title: Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  BACKGROUND
  The network file for analysis with the R BoolNet library is available in the Supplementary Information.
  
  
  BACKGROUND
  melanie.boerries@frias.uni-freiburg.de or hauke.busch@frias.uni-freiburg.de
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Freiburg Institute for Advanced Studies, LifeNet, Albert-Ludwigs-University of Freiburg, Albertstrasse 19, Freiburg, Germany.
authors.forename: Amit
authors.initials: A
authors.lastname: Singh
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Nascimento
authors.forename: Silke
authors.initials: S
authors.lastname: Kowar
authors.forename: Hauke
authors.initials: H
authors.lastname: Busch
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
mesh_terms: D019898:Autocrine Communication; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met