Expression of excess receptors and negative feedback control of signal pathways are required for rapid activation and prompt cessation of signal transduction

Hiroshi Kobayashi,Ryuzo Azuma,Takuo Yasunaga

doi:10.1186/1478-811x-7-3

Abstract

BackgroundCellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. Receptors are often expressed in excess, and cells are activated when a small number of receptors bind ligands. Intracellular signal proteins are activated at a high level soon after ligand binding, and the activation level decreases in a negative feedback manner without ligand clearance. Why are excess receptors required? What is the physiological significance of the negative feedback regulation?ResultsTo answer these questions, we developed a Monte Carlo simulation program to kinetically analyze signal pathways using the model in which ligands are bound to receptors and then membrane complexes with other membrane proteins are formed. Our simulation results showed that excess receptors are not required for cell activation when the dissociation constant (Kd) of the ligand-receptor complex is 10-10 M or less. However, such low Kd values cause delayed signal shutdown after ligand clearance from the extracellular space. In contrast, when the Kd was 10-8 M and the ligand level was less than 1 μM, excess receptors were required for prompt signal propagation and rapid signal cessation after ligand clearance. An initial increase in active cytosolic signal proteins to a high level is required for rapid activation of cellular signal pathways, and a low level of active signal proteins is essential for the rapid shutdown of signal pathways after ligand clearance.ConclusionThe present kinetic analysis revealed that excess receptors and negative feedback regulation promote activation and cessation of signal transduction with a low amount of extracellular ligand.

Highlights

Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors
It is generally accepted that the binding of extracellular ligands to membrane receptors initiates the phosphorylation of signal proteins in a stepwise manner
We considered a signal pathway consisting of 5 signal proteins, B to F, all of which were subjected to the same reaction as described above

Summary

Introduction

Cellular signal transduction is initiated by the binding of extracellular ligands to membrane receptors. It is generally accepted that the binding of extracellular ligands to membrane receptors initiates the phosphorylation of signal proteins in a stepwise manner. Many studies have suggested that the majority of signal proteins are phosphorylated immediately after the binding of a ligand to its receptor, after which the level of signal protein decreases [2,3,4,5,6,7] To explain this change, it has been hypothesized that the inactivation of signal proteins is regulated in a negative feedback manner by the active form of the signal protein of a late reaction step, thereby decreasing the levels of active proteins [8,9,10]. It remains unclear why this kind of negative feedback regulation is required

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Results

Conclusion