{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T02:14:38Z","timestamp":1767665678911},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: The modularity of biochemical networks in general, and signaling networks in particular, has been extensively studied over the past few years. It has been proposed to be a useful property to analyze signaling networks: by decomposing the network into subsystems, more manageable units are obtained that are easier to analyze. While many powerful algorithms are available to identify modules in protein interaction networks, less attention has been paid to signaling networks defined as chemical systems. Such a decomposition would be very useful as most quantitative models are defined using the latter, more detailed formalism.<\/jats:p>\n               <jats:p>Results: Here, we introduce a novel method to decompose biochemical networks into modules so that the bidirectional (retroactive) couplings among the modules are minimized. Our approach adapts a method to detect community structures, and applies it to the so-called retroactivity matrix that characterizes the couplings of the network. Only the structure of the network, e.g. in SBML format, is required. Furthermore, the modularized models can be loaded into ProMoT, a modeling tool which supports modular modeling. This allows visualization of the models, exploiting their modularity and easy generation of models of one or several modules for further analysis. The method is applied to several relevant cases, including an entangled model of the EGF-induced MAPK cascade and a comprehensive model of EGF signaling, demonstrating its ability to uncover meaningful modules. Our approach can thus help to analyze large networks, especially when little a priori knowledge on the structure of the network is available.<\/jats:p>\n               <jats:p>Availability: The decomposition algorithms implemented in MATLAB (Mathworks, Inc.) are freely available upon request. ProMoT is freely available at http:\/\/www.mpi-magdeburg.mpg.de\/projects\/promot<\/jats:p>\n               <jats:p>Contact: \u00a0gayers@mpi-magdeburg.mpg.de<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btn289","type":"journal-article","created":{"date-parts":[[2008,8,9]],"date-time":"2008-08-09T13:08:02Z","timestamp":1218287282000},"page":"i213-i219","source":"Crossref","is-referenced-by-count":33,"title":["Automatic decomposition of kinetic models of signaling networks minimizing the retroactivity among modules"],"prefix":"10.1093","volume":"24","author":[{"given":"Julio","family":"Saez-Rodriguez","sequence":"first","affiliation":[{"name":"Max-Planck-Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany"}]},{"given":"Stefan","family":"Gayer","sequence":"additional","affiliation":[{"name":"Max-Planck-Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany"}]},{"given":"Martin","family":"Ginkel","sequence":"additional","affiliation":[{"name":"Max-Planck-Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany"}]},{"given":"Ernst Dieter","family":"Gilles","sequence":"additional","affiliation":[{"name":"Max-Planck-Institute for Dynamics of Complex Technical Systems, Sandtorstr. 1, 39106 Magdeburg, Germany"}]}],"member":"286","published-online":{"date-parts":[[2008,8,9]]},"reference":[{"key":"2023020210501639000_B1","article-title":"An Introduction to Systems Biology","volume-title":"Design Principles of Biological Circuits.","author":"Alon","year":"2007"},{"key":"2023020210501639000_B2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/3-540-45848-4_54","article-title":"Pajek - analysis and visualization of large networks","volume":"2265","author":"Batagelj","year":"2002","journal-title":"Lect. Notes Comput. Sci"},{"key":"2023020210501639000_B3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0014-5793(00)02037-8","article-title":"Diferential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cell","volume":"482","author":"Brightman","year":"2000","journal-title":"FEBS Lett"},{"key":"2023020210501639000_B4","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1093\/bioinformatics\/btl370","article-title":"Detecting functional modules in the yeast protein-protein interaction network","volume":"22","author":"Chen","year":"2006","journal-title":"Bioinformatics"},{"key":"2023020210501639000_B5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/msb4100204","article-title":"Modular cell biology: retroactivity and insulation","volume":"4","author":"Del Vecchio","year":"2008","journal-title":"Mol. Sys. Biol"},{"key":"2023020210501639000_B6","doi-asserted-by":"crossref","first-page":"027104","DOI":"10.1103\/PhysRevE.72.027104","article-title":"Community detection in complex networks using extremal optimization","volume":"72","author":"Duch","year":"2005","journal-title":"Phys. Rev. E"},{"key":"2023020210501639000_B7","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1177\/0037549703040940","article-title":"An approach for dividing models of biological reaction networks into functional units","volume":"79","author":"Ederer","year":"2003","journal-title":"Simulation"},{"key":"2023020210501639000_B8","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0006-3495(03)74450-6","article-title":"The convex basis of the left null space of the stoichiometric matrix leads to the definition of metabolically meaningful pools","volume":"85","author":"Famili","year":"2003","journal-title":"Biophys. J"},{"key":"2023020210501639000_B9","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/(SICI)1521-4125(199802)21:2<211::AID-CEAT121>3.0.CO;2-U","article-title":"Network theory for chemical processes","volume":"21","author":"Gilles","year":"1998","journal-title":"Chem. Eng. Technol"},{"key":"2023020210501639000_B10","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/bioinformatics\/btg128","article-title":"Modular modeling of cellular systems with ProMoT\/Diva","volume":"19","author":"Ginkel","year":"2003","journal-title":"Bioinformatics"},{"key":"2023020210501639000_B11","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/nature03288","article-title":"Functional cartography of complex metabolic networks","volume":"433","author":"Guimera","year":"2005","journal-title":"Nature"},{"key":"2023020210501639000_B12","doi-asserted-by":"crossref","first-page":"C47","DOI":"10.1038\/35011540","article-title":"From molecular to modular cell