Department of Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, MO, USA.
Department of Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, MO, USA.
J Theor Biol. 2019 Nov 7;480:34-42. doi: 10.1016/j.jtbi.2019.07.016. Epub 2019 Jul 30.
Fn14 is a transmembrane receptor protein belonging to the tumor necrosis factor receptor (TNFR) superfamily. Many experimental reports have shown that crosslinking of the receptor by its extracellular ligand TWEAK induces prolonged activation of transcription factor NF-κB. This behavior is distinct from TNF-α receptor, which is a more well-characterized member of the TNFR family. TNF-α receptor, despite sharing many similar molecular interactions with Fn14, only transiently activates NF-κB in response to TNF-α stimulation. Here, we investigate molecular mechanisms that enable Fn14 to display such distinctive behavior. In particular, we focus on two specific features of the Fn14 pathway that potentially give rise to a positive feedback regulation and differentiate it from the TNF-α receptor signaling. By developing a mechanistic model, we analyze how these features may determine the dynamics of an Fn14-NF-κB response. Our analysis reveals that stimulation of Fn14 by TWEAK may generate highly non-linear dynamics, including stable limit cycles and bistable responses. The type of response depends both on the strength and duration of a TWEAK signal. Our predictions and analyses also show that the molecular interactions underlying the positive feedback explain the prolonged activation of NF-κB under certain parameter regimes. In light of the model predictions, we propose possible deregulations of Fn14 leading to its overexpression in solid tumors and tissue injuries.
Fn14 是一种跨膜受体蛋白，属于肿瘤坏死因子受体 (TNFR) 超家族。许多实验报告表明，受体的细胞外配体 TWEAK 的交联诱导转录因子 NF-κB 的持久激活。这种行为与 TNF-α 受体不同，后者是 TNFR 家族中更为人熟知的成员。尽管 TNF-α 受体与 Fn14 具有许多相似的分子相互作用，但仅在 TNF-α 刺激下短暂激活 NF-κB。在这里，我们研究了使 Fn14 表现出这种独特行为的分子机制。特别是，我们专注于 Fn14 途径的两个特定特征，这些特征可能导致正反馈调节，并将其与 TNF-α 受体信号区分开来。通过开发一种机制模型，我们分析了这些特征如何决定 Fn14-NF-κB 反应的动力学。我们的分析表明，TWEAK 对 Fn14 的刺激可能会产生高度非线性动力学，包括稳定的极限环和双稳态响应。响应的类型取决于 TWEAK 信号的强度和持续时间。我们的预测和分析还表明，正反馈的分子相互作用解释了在某些参数范围内 NF-κB 的持久激活。根据模型预测，我们提出了 Fn14 过度表达的可能失调，导致实体瘤和组织损伤。
