The EGFR demonstrates linear signal transmission

Abstract

Cells sense information encoded in extracellular ligand concentrations and process it using intracellular signalling cascades. Using mathematical modelling and high-throughput imaging of individual cells, we studied how a transient extracellular growth factor signal is sensed by the epidermal growth factor receptor system, processed by downstream signalling, and transmitted to the nucleus. We found that transient epidermal growth factor signals are linearly translated into an activated epidermal growth factor receptor integrated over time. This allows us to generate a simplified model of receptor signaling where the receptor acts as a perfect sensor of extracellular information, while the nonlinear input-output relationship of EGF-EGFR triggered signalling is a consequence of the downstream MAPK cascade alone. Insight, innovation, integrationWe derived an analytical formula from nonlinear models of receptor signalling that have been used to model the signalling of the epidermal growth factor receptor (EGFR). The formula predicted that the cumulative EGFR signalling is linearly dependent on the ligand concentration outside the cell. Quantitative imaging of HeLa cells suggests that the cumulative EGFR signalling indeed depends linearly on the EGF concentration. Our mathematical approach therefore allows a simplified view on complex networks of receptor dynamics and describes the EGFR as a linear sensor of extracellular information encoded in ligand concentrations.

Signaling pathways as linear transmitters

“…Linearity in the ERK pathway has been suggested in different parts of the pathway, e.g. Knauer et al (1984) used experimental and modeling analyses to infer linearity between receptor occupancy and the downstream cellular proliferation; Oyarzún et al (2014) suggests linearity in ligand-receptor processing. Here, we specifically probe linearity in the core transmission step of the pathway.…”

“…Detecting the input level, EGF-activated Ras GTP, requires a pull down step that makes it less quantifiable. Therefore, motivated by Oyarzún et al (2014) , we tested EGF ligand itself as the input. To track the output, we measured the level of doubly-phosphorylated ERK1/2 (on Thr202/Tyr204), dpERK.…”

Push-Pull and Feedback Mechanisms Can Align Signaling System Outputs with Inputs

“…This implies that the PRS senses and transmits the fraction of ligand-bound receptors, even as its protein abundance changes (Brent, 2009). Many other signaling systems, including the insulin, acetylcholine, TSH, angiotensin II, and EGF receptor systems also exhibit DoRA (Yu et al, 2008); in the EGF and EPO systems, downstream alignment is maintained in the face of changes in the number of active surface receptors over time (Knauer et al, 1984, Becker et al 2010, Oyarzún et al 2014). Systems that exhibit DoRA use the entire dynamic range of the signal from bound receptor, which can enable downstream outputs to exhibit more distinguishable responses (Yu et al, 2008).…”

“…Integral control can produce perfect adaptation, meaning that the output exactly returns to the ideal value even in the face of perturbations (Doyle, 2016). Many evolved systems also use negative feedback, for example to maintain constant concentrations of metabolites (Umbarger, 1978), to regulate the response to DNA damage (Brent and Ptashne, 1980, 1981), and to linearize integrated responses to extracellular signals (Becker et al, 2010; Oyarzún et al, 2014). In the PRS, negative feedback maintains alignment at one measurement point: the kinase activity of Fus3 MAPK is needed to shift the Fus3 MAPK phosphorylation dose-response curve to the right, toward alignment (Yu et al, 2008).…”

Signaling Tug-of-War Delivers the Whole Message

“…For example, there are other instances of linear input-output responses in the EGF and Epo systems (Sturm et al 2010;Oyarzún et al 2014;Becker et al 2010) that are conceptually similar to the results by (Andrews et al 2016), but slightly different when the input-output definitions are taken into account. While Andrews et al (2016) describe a linear relationship between receptor occupancy and downstream phosphorylation, Sturm et al (2010) reported linearity between ligand dose and phosphorylation of downstream signalling molecules, whereas Oyarzún et al (2014) and Becker et al (2010) showed a linear response between ligand dose and the time-integrated phosphorylation of membrane receptors. Although all these results may be equally described as 'linear input-output behaviour', this can be misleading unless we specify how inputs and outputs were defined.…”