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 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.Availability: The network file for analysis with the R BoolNet library is available in the Supplementary Information.Contact: melanie.boerries@frias.uni-freiburg.de or hauke.busch@frias.uni-freiburg.deSupplementary information: Supplementary data are available at Bioinformatics online.
Highlights
Cell migration and wound healing are complex cellular processes that involve keratinocytes, fibroblasts, blood vessels and inflammatory cells (Xue et al, 2007)
Model simulations highlight for the first time the necessity of a temporal sequence of initial, transient MET 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 developed a Boolean network model of the combined mitogen-activated protein kinase (MAPK) signalling pathways, gene regulation and autocrine feedback, which links known interactions of downstream protein and gene targets of MET with subsequent changes in the cellular homeostasis
Summary
Cell migration and wound healing are complex cellular processes that involve keratinocytes, fibroblasts, blood vessels and inflammatory cells (Xue et al, 2007). In its aberrant form, it can lead to scar formation (Heng, 2011) and has critical implications to cancer metastasis formation (Schäfer and Werner, 2008) Different growth factors such as hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), keratinocyte growth factor (KGF) and fibroblast growth factor (FGF) that activate and regulate cell migration have been extensively studied in many cell types (Birchmeier et al, 2003; Hudson and McCawley, 1998; Jaakkola et al, 1998; Pastore et al, 2008; Tsuboi et al, 1993). These growth factors have been found to overlap with mitogen-activated protein kinase (MAPK) pathways (Cho and Klemke, 2000; Kain and Klemke, 2001; Klemke et al, 1997)
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