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

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.

Molecular switch architecture drives response properties

“…These assumptions do not hold in case of some signaling pathways where stimulus-mediated removal of receptors occurs. Reported examples of such phenomena include GPCRs [54], EGFR [42], AMPA-type glutamate receptors [55], the receptor-like kinase FLS2 [56] and regulator of G-signaling (RGS) in Arabidopsis thaliana [11]. On the one hand, removal of active receptors is proposed to be a mechanism for desensitizing the response to a sustained stimulus [69,70], and consequently enabling signaling over a broad range [41,42].…”

“…Reported examples of such phenomena include GPCRs [54], EGFR [42], AMPA-type glutamate receptors [55], the receptor-like kinase FLS2 [56] and regulator of G-signaling (RGS) in Arabidopsis thaliana [11]. On the one hand, removal of active receptors is proposed to be a mechanism for desensitizing the response to a sustained stimulus [69,70], and consequently enabling signaling over a broad range [41,42]. On the other hand, phosphorylation and subsequent removal of RGS, which is both a receptor candidate and a GAP, is proposed to result in sustained activation of signaling in Arabidopsis thaliana [9,11,45].…”

“…1 by including production of inactive receptors (X ) at a rate k p , removal of inactive receptors with rate k d , and removal of active receptors with rate k * d . This model is simpler than those showing a broad range [41] or relative sensing [42], but is capable of adaptation [70] which is what we focus on.…”

“…For example, the classical Goldbeter-Koshland model studied zeroorder ultrasensitivity of an activation mechanism [15]. Further analyses have examined the effect of receptor numbers [36][37][38], feedback mechanisms [39,40], removal of active receptors via endocytosis and degradation [41,42], etc. Similarly, important properties of the concerted mechanism, such as its ability to do ratiometric signaling [13,14], to align dose responses at different stages of the signaling pathway [43], as well as its robustness [29,44] are well-known.…”

“…The third metric of comparison is motivated from the fact that signaling pathways are subject to inherent stochastic nature of biochemical reactions, further compounded by fluctuations in the number of components [48][49][50][51][52][53]. Lastly, we study the effect of receptor removal on the response of these signaling mechanisms because many signaling pathways evince receptor removal [11,42,[54][55][56]. We study these properties by constructing both deterministic ordinary differential equation models and stochastic models based on continuous-time Markov chains.…”