Gene network dynamics controlling keratinocyte migration

Abstract

Abstract 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.

Keywords

• cell‐cell communication
• cell migration
• gene network dynamics
• inverse modeling
• slavingprinciple