biology","volume":"402","author":"Hartwell","year":"1999","journal-title":"Nature"},{"key":"2023020210501639000_B13","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4613-1161-4","volume-title":"The Regulation of Cellular Systems.","author":"Heinrich","year":"1996"},{"key":"2023020210501639000_B14","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1093\/bioinformatics\/btg015","article-title":"The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models","volume":"19","author":"Hucka","year":"2003","journal-title":"Bioinformatics"},{"key":"2023020210501639000_B15","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/1471-2164-7-108","article-title":"Network motifs: structure does not determine function","volume":"7","author":"Ingram","year":"2006","journal-title":"BMC Genomics"},{"key":"2023020210501639000_B16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/35075138","article-title":"Lethality and centrality in protein networks","volume":"411","author":"Jeong","year":"2001","journal-title":"Nature"},{"key":"2023020210501639000_B17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0022-5193(05)80426-6","article-title":"Control theory of regulatory cascades","volume":"153","author":"Kahn","year":"1991","journal-title":"J. Theor. Biol"},{"key":"2023020210501639000_B18","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/S0014-5793(97)01018-1","article-title":"Quantification of information transfer via cellular signal transduction pathways","volume":"414","author":"Kholodenko","year":"1997","journal-title":"FEBS Lett"},{"key":"2023020210501639000_B19","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1073\/pnas.97.10.5031","article-title":"Cell signaling pathways as control modules: complexity for simplicity?","volume":"97","author":"Lauffenburger","year":"2000","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210501639000_B20","doi-asserted-by":"crossref","first-page":"D689","DOI":"10.1093\/nar\/gkj092","article-title":"BioModels Database: a free, centralized database of curated, published, quantitative kinetic models of biochemical and cellular systems","volume":"34","author":"Le Novre","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2023020210501639000_B21","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1126\/science.298.5594.824","article-title":"Network motifs: Simple building blocks of complex networks","volume":"298","author":"Milo","year":"2002","journal-title":"Science"},{"key":"2023020210501639000_B22","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1073\/pnas.0601602103","article-title":"Modularity and community structure in networks","volume":"103","author":"Newman","year":"2006","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210501639000_B23","doi-asserted-by":"crossref","first-page":"026113","DOI":"10.1103\/PhysRevE.69.026113","article-title":"Finding and evaluating community structure in networks","volume":"69","author":"Newman","year":"2004","journal-title":"Phys. Rev. E Stat. Nonlin. Soft. Matter Phys"},{"key":"2023020210501639000_B24","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1039\/b702142a","article-title":"Deduction of intracellular sub-systems from a topological description of the network","volume":"3","author":"Nordling","year":"2007","journal-title":"Mol. Biosyst"},{"key":"2023020210501639000_B25","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/msb4100014","article-title":"Acomprehensive pathway map of epidermal growth factor receptor signaling","volume":"1","author":"Oda","year":"2005","journal-title":"Mol. Syst. Biol"},{"key":"2023020210501639000_B26","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1126\/science.1073374","article-title":"Hierarchical organization of modularity in metabolic networks","volume":"297","author":"Ravasz","year":"2002","journal-title":"Science"},{"key":"2023020210501639000_B27","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1073\/pnas.0237338100","article-title":"Modular organization of cellular networks","volume":"100","author":"Rives","year":"2003","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023020210501639000_B28","doi-asserted-by":"crossref","first-page":"6423","DOI":"10.1111\/j.1742-4658.2005.05041.x","article-title":"Topology, tinkering and evolution of the human transcription factor network","volume":"272","author":"Rodriguez-Caso","year":"2005","journal-title":"FEBS J"},{"key":"2023020210501639000_B29","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.compchemeng.2004.08.035","article-title":"Dissecting the puzzle of life: modularization of signal transduction networks","volume":"29","author":"Saez-Rodriguez","year":"2005","journal-title":"Comput. Chem. Eng"},{"key":"2023020210501639000_B30","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/msb.2008.3","article-title":"Modularity defined","volume":"4","author":"Sauro","year":"2008","journal-title":"Mol. Syst. Biol"},{"key":"2023020210501639000_B31","first-page":"5","article-title":"Quantitative analysis of signaling networks Prog. Biophys","volume":"86","author":"Sauro","year":"2004","journal-title":"Mol. Biol"},{"key":"2023020210501639000_B32","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nbt0402-370","article-title":"Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors","volume":"20","author":"Schoeberl","year":"2002","journal-title":"Nat. Biotechnol"},{"key":"2023020210501639000_B33","article-title":"Mathematical Control Theory","author":"Sontag","year":"1998","edition":"2nd ed"},{"key":"2023020210501639000_B34","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1369-5274(03)00033-X","article-title":"Motifs, modules and games in bacteria","volume":"6","author":"Wolf","year":"2003","journal-title":"Curr. Opin. Microbiol"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/16\/i213\/49053075\/bioinformatics_24_16_i213.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/24\/16\/i213\/49053075\/bioinformatics_24_16_i213.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T12:49:18Z","timestamp":1675342158000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/24\/16\/i213\/200813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,8,9]]},"references-count":34,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2008,8,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btn289","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,8,15]]},"published":{"date-parts":[[2008,8,9]]}}}