{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T21:29:38Z","timestamp":1764019778920},"reference-count":68,"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":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID), PANTHER, Reactome, I2D, and STRING). We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a \u201cbow tie\u201d architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K\/AKT, MAPK\/ERK, JAK\/STAT, NF\u03baB, and apoptotic signaling. Individual pathways exhibit \u201cfuzzy\u201d modularity that is statistically significant but still involving a majority of \u201ccross-talk\u201d interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless), we find a multiplicity of network topologies in which receptors couple to downstream components through myriad alternate paths. Many of these paths are inconsistent with well-established mechanistic features of signalling networks, such as a requirement for a transmembrane receptor in sensing extracellular ligands.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Wide inconsistencies among interaction databases, pathway annotations, and the numbers and identities of nodes associated with a given pathway pose a major challenge for deriving causal and mechanistic insight from network graphs. We speculate that these inconsistencies are at least partially attributable to cell, and context-specificity of cellular signal transduction, which is largely unaccounted for in available databases, but the absence of standardized vocabularies is an additional confounding factor. As a result of discrepant annotations, it is very difficult to identify biologically meaningful pathways from interactome networks <jats:italic>a priori<\/jats:italic>. However, by incorporating prior knowledge, it is possible to successively build out network complexity with high confidence from a simple linear signal transduction scaffold. Such reduced complexity networks appear suitable for use in mechanistic models while being richer and better justified than the simple linear pathways usually depicted in diagrams of signal transduction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-6-29","type":"journal-article","created":{"date-parts":[[2012,5,1]],"date-time":"2012-05-01T14:14:22Z","timestamp":1335881662000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks"],"prefix":"10.1186","volume":"6","author":[{"given":"Daniel C","family":"Kirouac","sequence":"first","affiliation":[]},{"given":"Julio","family":"Saez-Rodriguez","sequence":"additional","affiliation":[]},{"given":"Jennifer","family":"Swantek","sequence":"additional","affiliation":[]},{"given":"John M","family":"Burke","sequence":"additional","affiliation":[]},{"given":"Douglas A","family":"Lauffenburger","sequence":"additional","affiliation":[]},{"given":"Peter K","family":"Sorger","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2012,5,1]]},"reference":[{"key":"914_CR1","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/376307a0","volume":"376","author":"D Bray","year":"1995","unstructured":"Bray D: Protein molecules as computational elements in living cells. Nature 1995, 376: 307-312. 10.1038\/376307a0","journal-title":"Nature"},{"key":"914_CR2","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/nrg2750","volume":"11","author":"DR Hyduke","year":"2010","unstructured":"Hyduke DR, Palsson BO: Towards genome-scale signalling-network reconstructions. Nat Rev Genet 2010, 11: 297-307.","journal-title":"Nat Rev Genet"},{"key":"914_CR3","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","volume":"100","author":"D Hanahan","year":"2000","unstructured":"Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000, 100: 57-70. 10.1016\/S0092-8674(00)81683-9","journal-title":"Cell"},{"key":"914_CR4","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1093\/bioinformatics\/btn200","volume":"24","author":"Y Li","year":"2008","unstructured":"Li Y, Agarwal P, Rajagopalan D: A global pathway crosstalk network. Bioinformatics 2008, 24: 1442-1447. 