The plasticity of TGF-beta signaling

TL;DR

This study investigates how the TGF-beta signaling network can produce different response types, such as transient, sustained, or oscillatory, based on various kinetic parameters and protein concentrations, revealing its inherent plasticity.

Contribution

It identifies key parameter modifications that switch TGF-beta signaling responses, highlighting the pathway's architectural basis for signaling plasticity.

Findings

Negative feedback and fast nuclear shuttling favor transient responses

Weak ligand-receptor binding and rapid I-Smad turnover cause oscillations

Low receptor activation and affinity enable proportional responses

Abstract

The family of TGFb ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGFb ligands eliciting both sustained or transient responses. Members of the TGFb family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGFb signaling network. To define the key aspects for signaling plasticity we focused on the core of the TGFb signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The architecture of the TGFb pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGFb ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways.