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
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
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DOI：
10.3389/fphys.2020.00803
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发表时间：
2020-07-28
影响因子：
4
通讯作者：
Starz-Gaiano, Michelle
中科院分区：
文献类型：
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作者：
Berez, Alyssa;Peercy, Bradford E.;Starz-Gaiano, Michelle
细胞迁移是发育、稳态、免疫功能和病理学的关键组成部分。了解使某些细胞迁移的分子活性是很重要的。果蝇是一个有用的模型系统，因为它的基因在很大程度上与人类保守，并且很容易进行生物学研究。转录调节因子信号转导和转录激活因子（STAT）促进细胞迁移，但其信号转导受下游靶点无桥细胞（APT）和慢边界细胞（SLBO）的调节。APT对STAT活性的抑制以及APT和SLBO的交叉阻遏决定了果蝇卵室中的上皮细胞是能动的还是静止的。通过数学建模和分析，我们研究了STAT，APT和SLBO的相互作用如何在Janus激酶（JAK）/STAT信号通路中产生双稳态。在本文中，我们更新和分析早期的模型，代表机械的JAK/STAT途径的过程。我们利用参数，分叉，和相图分析，并减少系统产生一个最小的三变量定量模型。我们分析了在这个最小模型中迁移和静止稳定状态之间的流形，并表明当我们的模型的初始条件接近这个流形时，细胞迁移可以延迟。
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 melanogasteris 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 theDrosophilaegg 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.