10.1093\/bioinformatics\/btn200","journal-title":"Bioinformatics"},{"key":"914_CR5","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/ncb1086","volume":"6","author":"T Bouwmeester","year":"2004","unstructured":"Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G: A physical and functional map of the human TNF-alpha\/NF-kappa B signal transduction pathway. Nat Cell Biol 2004, 6: 97-105. 10.1038\/ncb1086","journal-title":"Nat Cell Biol"},{"key":"914_CR6","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1126\/science.1105776","volume":"307","author":"M Barrios-Rodiles","year":"2005","unstructured":"Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL: High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005, 307: 1621-1625. 10.1126\/science.1105776","journal-title":"Science"},{"key":"914_CR7","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/nmeth.1506","volume":"7","author":"S Bandyopadhyay","year":"2010","unstructured":"Bandyopadhyay S, Chiang CY, Srivastava J, Gersten M, White S, Bell R, Kurschner C, Martin CH, Smoot M, Sahasrabudhe S, Barber DL, Chanda SK, Ideker T: A human MAP kinase interactome. Nat Methods 2010, 7: 801-805. 10.1038\/nmeth.1506","journal-title":"Nat Methods"},{"key":"914_CR8","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1038\/ncb1497","volume":"8","author":"BB Aldridge","year":"2006","unstructured":"Aldridge BB, Burke JM, Lauffenburger DA, Sorger PK: Physicochemical modelling of cell signalling pathways. Nat Cell Biol 2006, 8: 1195-1203. 10.1038\/ncb1497","journal-title":"Nat Cell Biol"},{"key":"914_CR9","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/msb.2009.87","volume":"5","author":"J Saez-Rodriguez","year":"2009","unstructured":"Saez-Rodriguez J, Alexopoulos LG, Epperlein J, Samaga R, Lauffenburger DA, Klamt S, Sorger PK: Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transduction. Mol Syst Biol 2009, 5: 331.","journal-title":"Mol Syst Biol"},{"key":"914_CR10","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: 255-262. 10.1016\/S0167-7799(03)00115-X","journal-title":"Trends Biotechnol"},{"key":"914_CR11","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.jbiotec.2007.02.009","volume":"129","author":"A Kremling","year":"2007","unstructured":"Kremling A, Saez-Rodriguez J: Systems biology\u2013an engineering perspective. J Biotechnol 2007, 129: 329-351. 10.1016\/j.jbiotec.2007.02.009","journal-title":"J Biotechnol"},{"key":"914_CR12","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1038\/sj.onc.1210255","volume":"26","author":"T Pawson","year":"2007","unstructured":"Pawson T, Warner N: Oncogenic re-wiring of cellular signaling pathways. Oncogene 2007, 26: 1268-1275. 10.1038\/sj.onc.1210255","journal-title":"Oncogene"},{"key":"914_CR13","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/msb.2009.49","volume":"5","author":"DC Kirouac","year":"2009","unstructured":"Kirouac DC, Madlambayan GJ, Yu M, Sykes EA, Ito C, Zandstra PW: Cell-cell interaction networks regulate blood stem and progenitor cell fate. Mol Syst Biol 2009, 5: 293.","journal-title":"Mol Syst Biol"},{"key":"914_CR14","doi-asserted-by":"publisher","first-page":"e1001099","DOI":"10.1371\/journal.pcbi.1001099","volume":"7","author":"MK Morris","year":"2011","unstructured":"Morris MK, Saez-Rodriguez J, Clarke DC, Sorger PK, Lauffenburger DA: Training signaling pathway maps to biochemical data with constrained fuzzy logic: quantitative analysis of liver cell responses to inflammatory stimuli. PLoS Comput Biol 2011, 7: e1001099. 10.1371\/journal.pcbi.1001099","journal-title":"PLoS Comput Biol"},{"key":"914_CR15","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1074\/mcp.M110.000406","volume":"9","author":"LG Alexopoulos","year":"2010","unstructured":"Alexopoulos LG, Saez-Rodriguez J, Cosgrove BD, Lauffenburger DA, Sorger PK: Networks inferred from biochemical data reveal profound differences in toll-like receptor and inflammatory signaling between normal and transformed hepatocytes. Mol Cell Proteomics 2010, 9: 1849-1865. 