Properties of cell signaling pathways and gene expression systems operating far from steady-state

Juan Pablo Di-Bella,Alejandra C Ventura,Alejandro Colman-Lerner

doi:10.1038/s41598-018-34766-0

Abstract

Ligand-receptor systems, covalent modification cycles, and transcriptional networks are basic units of signaling systems and their steady-state properties are well understood. However, the behavior of such systems before steady-state is poorly characterized. Here, we analyzed the properties of input-output curves for each of these systems as they approach steady-state. In ligand-receptor systems, the EC50 (concentration of the ligand that occupies 50% of the receptors) is higher before the system reaches steady-state. Based on this behavior, we have previously defined PRESS (for pre-equilibrium sensing and signaling), a general “systems level” mechanism cells may use to overcome input saturation. Originally, we showed that, given a step stimulation, PRESS operates when the kinetics of ligand-receptor binding are slower than the downstream signaling steps. Now, we show that, provided the input increases slowly, it is not essential for the ligand binding reaction itself to be slow. In addition, we demonstrate that covalent modification cycles and gene expression systems may also operate in PRESS mode. Thus, nearly all biochemical processes may operate in PRESS mode, suggesting that this mechanism may be ubiquitous in cell signaling systems.

Highlights

Cells detect input signaling molecules using receptors, proteins usually located on the cell surface embedded in the plasma membrane
With a time-scale compatible with acting before the ligand:receptor binding process achieves equilibrium, this signaling component will use the information contained in the pre-steady-state binding curve, and produce an output with an EC50 shifted to the high ligand concentration region
We studied the system in these two extreme regimes, for the case in which the input x increases fast relative to the timescale of the covalent modification cycle, and it is essentially a step given by x(tn) = xmax; and the case in which it is slow compared with the cycle

Summary

Introduction

Cells detect input signaling molecules using receptors, proteins usually located on the cell surface embedded in the plasma membrane. Note that a shift in the binding curve over time implies that a ligand-receptor system is sensitive (i.e., a change in the input concentration elicits a change in the output) in different regions of ligand concentration at different times before steady-state[4] Based on this property, we observed that when the ligand-receptor complex activates a downstream signaling component www.nature.com/scientificreports/. With a time-scale compatible with acting before the ligand:receptor binding process achieves equilibrium, this signaling component will use the information contained in the pre-steady-state binding curve, and produce an output with an EC50 shifted to the high ligand concentration region. Such a system provides distinguishable responses to ligand concentrations that saturate the receptors at steady-state. We show that by introducing dynamics to the input it is possible to extend PRESS to fast signaling components, effectively extending this property to most signaling motifs and parameter sets

Methods

Results

Conclusion