Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks.

Purushottam D Dixit,Eugenia Lyashenko,Sang Kyun Lim,Mario Niepel,Dennis Vitkup,Peter K Sorger

doi:10.7554/elife.50342

Purushottam D Dixit, Eugenia Lyashenko + Show 4 more

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https://doi.org/10.7554/elife.50342

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Abstract

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in constantly fluctuating environments. It is currently not well understood how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, that is perform fold change detection. Using the growth factor-activated PI3K-Akt signaling pathway, we develop here computational and analytical models, and experimentally validate a novel non-transcriptional mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. The surface receptor abundance is regulated by background signal-dependent receptor endocytosis and down-regulation. We show the robustness and specificity of relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of cell memory and fold change detection may be important in diverse signaling cascades and multiple biological contexts.

Highlights

In biological systems, concentrations of extracellular signaling molecules, such as hormones and growth factors, often vary by orders of magnitude
To understand how the immediate-early dynamics of the Akt pathway depend on the background level of growth factors, we used immunofluorescence to quantify the levels of pAkt in epidermal growth factor (EGF)- stimulated human non-transformed mammary epithelial MCF10A cells (Materials and methods, Figure 1—figure supplement 1)
The logarithmic dependence of EGF receptors (EGFRs) phosphorylation levels on EGF stimulation has been previously attributed to a mixture of receptor species with varying affinities to the ligand, negative cooperativity of ligand binding to receptor dimers, and oligomeric aggregation of receptors (Kawamoto et al, 1983; Chatelier et al, 1986; Wofsy et al, 1992; Macdonald and Pike, 2008; Huang et al, 2016)

Summary

Introduction

Concentrations of extracellular signaling molecules, such as hormones and growth factors, often vary by orders of magnitude. The ability to sense relative rather than absolute signals, that is detect fold changes in extracellular cues, is critical for making accurate decisions in different biological contexts (Alon, 2019). Relative sensing requires both the ability to store memories of past environmental stimuli and the capacity to quickly and efficiently compute relative signals (Adler and Alon, 2018). When responding to constant stimuli, experiments with the signaling proteins ERK (Cohen-Saidon et al, 2009) and b-catenin (Goentoro and Kirschner, 2009) showed that fold changes in their nuclear activity were robust to cell-to-cell variability (Cohen-Saidon et al, 2009) and variability in signaling network parameters (Goentoro and Kirschner, 2009).

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