10.1074\/mcp.M110.000406","journal-title":"Mol Cell Proteomics"},{"key":"914_CR16","doi-asserted-by":"publisher","first-page":"3216","DOI":"10.1021\/bi902202q","volume":"49","author":"MK Morris","year":"2010","unstructured":"Morris MK, Saez-Rodriguez J, Sorger PK, Lauffenburger DA: Logic-based models for the analysis of cell signaling networks. Biochemistry 2010, 49: 3216-3224. 10.1021\/bi902202q","journal-title":"Biochemistry"},{"key":"914_CR17","doi-asserted-by":"publisher","first-page":"D685","DOI":"10.1093\/nar\/gkq1039","volume":"39","author":"EG Cerami","year":"2011","unstructured":"Cerami EG, Gross BE, Demir E, Rodchenkov I, Babur O, Anwar N, Schultz N, Bader GD, Sander C: Pathway Commons, a web resource for biological pathway data. Nucleic Acids Res 2011, 39: D685-690. 10.1093\/nar\/gkq1039","journal-title":"Nucleic Acids Res"},{"key":"914_CR18","doi-asserted-by":"publisher","first-page":"D504","DOI":"10.1093\/nar\/gkj126","volume":"34","author":"GD Bader","year":"2006","unstructured":"Bader GD, Cary MP, Sander C: Pathguide: a pathway resource list. Nucleic Acids Res 2006, 34: D504-506. 10.1093\/nar\/gkj126","journal-title":"Nucleic Acids Res"},{"key":"914_CR19","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1038\/468851a","volume":"468","author":"L Bonetta","year":"2010","unstructured":"Bonetta L: Protein-protein interactions: Interactome under construction. Nature 2010, 468: 851-854. 10.1038\/468851a","journal-title":"Nature"},{"key":"914_CR20","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1002\/pmic.200600924","volume":"7","author":"F Ramirez","year":"2007","unstructured":"Ramirez F, Schlicker A, Assenov Y, Lengauer T, Albrecht M: Computational analysis of human protein interaction networks. Proteomics 2007, 7: 2541-2552. 10.1002\/pmic.200600924","journal-title":"Proteomics"},{"key":"914_CR21","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1002\/pmic.200700767","volume":"8","author":"E Pieroni","year":"2008","unstructured":"Pieroni E, de la Fuente van Bentem S, Mancosu G, Capobianco E, Hirt H, de la Fuente A: Protein networking: insights into global functional organization of proteomes. Proteomics 2008, 8: 799-816. 10.1002\/pmic.200700767","journal-title":"Proteomics"},{"key":"914_CR22","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/nmeth.1284","volume":"6","author":"ME Cusick","year":"2009","unstructured":"Cusick ME, Yu H, Smolyar A, Venkatesan K, Carvunis AR, Simonis N, Rual JF, Borick H, Braun P, Dreze M, Vandenhaute J, Galli M, Yazaki J, Hill DE, Ecker JR, Roth FP, Vidal M: Literature-curated protein interaction datasets. Nat Methods 2009, 6: 39-46. 10.1038\/nmeth.1284","journal-title":"Nat Methods"},{"key":"914_CR23","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.tibtech.2010.04.005","volume":"28","author":"S Ananiadou","year":"2010","unstructured":"Ananiadou S, Pyysalo S, Tsujii J, Kell DB: Event extraction for systems biology by text mining the literature. Trends Biotechnol 2010, 28: 381-390. 10.1016\/j.tibtech.2010.04.005","journal-title":"Trends Biotechnol"},{"key":"914_CR24","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1038\/nbt.1666","volume":"28","author":"E Demir","year":"2010","unstructured":"Demir E, Cary MP, Paley S, Fukuda K, Lemer C, Vastrik I, Wu G, D'Eustachio P, Schaefer C, Luciano J, Schacherer F, Martinez-Flores I, Hu Z, Jimenez-Jacinto V, Joshi-Tope G, Kandasamy K, Lopez-Fuentes AC, Mi H, Pichler E, Rodchenkov I, Splendiani A, Tkachev S, Zucker J, Gopinath G, Rajasimha H, Ramakrishnan R, Shah I, Syed M, Anwar N, Babur O, Blinov M, Brauner E, Corwin D, Donaldson S, Gibbons F, Goldberg R, Hornbeck P, Luna A, Murray-Rust P, Neumann E, Reubenacker O, Samwald M, van Iersel M, Wimalaratne S, Allen K, Braun B, Whirl-Carrillo M, Cheung KH, Dahlquist K, Finney A, Gillespie M, Glass E, Gong L, Haw R, Honig M, Hubaut O, Kane D, Krupa S, Kutmon M, Leonard J, Marks D, Merberg D, Petri V, Pico A, Ravenscroft D, Ren L, Shah N, Sunshine M, Tang R, Whaley R, Letovksy S, Buetow KH, Rzhetsky A, Schachter V, Sobral BS, Dogrusoz U, McWeeney S, Aladjem M, Birney E, Collado-Vides J, Goto S, Hucka M, Le Novere N, Maltsev N, Pandey A, Thomas P, Wingender E, Karp PD, Sander C, Bader GD: The BioPAX community standard for pathway data sharing. Nat Biotechnol 2010, 28: 935-942. 