of the dynamics of signal propagation in signaling pathways. Bioinformatics. 2008, 24 (2): 209-17. 10.1093\/bioinformatics\/btm560","journal-title":"Bioinformatics"},{"key":"356_CR20","unstructured":"Schlessinger J: Epidermal Growth Factor Receptor Pathway. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal."},{"key":"356_CR21","unstructured":"White MF: IInsulin Signaling Pathway. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal, Washington DC."},{"key":"356_CR22","unstructured":"Lefkowitz RJ, Shenoy SK: IGF-1 Receptor Signaling through beta-Arrestin. (Connections Map in the Database of Cell Signaling, as seen 7 June 2008) Sci Signal, Washington DC."},{"key":"356_CR23","doi-asserted-by":"publisher","first-page":"3273","DOI":"10.2741\/2925","volume":"13","author":"AJ Casa","year":"2008","unstructured":"Casa AJ, et al.: The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front Biosci. 2008, 13: 3273-87. 10.2741\/2925","journal-title":"Front Biosci"},{"issue":"7","key":"356_CR24","doi-asserted-by":"publisher","first-page":"e88","DOI":"10.1371\/journal.pcbi.0020088","volume":"2","author":"NN Batada","year":"2006","unstructured":"Batada NN, Hurst LD, Tyers M: Evolutionary and physiological importance of hub proteins. PLoS Comput Biol. 2006, 2 (7): e88- 10.1371\/journal.pcbi.0020088","journal-title":"PLoS Comput Biol"},{"issue":"6804","key":"356_CR25","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/35036627","volume":"407","author":"H Jeong","year":"2000","unstructured":"Jeong H, et al.: The large-scale organization of metabolic networks. Nature. 2000, 407 (6804): 651-4. 10.1038\/35036627","journal-title":"Nature"},{"issue":"4","key":"356_CR26","doi-asserted-by":"publisher","first-page":"e59","DOI":"10.1371\/journal.pcbi.0030059","volume":"3","author":"H Yu","year":"2007","unstructured":"Yu H, et al.: The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol. 2007, 3 (4): e59- 10.1371\/journal.pcbi.0030059","journal-title":"PLoS Comput Biol"},{"issue":"3","key":"356_CR27","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/0022-5193(73)90247-6","volume":"42","author":"R Thomas","year":"1973","unstructured":"Thomas R: Boolean formalization of genetic control circuits. J Theor Biol. 1973, 42 (3): 563-85. 10.1016\/0022-5193(73)90247-6","journal-title":"J Theor Biol"},{"issue":"3","key":"356_CR28","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.bbrc.2003.12.007","volume":"313","author":"Y Lu","year":"2004","unstructured":"Lu Y, et al.: Overexpression of ErbB2 receptor inhibits IGF-I-induced Shc-MAPK signaling pathway in breast cancer cells. Biochem Biophys Res Commun. 2004, 313 (3): 709-15. 10.1016\/j.bbrc.2003.12.007","journal-title":"Biochem Biophys Res Commun"},{"key":"356_CR29","unstructured":"Lefkowitz RJ, Shenoy SK: IGF-1 Receptor Signaling through beta-Arrestin. Sci Signal, (Connections Map in the Database of Cell Signaling, as seen 7 June 2008), Washington DC."},{"issue":"15","key":"356_CR30","doi-asserted-by":"publisher","first-page":"11329","DOI":"10.1074\/jbc.M611526200","volume":"282","author":"L Girnita","year":"2007","unstructured":"Girnita L, et al.: Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. J Biol Chem. 2007, 282 (15): 11329-38. 10.1074\/jbc.M611526200","journal-title":"J Biol Chem"},{"issue":"51","key":"356_CR31","doi-asserted-by":"publisher","first-page":"51334","DOI":"10.1074\/jbc.M309968200","volume":"278","author":"TJ Povsic","year":"2003","unstructured":"Povsic TJ, Kohout TA, Lefkowitz RJ: Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. J Biol Chem. 2003, 278 (51): 51334-9. 10.1074\/jbc.M309968200","journal-title":"J Biol Chem"},{"issue":"29","key":"356_CR32","doi-asserted-by":"publisher","first-page":"20139","DOI":"10.1074\/jbc.274.29.20139","volume":"274","author":"A Hashimoto","year":"1999","unstructured":"Hashimoto A, et al.: Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway. J Biol Chem. 1999, 274 (29): 20139-43. 10.1074\/jbc.274.29.20139","journal-title":"J Biol Chem"},{"issue":"42","key":"356_CR33","doi-asserted-by":"publisher","first-page":"16308","DOI":"10.1073\/pnas.0806447105","volume":"105","author":"R Zhang","year":"2008","unstructured":"Zhang R, et al.: Network model of survival signaling in large granular lymphocyte leukemia. Proc Natl Acad Sci USA. 2008, 105 (42): 16308-13. 10.1073\/pnas.0806447105","journal-title":"Proc Natl Acad Sci USA"},{"key":"356_CR34","first-page":"1028","volume-title":"MIT electrical engineering and computer science series","author":"TH Cormen","year":"1990","unstructured":"Cormen TH, Leiserson CE, Rivest RL: Introduction to algorithms. MIT electrical engineering and computer science series. 1990, xvii: 1028-Cambridge, Mass. New York: MIT Press; McGraw-Hill"},{"issue":"11","key":"356_CR35","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, et al.: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003, 13 (11): 2498-504. 10.1101\/gr.1239303","journal-title":"Genome Res"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-3-88.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T03:18:34Z","timestamp":1630466314000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-3-88"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,4]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["356"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-3-88","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,4]]},"assertion":[{"value":"28 September 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"88"}}