A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems

JUAN IGNACIO MARRONE; JACQUES-ALEXANDRE SEPULCHRE; ALEJANDRA C. VENTURA

Simposio; I Simposio de Modelado Multiescala para Biociencias y Nanomateriales en Argentina; 2022

We consider signaling components, like a double phosphorylation cycle, having the ability to display bistability. The existence of more than one steady state under particular biological conditions is strongly related to the existence of positive feedback loops. If these components are connected to other signaling elements, they very likely undergo some sort of protein-protein interaction. Many times, these interactions result in a non-explicit negative feedback effect, leading to interlinked positive and negative feedbacks. This combination was studied in the literature as a way to generate relaxation-type oscillations. Here we show that the two feedbacks together ensure two types of oscillations, the relaxation-type ones and a smoother type of oscillations functioning in a very narrow range of frequencies. Even more, we show that the two feedbacks are essential for both oscillatory types to emerge, and it is their hierarchy what determines the type of oscillation at work. We first study a double phosphorylation cycle with minimal additions that ensure sequestration. We identify two types of oscillatory behavior and a path in the parameter space connecting both of them, evidencing the change in feedback hierarchies. Then, we apply a similar study to the first part of the MAPK cascade, finding similar results. Finally, we evaluate the performance of a simplified model that deals with a different bistable module.