10.1038\/nbt.1666","journal-title":"Nat Biotechnol"},{"key":"914_CR25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.gde.2008.01.003","volume":"18","author":"P Allavena","year":"2008","unstructured":"Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A: Pathways connecting inflammation and cancer. Curr Opin Genet Dev 2008, 18: 3-10. 10.1016\/j.gde.2008.01.003","journal-title":"Curr Opin Genet Dev"},{"key":"914_CR26","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/1752-0509-4-63","volume":"4","author":"S Raza","year":"2010","unstructured":"Raza S, McDerment N, Lacaze PA, Robertson K, Watterson S, Chen Y, Chisholm M, Eleftheriadis G, Monk S, O'Sullivan M, Turnbull A, Roy D, Theocharidis A, Ghazal P, Freeman TC: Construction of a large scale integrated map of macrophage pathogen recognition and effector systems. BMC Syst Biol 2010, 4: 63. 10.1186\/1752-0509-4-63","journal-title":"BMC Syst Biol"},{"key":"914_CR27","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T: Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003, 13: 2498-2504. 10.1101\/gr.1239303","journal-title":"Genome Res"},{"key":"914_CR28","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1093\/bioinformatics\/bti273","volume":"21","author":"KR Brown","year":"2005","unstructured":"Brown KR, Jurisica I: Online predicted human interaction database. Bioinformatics 2005, 21: 2076-2082. 10.1093\/bioinformatics\/bti273","journal-title":"Bioinformatics"},{"key":"914_CR29","doi-asserted-by":"publisher","first-page":"D412","DOI":"10.1093\/nar\/gkn760","volume":"37","author":"LJ Jensen","year":"2009","unstructured":"Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, Doerks T, Julien P, Roth A, Simonovic M, Bork P, von Mering C: STRING 8\u2013a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res 2009, 37: D412-416. 10.1093\/nar\/gkn760","journal-title":"Nucleic Acids Res"},{"key":"914_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrg1272","volume":"5","author":"AL Barabasi","year":"2004","unstructured":"Barabasi AL, Oltvai ZN: Network biology: understanding the cell's functional organization. Nat Rev Genet 2004, 5: 101-113. 10.1038\/nrg1272","journal-title":"Nat Rev Genet"},{"key":"914_CR31","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1038\/nrg1471","volume":"5","author":"H Kitano","year":"2004","unstructured":"Kitano H: Biological robustness. Nat Rev Genet 2004, 5: 826-837.","journal-title":"Nat Rev Genet"},{"key":"914_CR32","doi-asserted-by":"publisher","first-page":"e1002010","DOI":"10.1371\/journal.pgen.1002010","volume":"7","author":"MD Nelson","year":"2011","unstructured":"Nelson MD, Zhou E, Kiontke K, Fradin H, Maldonado G, Martin D, Shah K, Fitch DH: A bow-tie genetic architecture for morphogenesis suggested by a genome-wide RNAi screen in Caenorhabditis elegans. PLoS Genet 2011, 7: e1002010. 10.1371\/journal.pgen.1002010","journal-title":"PLoS Genet"},{"key":"914_CR33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/1752-0509-4-20","volume":"4","author":"YC Wang","year":"2010","unstructured":"Wang YC, Chen BS: Integrated cellular network of transcription regulations and protein-protein interactions. BMC Syst Biol 2010, 4: 20. 10.1186\/1752-0509-4-20","journal-title":"BMC Syst Biol"},{"key":"914_CR34","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1039\/b904960f","volume":"5","author":"C Rodriguez-Caso","year":"2009","unstructured":"Rodriguez-Caso C, Corominas-Murtra B, Sole RV: On the basic computational structure of gene regulatory networks. Mol Biosyst 2009, 5: 1617-1629. 10.1039\/b904960f","journal-title":"Mol Biosyst"},{"key":"914_CR35","doi-asserted-by":"publisher","first-page":"e4189","DOI":"10.1371\/journal.pone.0004189","volume":"4","author":"N Polouliakh","year":"2009","unstructured":"Polouliakh N, Nock R, Nielsen F, Kitano H: G-protein coupled receptor signaling architecture of mammalian immune cells. PLoS One 2009, 4: e4189. 