Signaling pathways as linear transmitters

Abstract

One challenge in biology is to make sense of the complexity of biological networks. A good system to approach this is signaling pathways, whose well-characterized molecular details allow us to relate the internal processes of each pathway to their input-output behavior. In this study, we analyzed mathematical models of three metazoan signaling pathways: the canonical Wnt, MAPK/ERK, and Tgfβ pathways. We find an unexpected convergence: the three pathways behave in some physiological contexts as linear signal transmitters. Testing the results experimentally, we present direct measurements of linear input-output behavior in the Wnt and ERK pathways. Analytics from each model further reveal that linearity arises through different means in each pathway, which we tested experimentally in the Wnt and ERK pathways. Linearity is a desired property in engineering where it facilitates fidelity and superposition in signal transmission. Our findings illustrate how cells tune different complex networks to converge on the same behavior.

Context-aware synthetic biology by controller design: Engineering the mammalian cell

“…Controllers can generally work via ''feedforward'' or ''feedback'' actuation (Figure 6A). In natural regulatory networks, both feedforward and feedback control motifs have been observed to impart high robustness and adaptation to disturbances (Araujo and Liotta, 2018;Barkai and Leibler, 1997;Becskel and Serrano, 2000;Ferrell, 2016;Ma et al, 2009;Nunns and Goentoro, 2018;Sturm et al, 2010;Yi et al, 2000). A feedback controller measures the system's output, compares it with a desired output, and actuates an input to the system to decrease the measured discrepancy between the desired and actual output.…”

“…Early evidence for controllers enabling such behavior has been observed with the endoRNase feedforward controller, with which expression levels across several cell lines were precisely aligned (Jones et al, 2020). Robustness to noise via linearization of the transfer curve In natural biological circuits, linear amplification is observed for many signaling networks (Nunns and Goentoro, 2018). For example, the ERK/MAPK pathway resembles an enzymatic feedback controller: Raf phosphorylates and activates MEK, which phosphorylates and activates ERK, which then feeds back by phosphorylating and deactivating Raf (Sturm et al, 2010).…”

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

“…In this pathway, Mek is analogous to our HK kinase, Erk is analogous to OmpR-VP64 (though Erk itself only indirectly activates transcription through its targets 102,103 ), and the Erk-induced phosphatases DUSP5/6 are analogous to our HK phosphatase 101,104 . Negative feedback in both natural and engineered systems has been shown to convert digital, multimodal input-output responses to more graded, linear, and uniform responses 79,80,105 . Likewise, our feedback controller is capable of imparting graded, uniform activation of gene expression in the cell population.…”

Fractional response analysis reveals logarithmic cytokine responses in cellular populations

“…For instance, low doses of TNF-α may induce one peak of nuclear factor-κB (NF-κB) signaling activity, whereas higher doses may induce additional peaks 7,24 . Besides, the dose may control the onset, shut off, amplitude, or, in principle, any other characteristics of the responses [25][26][27][28] . Overall, conventional dose-response curves do not capture the inherent complexity of single-cell high-throughput data, and an alternative approach is required.…”