Data-driven modelling of receptor tyrosine kinase signalling networks quantifies receptor-specific potencies of PI3K- and Ras-dependent ERK activation

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Murat Cirit¹, Jason M Haugh

¹Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695-7905, USA.

The Biochemical Journal

|September 28, 2011

Abstract:

Signal transduction networks in mammalian cells, comprising a limited set of interacting biochemical pathways, are accessed by various growth factor and cytokine receptors to elicit distinct cell responses. This raises the question as to how specificity of the stimulus-response relationship is encoded at the molecular level. It has been proposed that specificity arises not only from the activation of unique signalling pathways, but also from quantitative differences in the activation and regulation of shared receptor-proximal signalling proteins. To address such hypotheses, data sets with greater precision and coverage of experimental conditions will need to be acquired, and rigorous frameworks that codify and parameterize the inherently non-linear relationships among signalling activities will need to be developed. In the present study we apply a systematic approach combining quantitative measurements and mathematical modelling to compare the signalling networks accessed by FGF (fibroblast growth factor) and PDGF (platelet-derived growth factor) receptors in mouse fibroblasts, in which the ERK (extracellular-signal-regulated kinase) cascade is activated by Ras- and PI3K (phosphoinositide 3-kinase)-dependent pathways. We show that, whereas the FGF stimulation of PI3K signalling is relatively weak, this deficiency is compensated for by a more potent Ras-dependent activation of ERK. Thus, as the modelling would predict, the ERK pathway is activated to a greater extent in cells co-stimulated with FGF and PDGF, relative to the saturated levels achieved with either ligand alone. It is envisaged that similar approaches will prove valuable in the elucidation of quantitative differences among other closely related receptor signalling networks.

Insights

Specificity in cell signaling arises from quantitative differences in pathway activation. This study shows fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) receptors differentially activate ERK signaling, revealing molecular mechanisms of stimulus-response specificity.

Area of Science:

Cellular and Molecular Biology
Biochemistry
Systems Biology

Background:

Mammalian cells use interconnected signaling pathways for diverse responses to growth factors and cytokines.
Understanding stimulus-response specificity at the molecular level is crucial for cell signaling research.
Quantitative differences in shared signaling protein activation may encode specificity.

Purpose of the Study:

To investigate how fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) receptor signaling achieve stimulus-response specificity.
To compare the activation of the extracellular-signal-regulated kinase (ERK) cascade by FGF and PDGF receptors in mouse fibroblasts.
To develop and apply quantitative measurement and mathematical modeling frameworks for analyzing non-linear signaling relationships.

Main Methods:

Quantitative measurements of signaling pathway activation.
Mathematical modeling of signal transduction networks.
Comparison of signaling activated by FGF and PDGF receptors in mouse fibroblasts.
Analysis of Ras- and phosphoinositide 3-kinase (PI3K)-dependent pathways in ERK activation.

Main Results:

FGF receptor stimulation shows weaker phosphoinositide 3-kinase (PI3K) signaling compared to PDGF.
This PI3K deficiency is compensated by more potent Ras-dependent activation of the extracellular-signal-regulated kinase (ERK) cascade by FGF.
Co-stimulation with FGF and PDGF leads to greater ERK pathway activation than either ligand alone, consistent with model predictions.

Conclusions:

Quantitative differences in signaling pathway activation contribute to stimulus-response specificity.
The interplay between PI3K and Ras pathways modulates ERK activation by FGF and PDGF receptors.
The applied quantitative and modeling approach is valuable for dissecting other related receptor signaling networks.

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