10.1371\/journal.pone.0004189","journal-title":"PLoS One"},{"key":"914_CR36","doi-asserted-by":"publisher","first-page":"0015","DOI":"10.1038\/msb4100057","volume":"2","author":"K Oda","year":"2006","unstructured":"Oda K, Kitano H: A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2006, 2: 0015.","journal-title":"Mol Syst Biol"},{"key":"914_CR37","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/1752-0509-3-67","volume":"3","author":"J Supper","year":"2009","unstructured":"Supper J, Spangenberg L, Planatscher H, Drager A, Schroder A, Zell A: BowTieBuilder: modeling signal transduction pathways. BMC Syst Biol 2009, 3: 67. 10.1186\/1752-0509-3-67","journal-title":"BMC Syst Biol"},{"key":"914_CR38","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1038\/msb.2010.71","volume":"6","author":"DC Kirouac","year":"2010","unstructured":"Kirouac DC, Ito C, Csaszar E, Roch A, Yu M, Sykes EA, Bader GD, Zandstra PW: Dynamic interaction networks in a hierarchically organized tissue. Mol Syst Biol 2010, 6: 417.","journal-title":"Mol Syst Biol"},{"key":"914_CR39","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1093\/bioinformatics\/btl683","volume":"23","author":"ME Futschik","year":"2007","unstructured":"Futschik ME, Chaurasia G, Herzel H: Comparison of human protein-protein interaction maps. Bioinformatics 2007, 23: 605-611. 10.1093\/bioinformatics\/btl683","journal-title":"Bioinformatics"},{"key":"914_CR40","doi-asserted-by":"publisher","first-page":"C47","DOI":"10.1038\/35011540","volume":"402","author":"LH Hartwell","year":"1999","unstructured":"Hartwell LH, Hopfield JJ, Leibler S, Murray AW: From molecular to modular cell biology. Nature 1999, 402: C47-52. 10.1038\/35011540","journal-title":"Nature"},{"key":"914_CR41","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/bioinformatics\/btl562","volume":"23","author":"F Luo","year":"2007","unstructured":"Luo F, Yang Y, Chen CF, Chang R, Zhou J, Scheuermann RH: Modular organization of protein interaction networks. Bioinformatics 2007, 23: 207-214. 10.1093\/bioinformatics\/btl562","journal-title":"Bioinformatics"},{"key":"914_CR42","doi-asserted-by":"publisher","first-page":"056117","DOI":"10.1103\/PhysRevE.80.056117","volume":"80","author":"A Lancichinetti","year":"2009","unstructured":"Lancichinetti A, Fortunato S: Community detection algorithms: a comparative analysis. Phys Rev E Stat Nonlin Soft Matter Phys 2009, 80: 056117.","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"key":"914_CR43","doi-asserted-by":"publisher","first-page":"13773","DOI":"10.1073\/pnas.0503610102","volume":"102","author":"N Kashtan","year":"2005","unstructured":"Kashtan N, Alon U: Spontaneous evolution of modularity and network motifs. Proc Natl Acad Sci U S A 2005, 102: 13773-13778. 10.1073\/pnas.0503610102","journal-title":"Proc Natl Acad Sci U S A"},{"key":"914_CR44","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/nature03288","volume":"433","author":"R Guimera","year":"2005","unstructured":"Guimera R, Nunes Amaral LA: Functional cartography of complex metabolic networks. Nature 2005, 433: 895-900. 10.1038\/nature03288","journal-title":"Nature"},{"key":"914_CR45","doi-asserted-by":"publisher","first-page":"e23","DOI":"10.1371\/journal.pcbi.0040023","volume":"4","author":"A Hintze","year":"2008","unstructured":"Hintze A, Adami C: Evolution of complex modular biological networks. PLoS Comput Biol 2008, 4: e23. 10.1371\/journal.pcbi.0040023","journal-title":"PLoS Comput Biol"},{"key":"914_CR46","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/35052073","volume":"2","author":"Y Yarden","year":"2001","unstructured":"Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001, 2: 127-137. 10.1038\/35052073","journal-title":"Nat Rev Mol Cell Biol"},{"key":"914_CR47","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1073\/pnas.0705088105","volume":"105","author":"T Helikar","year":"2008","unstructured":"Helikar T, Konvalina J, Heidel J, Rogers JA: Emergent decision-making in biological signal transduction networks. Proc Natl Acad Sci U S A 2008, 105: 1913-1918. 