Identification of the network signature that characterizes critical information processing in a biomolecular regulatory network for cell migration

Abstract

Biomolecular regulatory networks such as gene regulatory networks, protein interaction networks, sig-naling networks and metabolic networks involve many biomolecules which are complexly interconnected to each other, giving rise to complicated cellular dynamics and emergent properties. Hence, it is often too diffi-cult to decipher the underlying regula tory mechanisms, and to identify key regulatory components or network signature that characterizes critical information processing embedded in the complex network, just by using traditional biochemical experiments. Computational analysis based on mathematical models enables us to efficiently conduct many in silico virtual experiments that would be very expensive, time-consuming or often unfeasible due to the lack of antibodies, biosensors, etc. In this study, systems biological analysis is carried out by combining mathematical modeling and experimental validations of the simulation-derived hypotheses with an example of a signaling network involved in cell migration. Cell migration is a complex cell-type dependent process which is strictly confined to the developmen-tal phase for most cell types. Cancer cells, however, often escape from this stringent control of migration, and metastasize causing most cancer deaths. Accumulating evidence has highlighted the importance of Rho-family GTPases for cell migration, but since Rho-family GTPases are parts of a highly-interconnected feedback net-work, it remains elusive what controls the dynamical behavior of the Rho-family GTPases during cell migra-tion. To address this question, the Rho-family GTPases signaling network involved in cell migration is recon-structed, and a Boolean network model is developed to analyze the emergent kinetic behavior that enables migration. Through extensive in silico simulations and experimental validations, the results showed that cycli-cal bursts of RhoA and/or Rac activities are essential for cell migration, and that the negative feedbacks com-posed of Src, FAK and/or CSK are the critical driving source of cyclical RhoA/Rac activity. Furthermore, the results suggest that CSK inhibition can be an effective intervention strategy for interfering with cancer cell migration. Thus, this study provides new insights into the mechanisms that regulate the intricate activation dynamics of Rho-family GTPases required for cell migration, revealing potential new targets for interfering with cancer cell migration and invasion.