{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:33:32Z","timestamp":1772138012938,"version":"3.50.1"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T00:00:00Z","timestamp":1617926400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medicines Initiative Joint Undertaking","award":["115446"],"award-info":[{"award-number":["115446"]}]},{"name":"European Union\u2019s Seventh Framework Programme","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R35GM119771"],"award-info":[{"award-number":["5R35GM119771"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Detailed maps of the molecular basis of the disease are powerful tools for interpreting data and building predictive models. Modularity and composability are considered necessary network features for large-scale collaborative efforts to build comprehensive molecular descriptions of disease mechanisms. An effective way to create and manage large systems is to compose multiple subsystems. Composable network components could effectively harness the contributions of many individuals and enable teams to seamlessly assemble many individual components into comprehensive maps. We examine manually built versions of the RAS\u2013RAF\u2013MEK\u2013ERK cascade from the Atlas of Cancer Signalling Network, PANTHER and Reactome databases and review them in terms of their reusability and composability for assembling new disease models. We identify design principles for managing complex systems that could make it easier for investigators to share and reuse network components. We demonstrate the main challenges including incompatible levels of detail and ambiguous representation of complexes and highlight the need to address these challenges.<\/jats:p>","DOI":"10.1093\/bib\/bbab103","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T23:12:35Z","timestamp":1615504355000},"source":"Crossref","is-referenced-by-count":3,"title":["Reusability and composability in process description maps: RAS\u2013RAF\u2013MEK\u2013ERK signalling"],"prefix":"10.1093","volume":"22","author":[{"given":"Alexander","family":"Mazein","sequence":"first","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg"},{"name":"European Institute for Systems Biology and Medicine, CIRI UMR5308, CNRS-ENS-UCBL-INSERM, Universit\u00e9 de Lyon, 50 Avenue Tony Garnier, 69007 Lyon, France"}]},{"given":"Adrien","family":"Rougny","sequence":"additional","affiliation":[{"name":"Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Aomi, Tokyo, Japan"},{"name":"Com. Bio Big Data Open Innovation Lab. (CBBD-OIL), AIST, Aomi, Tokyo, Japan"}]},{"given":"Jonathan R","family":"Karr","sequence":"additional","affiliation":[{"name":"Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA"}]},{"given":"Julio","family":"Saez-Rodriguez","sequence":"additional","affiliation":[{"name":"Joint Research Centre for Computational Biomedicine (JRC-COMBINE), RWTH Aachen University, Faculty of Medicine, 52074 Aachen, Germany"},{"name":"Institute for Computational Biomedicine, Heidelberg University Hospital and Heidelberg University, Faculty of Medicine, Bioquant Heidelberg, Heidelberg 69120, Germany"}]},{"given":"Marek","family":"Ostaszewski","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg"}]},{"given":"Reinhard","family":"Schneider","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg"}]}],"member":"286","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"key":"2021090815023133400_ref1","doi-asserted-by":"crossref","DOI":"10.1038\/s41540-018-0059-y","article-title":"Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms","volume":"4","author":"Mazein","year":"2018","journal-title":"Npj Syst Biol Appl"},{"key":"2021090815023133400_ref2","doi-asserted-by":"crossref","DOI":"10.1093\/bib\/bby024","article-title":"Community-driven roadmap for integrated disease maps","volume":"20","author":"Ostaszewski","year":"2019","journal-title":"Brief Bioinform"},{"key":"2021090815023133400_ref3","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1093\/bib\/bby031","article-title":"Application of Atlas of Cancer Signalling Network in preclinical studies","volume":"20","author":"Monraz Gomez","year":"2019","journal-title":"Brief Bioinform"},{"key":"2021090815023133400_ref4","article-title":"Comprehensive map of the regulated cell death signaling network: a powerful analytical tool for studying diseases","volume":"12","author":"Ravel","year":"2020","journal-title":"Cancer"},{"key":"2021090815023133400_ref5","article-title":"Drug-driven synthetic lethality: bypassing tumor cell genetics with a combination of AsiDNA and PARP inhibitors","volume":"23","author":"Jdey","year":"2016","journal-title":"Clin Cancer Res Off J Am Assoc Cancer Res"},{"key":"2021090815023133400_ref6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1093\/mutage\/geu078","article-title":"The shortest path is not the one you know: application of biological network resources in precision oncology