10.1073\/pnas.0705088105","journal-title":"Proc Natl Acad Sci U S A"},{"key":"914_CR48","doi-asserted-by":"publisher","first-page":"e1000438","DOI":"10.1371\/journal.pcbi.1000438","volume":"5","author":"R Samaga","year":"2009","unstructured":"Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S: The logic of EGFR\/ErbB signaling: theoretical properties and analysis of high-throughput data. PLoS Comput Biol 2009, 5: e1000438. 10.1371\/journal.pcbi.1000438","journal-title":"PLoS Comput Biol"},{"key":"914_CR49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/msb.2008.74","volume":"5","author":"WW Chen","year":"2009","unstructured":"Chen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK: Input\u2013output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Mol Syst Biol 2009, 5: 239.","journal-title":"Mol Syst Biol"},{"key":"914_CR50","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1038\/nbt0402-370","volume":"20","author":"B Schoeberl","year":"2002","unstructured":"Schoeberl B, Eichler-Jonsson C, Gilles ED, Muller G: Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat Biotechnol 2002, 20: 370-375. 10.1038\/nbt0402-370","journal-title":"Nat Biotechnol"},{"key":"914_CR51","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/msb4100188","volume":"3","author":"MR Birtwistle","year":"2007","unstructured":"Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN: Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol 2007, 3: 144.","journal-title":"Mol Syst Biol"},{"key":"914_CR52","doi-asserted-by":"publisher","first-page":"37650","DOI":"10.1074\/jbc.M110.138818","volume":"285","author":"E Frijns","year":"2010","unstructured":"Frijns E, Sachs N, Kreft M, Wilhelmsen K, Sonnenberg A: EGF-induced MAPK signaling inhibits hemidesmosome formation through phosphorylation of the integrin {beta}4. J Biol Chem 2010, 285: 37650-37662. 10.1074\/jbc.M110.138818","journal-title":"J Biol Chem"},{"key":"914_CR53","doi-asserted-by":"publisher","first-page":"8497","DOI":"10.1074\/jbc.M312575200","volume":"279","author":"Y Ren","year":"2004","unstructured":"Ren Y, Meng S, Mei L, Zhao ZJ, Jove R, Wu J: Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J Biol Chem 2004, 279: 8497-8505.","journal-title":"J Biol Chem"},{"key":"914_CR54","doi-asserted-by":"publisher","first-page":"12546","DOI":"10.1021\/bi050560g","volume":"44","author":"I Matsuura","year":"2005","unstructured":"Matsuura I, Wang G, He D, Liu F: Identification and characterization of ERK MAP kinase phosphorylation sites in Smad3. Biochemistry 2005, 44: 12546-12553. 10.1021\/bi050560g","journal-title":"Biochemistry"},{"key":"914_CR55","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.4161\/cbt.8.15.8939","volume":"8","author":"S Agelaki","year":"2009","unstructured":"Agelaki S, Spiliotaki M, Markomanolaki H, Kallergi G, Mavroudis D, Georgoulias V, Stournaras C: Caveolin-1 regulates EGFR signaling in MCF-7 breast cancer cells and enhances gefitinib-induced tumor cell inhibition. Cancer Biol Ther 2009, 8: 1470-1477. 10.4161\/cbt.8.15.8939","journal-title":"Cancer Biol Ther"},{"key":"914_CR56","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/1752-0509-5-44","volume":"5","author":"RS Wang","year":"2011","unstructured":"Wang RS, Albert R: Elementary signaling modes predict the essentiality of signal transduction network components. BMC Syst Biol 2011, 5: 44. 10.1186\/1752-0509-5-44","journal-title":"BMC Syst Biol"},{"key":"914_CR57","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/nrm2042","volume":"7","author":"JG Albeck","year":"2006","unstructured":"Albeck JG, MacBeath G, White FM, Sorger PK, Lauffenburger DA, Gaudet S: Collecting and organizing systematic sets of protein data. Nat Rev Mol Cell Biol 2006, 7: 803-812. 