Gene network dynamics controlling keratinocyte migration.
Translation of large-scale data into a coherent model that allows one to simulate, predict and control cellular behavior is far from being resolved. Assuming that long-term cellular behavior is reflected in the gene expression kinetics, we infer a dynamic gene regulatory network from time-series measurements of DNA microarray data of hepatocyte growth factor-induced migration of primary human keratinocytes. Transferring the obtained interactions to the level of signaling pathways, we predict in silico and verify in vitro the necessary and sufficient time-ordered events that control migration. We show that pulse-like activation of the proto-oncogene receptor Met triggers a responsive state, whereas time sequential activation of EGF-R is required to initiate and maintain migration. Context information for enhancing, delaying or stopping migration is provided by the activity of the protein kinase A signaling pathway. Our study reveals the complex orchestration of multiple pathways controlling cell migration.
Busch
Hauke
H
B080 Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Camacho-Trullio
David
D
Rogon
Zbigniew
Z
Breuhahn
Kai
K
Angel
Peter
P
Eils
Roland
R
Szabowski
Axel
A
D002465:Cell Movement / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met