{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:28:31Z","timestamp":1761611311838},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"18","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":1490,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Cell migration is a complex process that is controlled through the time-sequential feedback regulation of protein signalling and gene regulation. Based on prior knowledge and own experimental data, we developed a large-scale dynamic network describing the onset and maintenance of hepatocyte growth factor-induced migration of primary human keratinocytes. We applied Boolean logic to capture the qualitative behaviour as well as short-and long-term dynamics of the complex signalling network involved in this process, comprising protein signalling, gene regulation and autocrine feedback.<\/jats:p>\n               <jats:p>Results: A Boolean model has been compiled from time-resolved transcriptome data and literature mining, incorporating the main pathways involved in migration from initial stimulation to phenotype progress. Steady-state analysis under different inhibition and stimulation conditions of known key molecules reproduces existing data and predicts novel interactions based on our own experiments. Model simulations highlight for the first time the necessity of a temporal sequence of initial, transient MET receptor (met proto-oncogene, hepatocyte growth factor receptor) and subsequent, continuous epidermal growth factor\/integrin signalling to trigger and sustain migration by autocrine signalling that is integrated through the Focal adhesion kinase protein. We predicted in silico and verified in vitro that long-term cell migration is stopped if any of the two feedback loops are inhibited.<\/jats:p>\n               <jats:p>Availability: The network file for analysis with the R BoolNet library is available in the Supplementary Information.<\/jats:p>\n               <jats:p>Contact: \u00a0melanie.boerries@frias.uni-freiburg.de or hauke.busch@frias.uni-freiburg.de<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/bts410","type":"journal-article","created":{"date-parts":[[2012,9,7]],"date-time":"2012-09-07T20:35:22Z","timestamp":1347050122000},"page":"i495-i501","source":"Crossref","is-referenced-by-count":46,"title":["Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration"],"prefix":"10.1093","volume":"28","author":[{"given":"Amit","family":"Singh","sequence":"first","affiliation":[{"name":"1 Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19"},{"name":"2 Center for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Habsburger Strasse 49, 79104 Freiburg, Germany"}]},{"given":"Juliana M.","family":"Nascimento","sequence":"additional","affiliation":[{"name":"1 Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19"},{"name":"2 Center for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Habsburger Strasse 49, 79104 Freiburg, Germany"}]},{"given":"Silke","family":"Kowar","sequence":"additional","affiliation":[{"name":"1 Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19"},{"name":"2 Center for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Habsburger Strasse 49, 79104 Freiburg, Germany"}]},{"given":"Hauke","family":"Busch","sequence":"additional","affiliation":[{"name":"1 Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19"},{"name":"2 Center for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Habsburger Strasse 49, 79104 Freiburg, Germany"}]},{"given":"Melanie","family":"Boerries","sequence":"additional","affiliation":[{"name":"1 Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19"},{"name":"2 Center for Biological Systems Analysis, Albert-Ludwigs-University of Freiburg, Habsburger Strasse 49, 79104 Freiburg, Germany"}]}],"member":"286","published-online":{"date-parts":[[2012,9,3]]},"reference":[{"key":"2023012513052180900_B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-5193(03)00035-3","article-title":"The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in drosophila melanogaster","volume":"223","author":"Albert","year":"2003","journal-title":"J. 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Cell."},{"key":"2023012513052180900_B23","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.biosystems.2005.10.004","article-title":"A network model for the control of the differentiation process in th cells","volume":"84","author":"Mendoza","year":"2006","journal-title":"Biosystems"},{"key":"2023012513052180900_B24","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1093\/bioinformatics\/15.7.593","article-title":"Genetic control of flower morphogenesis in Arabidopsis thaliana: a logical analysis","volume":"15","author":"Mendoza","year":"1999","journal-title":"Bioinformatics"},{"key":"2023012513052180900_B25","doi-asserted-by":"crossref","first-page":"ra36","DOI":"10.1126\/scisignal.2001325","article-title":"Integration of activating and inhibitory receptor signaling by regulated phosphorylation of vav1 in immune cells","volume":"4","author":"Mesecke","year":"2011","journal-title":"Sci. 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