10.1038\/nrm2042","journal-title":"Nat Rev Mol Cell Biol"},{"key":"914_CR58","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1186\/1471-2105-11-597","volume":"11","author":"E Glaab","year":"2011","unstructured":"Glaab E, Baudot A, Krasnogor N, Valencia A: Extending pathways and processes using molecular interaction networks to analyse cancer genome data. BMC Bioniformatics 2011, 11: 597.","journal-title":"BMC Bioniformatics"},{"key":"914_CR59","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, Gaudet S, Albeck JG, Nielsen UB, Lauffenburger DA, Sorger PK: The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 2006, 124: 1225-1239. 10.1016\/j.cell.2006.01.041","journal-title":"Cell"},{"key":"914_CR60","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1038\/nrg2267","volume":"8","author":"GP Wagner","year":"2007","unstructured":"Wagner GP, Pavlicev M, Cheverud JM: The road to modularity. Nat Rev Genet 2007, 8: 921-931.","journal-title":"Nat Rev Genet"},{"key":"914_CR61","doi-asserted-by":"publisher","first-page":"e8918","DOI":"10.1371\/journal.pone.0008918","volume":"5","author":"E Cerami","year":"2010","unstructured":"Cerami E, Demir E, Schultz N, Taylor BS, Sander C: Automated network analysis identifies core pathways in glioblastoma. PLoS One 2010, 5: e8918. 10.1371\/journal.pone.0008918","journal-title":"PLoS One"},{"key":"914_CR62","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1126\/science.1164368","volume":"321","author":"S Jones","year":"2008","unstructured":"Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008, 321: 1801-1806. 10.1126\/science.1164368","journal-title":"Science"},{"key":"914_CR63","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1126\/science.1164382","volume":"321","author":"DW Parsons","year":"2008","unstructured":"Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW: An integrated genomic analysis of human glioblastoma multiforme. Science 2008, 321: 1807-1812. 10.1126\/science.1164382","journal-title":"Science"},{"key":"914_CR64","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/msb.2009.47","volume":"5","author":"A Bauer-Mehren","year":"2009","unstructured":"Bauer-Mehren A, Furlong LI, Sanz F: Pathway databases and tools for their exploitation: benefits, current limitations and challenges. Mol Syst Biol 2009, 5: 290.","journal-title":"Mol Syst Biol"},{"key":"914_CR65","doi-asserted-by":"publisher","first-page":"10078","DOI":"10.1073\/pnas.93.19.10078","volume":"93","author":"CY Huang","year":"1996","unstructured":"Huang CY, Ferrell JE Jr: Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 1996, 93: 10078-10083. 10.1073\/pnas.93.19.10078","journal-title":"Proc Natl Acad Sci U S A"},{"key":"914_CR66","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1016\/j.cell.2009.06.013","volume":"138","author":"W Ma","year":"2009","unstructured":"Ma W, Trusina A, El-Samad H, Lim WA, Tang C: Defining network topologies that can achieve biochemical adaptation. Cell 2009, 138: 760-773. 10.1016\/j.cell.2009.06.013","journal-title":"Cell"},{"key":"914_CR67","doi-asserted-by":"publisher","first-page":"ra40","DOI":"10.1126\/scisignal.2000350","volume":"2","author":"SS Huang","year":"2009","unstructured":"Huang SS, Fraenkel E: Integrating proteomic, transcriptional, and interactome data reveals hidden components of signaling and regulatory networks. Sci Signal 2009, 2: ra40. 10.1126\/scisignal.2000350","journal-title":"Sci Signal"},{"key":"914_CR68","doi-asserted-by":"publisher","first-page":"R7","DOI":"10.1186\/gb-2003-4-1-r7","volume":"4","author":"SW Doniger","year":"2003","unstructured":"Doniger SW, Salomonis N, Dahlquist KD, Vranizan K, Lawlor SC, Conklin BR: MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol 2003, 4: R7. 10.1186\/gb-2003-4-1-r7","journal-title":"Genome Biol"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-6-29.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T19:33:39Z","timestamp":1630524819000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-6-29"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,1]]},"references-count":68,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["914"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-6-29","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,1]]},"assertion":[{"value":"8 December 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"29"}}