Data-driven modelling of receptor tyrosine kinase signalling networks quantifies receptor-specific potencies of PI3K- and Ras-dependent ERK activation.
Data-driven modelling of receptor tyrosine kinase signalling networks quantifies receptor-specific potencies of PI3K- and Ras-dependent ERK activation.
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DOI：
10.1042/bj20110833
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Haugh JM
中科院分区：
文献类型：
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作者：
Cirit M;Haugh JM
Signal transduction networks in mammalian cells, comprised of 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 simply 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 parameterise the inherently nonlinear relationships among signalling activities will need to be developed. Here we apply a systematic approach combining quantitative measurements and mathematical modelling to compare the signalling networks accessed by fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) receptors in mouse fibroblasts, in which the extracellular signal-regulated kinase (ERK) cascade is activated by Ras- and phosphoinositide 3-kinase (PI3K)-dependent pathways. We show that while 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 envisioned that similar approaches will prove valuable in the elucidation of quantitative differences among other, closely related receptor signalling networks.
