Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration

Amit Singh, Juliana M. Nascimento, Silke Kowar, Hauke Busch, Melanie Boerries*

*Corresponding author for this work

Abstract

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 factorinduced 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.

Original languageEnglish
Article numberbts410
JournalBioinformatics
Volume28
Issue number18
Pages (from-to)i495-i501
ISSN1367-4803
DOIs
Publication statusPublished - 09.2012

Research Areas and Centers

  • Research Area: Intelligent Systems

DFG Research Classification Scheme

  • 409-06 Information Systems, Process and Knowledge Management

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