A Minimal Model of Signaling Network Elucidates Cell-to-Cell Stochastic Variability in Apoptosis

TL;DR

This paper introduces a minimal stochastic signaling network model that captures key behaviors of apoptosis signaling, including cell-to-cell variability and response to stimuli, providing insights into the fundamental design principles of cell death pathways.

Contribution

The study presents a novel minimal model of apoptosis signaling that reproduces complex behaviors of real networks and elucidates the effect of apoptotic inhibitors in a cell-type independent manner.

Findings

The model exhibits deterministic rapid activation at high stimulus strength.

At low stimulus strength, stochastic variability dominates the response.

The model captures essential behaviors of complex apoptotic signaling networks.

Abstract

Signaling networks are designed to sense an environmental stimulus and adapt to it. We propose and study a minimal model of signaling network that can sense and respond to external stimuli of varying strength in an adaptive manner. The structure of this minimal network is derived based on some simple assumptions on its differential response to external stimuli. We employ stochastic differential equations and probability distributions obtained from stochastic simulations to characterize differential signaling response in our minimal network model. We show that the proposed minimal signaling network displays two distinct types of response as the strength of the stimulus is decreased. The signaling network has a deterministic part that undergoes rapid activation by a strong stimulus in which case cell-to-cell fluctuations can be ignored. As the strength of the stimulus decreases, the stochastic part of the network begins dominating the signaling response where slow activation is observed with characteristic large cell-to-cell stochastic variability. Interestingly, this proposed stochastic signaling network can capture some of the essential signaling behaviors of a complex apoptotic cell death signaling network that has been studied through experiments and large-scale computer simulations. Thus we claim that the proposed signaling network is an appropriate minimal model of apoptosis signaling. Elucidating the fundamental design principles of complex cellular signaling pathways such as apoptosis signaling remains a challenging task. We demonstrate how our proposed minimal model can help elucidate the effect of a specific apoptotic inhibitor Bcl-2 on apoptotic signaling in a cell-type independent manner. We also discuss the implications of our study in elucidating the adaptive strategy of cell death signaling pathways.