research","volume":"30","author":"Kuperstein","year":"2015","journal-title":"Mutagenesis"},{"key":"2021090815023133400_ref7","doi-asserted-by":"crossref","first-page":"5005","DOI":"10.1038\/ncomms6005","article-title":"Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut","volume":"5","author":"Chanrion","year":"2014","journal-title":"Nat Commun"},{"key":"2021090815023133400_ref8","doi-asserted-by":"crossref","first-page":"6817","DOI":"10.1113\/JP272633","article-title":"Modular modelling with Physiome standards","volume":"594","author":"Cooling","year":"2016","journal-title":"J Physiol"},{"key":"2021090815023133400_ref9","first-page":"136","article-title":"COVID-19 disease map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms. Sci","volume":"7","author":"Ostaszewski","year":"2020","journal-title":"Data"},{"key":"2021090815023133400_ref10","article-title":"Targeting aberrant RAS\/RAF\/MEK\/ERK signaling for cancer therapy","volume":"9","author":"Degirmenci","year":"2020","journal-title":"Cell"},{"key":"2021090815023133400_ref11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1158\/2159-8290.CD-18-1321","article-title":"Targeting alterations in the RAF\u2013MEK pathway","volume":"9","author":"Yaeger","year":"2019","journal-title":"Cancer Discov"},{"key":"2021090815023133400_ref12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J Hematol Oncol J Hematol Oncol"},{"key":"2021090815023133400_ref13","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis","volume":"19","author":"Guo","year":"2020","journal-title":"Exp Ther Med"},{"key":"2021090815023133400_ref14","article-title":"Divergent dynamics and functions of ERK MAP kinase signaling in development, homeostasis and cancer: lessons from fluorescent bioimaging","volume":"11","author":"Muta","year":"2019","journal-title":"Cancer"},{"key":"2021090815023133400_ref15","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.1007\/s00018-016-2297-8","article-title":"Negative feedback regulation of the ERK1\/2 MAPK pathway","volume":"73","author":"Lake","year":"2016","journal-title":"Cell Mol Life Sci CMLS"},{"key":"2021090815023133400_ref16","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nrm3048","article-title":"Feedback regulation of EGFR signalling: decision making by early and delayed loops","volume":"12","author":"Avraham","year":"2011","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2021090815023133400_ref17","doi-asserted-by":"crossref","DOI":"10.1515\/jib-2019-0022","article-title":"Systems biology graphical notation: process description language level 1 version 2.0","volume":"16","author":"Rougny","year":"2019","journal-title":"J Integr Bioinform"},{"key":"2021090815023133400_ref18","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nbt.1558","article-title":"The systems biology graphical notation","volume":"27","author":"Le Nov\u00e8re","year":"2009","journal-title":"Nat Biotechnol"},{"key":"2021090815023133400_ref19","doi-asserted-by":"crossref","first-page":"e160","DOI":"10.1038\/oncsis.2015.19","article-title":"Atlas of Cancer Signalling Network: a systems biology resource for integrative analysis of cancer data with Google Maps","volume":"4","author":"Kuperstein","year":"2015","journal-title":"Oncogene"},{"key":"2021090815023133400_ref20","doi-asserted-by":"crossref","first-page":"D419","DOI":"10.1093\/nar\/gky1038","article-title":"PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools","volume":"47","author":"Mi","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2021090815023133400_ref21","first-page":"D498","article-title":"The reactome pathway knowledgebase","volume":"48","author":"Jassal","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2021090815023133400_ref22","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1005968","article-title":"Reactome graph database: efficient access to complex pathway data","volume":"14","author":"Fabregat","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"2021090815023133400_ref23","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.devcel.2004.05.019","article-title":"Sef is a spatial regulator for Ras\/MAP kinase signaling","volume":"7","author":"Torii","year":"2004","journal-title":"Dev Cell"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/5\/bbab103\/40261243\/bbab103.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/5\/bbab103\/40261243\/bbab103.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T11:17:37Z","timestamp":1631099857000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbab103\/6217719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,8]]},"references-count":23,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,9,2]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbab103","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.12.08.416719","asserted-by":"object"}]},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9]]},"published":{"date-parts":[[2021,4,8]]},"article-number":"bbab103"}}