  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.
