Systematic Analysis of Crosstalk in the PDGF Receptor Signal Transduction Network

Jason Haugh (North Carolina State University)

Abstract

Intracellular signal transduction is traditionally characterized in terms of pathways, comprised of serial activation processes. Although it has long been appreciated that signaling pathways are simply dominant routes of regulation embedded in larger networks of interactions, relatively little has been done in practice to quantify pathway crosstalk in signaling networks. Using a systematic combination of quantitative measurements and kinetic modeling, we have elucidated crosstalk mechanisms in signaling mediated by platelet-derived growth factor (PDGF) receptors, which strongly activate the phosphoinositide 3-kinase (PI3K) and Ras/extracellular signal-regulated kinase (Erk) pathways. The data set is comprised of more than 1,500 measurements, collected under approximately 150 experimental conditions. It is shown that signaling to Erk is enhanced in complex ways by PI3K, while the PI3K pathway is largely insulated from crosstalk. Whereas blocking both Ras and PI3K abolishes PDGF-stimulated Erk phosphorylation, each pathway makes an independent contribution to Erk activation. PI3K affects Erk at points both upstream and downstream of Ras, to an extent that depends on PDGF dose as well as time, subject to saturation effects in the respective pathways and at least two distinct negative feedback loops in the Ras/Erk pathway. Building on our previously validated model of PDGF receptor and PI3K activation, a kinetic description of the network was constructed at coarse-grain resolution (< 25 new parameters), and using the dense data set to constrain the parameter space, magnitudes are assigned to the constituent processes. Thus, the inputs from Ras and PI3K to Erk, including the contributions of PI3K at multiple points in the pathway, are parsed out in quantitative terms.

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