(175ag) Analysis of Fn14--NF-?b Signaling Response Dynamics Using a Mechanistic Model

Fn14 is a transmembrane receptor protein belonging to the tumor necrosis factor receptor (TNFR) superfamily. Fn14 is activated by its cognate ligand TWEAK, a multifunctional cytokine. A trimeric form of TWEAK mediates crosslinking of Fn14 in the plasma membrane. The crosslinked receptor trimers activate multiple intracellular signaling pathways, including the canonical NF-κB cascade. An important feature of the Fn14 - NF-κB pathway is that its activation induces expression of the Fn14 gene, thus potentially giving rise to a positive feedback loop in the system. Another interesting feature is that Fn14 can self-assemble constitutively and form signaling-competent trimers even in the absence of TWEAK. Although key molecular players have been identified, the regulatory roles of these features in Fn14 signaling remain poorly understood. By developing a mechanistic model, this work interrogates potential roles of these features in determining the dynamics of Fn14 - NF-κB signaling. Our analysis reveals that these two features together generate distinct 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 model predictions and analysis of these responses explain potential molecular mechanisms whereby TWEAK stimulation can cause prolonged activation of NF-κB reported in the literature. Moreover, the model also sheds light on the mechanisms that may give rise to Fn14 overexpression in solid tumors and tissue injuries.