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. 2015 Nov 27;11(11):843.
doi: 10.15252/msb.20156642.

Signaling Output: It's All About Timing and Feedbacks

Free PMC article

Signaling Output: It's All About Timing and Feedbacks

Nils Blüthgen. Mol Syst Biol. .
Free PMC article


The central questions in understanding signaling pathway specificity are how these pathways encode which stimulus is present and how this stimulus is decoded to yield the correct cell fate decision. In their recent work, Ryu et al (2015) show by stimulation experiments with different ligands how the differential engagement of feedback and feed-forward regulation leads to different dynamics of pathway activity, which in turn alters cell fate.Moreover, they show that by considering the timescales of the feedback regulations,the different cellular responses can be triggered with pulsed stimulations by a single ligand.


Figure 1
Figure 1. Response and wiring of the EGF/NGF network
(A) When PC‐12 cells are stimulated with NGF, cells show long ERK activity and differentiate. When they are stimulated with EGF, they show a short peak of ERK activity and proliferate. (B) Stimulation of PC‐12 cells with short pulses (3 min) with low EGF concentration results in prolonged ERK activity, similar to NGF treatment, and subsequent differentiation. Pulses with higher EGF concentration lead to a short response, followed by proliferation. (C) The proposed network topology includes an EGF‐dependent negative feedback, an NGF‐dependent positive feedback, intertwined with stimulus‐dependent feed‐forward loops (FFL). Long‐term desensitization occurs via transcriptional induction of phosphatases (DUSP proteins).

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