Development and Analysis of a Quantitative Mathematical Model of Bistability in the Cross Repression System Between APT and SLBO Within the JAK/STAT Signaling Pathway

Abstract

Cell migration is a key component in development, homeostasis, immune function, and pathology. It is important to understand the molecular activity that allows some cells to migrate. Drosophila melanogaster is a useful model system because its genes are largely conserved with humans and it is straightforward to study biologically. The well-conserved transcriptional regulator Signal Transducer and Activator of Transcription (STAT) promotes cell migration, but its signaling is modulated by downstream targets Apontic (APT) and Slow Border Cells (SLBO). Inhibition of STAT activity by APT and cross-repression of APT and SLBO determines whether an epithelial cell in the Drosophila egg chamber becomes motile or remains stationary. Through mathematical modeling and analysis, we examine how the interaction of STAT, APT, and SLBO creates bistability in the Janus Kinase (JAK)/STAT signaling pathway. In this paper, we update and analyze earlier models to represent mechanistically the processes of the JAK/STAT pathway. We utilize parameter, bifurcation, and phase portrait analyses, and make reductions to the system to produce a minimal three-variable quantitative model. We analyze the manifold between migratory and stationary steady states in this minimal model and show that when the initial conditions of our model are near this manifold, cell migration can be delayed.