Rate thresholds in cell signaling have functional and phenotypic consequences in non-linear time-dependent environments

Abstract

All cells employ signal transduction pathways to respond to physiologically relevant extracellular cytokines, stressors, nutrient levels, hormones, morphogens, and other stimuli that vary in concentration and rate in healthy and diseased states. A central unsolved fundamental question in cell signaling is whether and how cells sense and integrate information conveyed by changes in the rate of extracellular stimuli concentrations, in addition to the absolute difference in concentration. We propose that different environmental changes over time influence cell behavior in addition to different signaling molecules or different genetic backgrounds. However, most current biomedical research focuses on acute environmental changes and does not consider how cells respond to environments that change slowly over time. As an example of such environmental change, we review cell sensitivity to environmental rate changes, including the novel mechanism of rate threshold. A rate threshold is defined as a threshold in the rate of change in the environment in which a rate value below the threshold does not activate signaling and a rate value above the threshold leads to signal activation. We reviewed p38/Hog1 osmotic stress signaling in yeast, chemotaxis and stress response in bacteria, cyclic adenosine monophosphate signaling in Amoebae, growth factors signaling in mammalian cells, morphogen dynamics during development, temporal dynamics of glucose and insulin signaling, and spatio-temproral stressors in the kidney. These reviewed examples from the literature indicate that rate thresholds are widespread and an underappreciated fundamental property of cell signaling. Finally, by studying cells in non-linear environments, we outline future directions to understand cell physiology better in normal and pathophysiological conditions.

Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

“…Regulation of cellular fate, particularly during development, depends on the concentration gradient of morphogens, including ligands for different RTKs ( Stapornwongkul and Vincent, 2021 ; Yang et al, 2023 ). Several studies suggest that concentration-dependent signalling is regulated by a switch-like mechanism, whereby cells respond to extracellular cues only past certain concentration thresholds ( Greenfeld et al, 2021 ; Johnson et al, 2021 ; Thiemicke and Neuert, 2023 ). This has been shown for BPM and FGF signalling during early phase of development ( Serls et al, 2005 ; Greenfeld et al, 2021 ).…”

Phenotypic consequences of logarithmic signaling in MAPK stress response

“…However, in their physiological context, cells encounter stress concentrations that change in various forms such as a sudden, linear, nonlinear, and repetitive forms over time, space, or both (15, 16). These changes occur at time scales and length scales that are different from those involving acute transitions between two constant levels (17). For example, circadian oscillations occur once per day, synaptic firing happens multiple times per second, and various hormones, including blood insulin, exhibit unique temporal patterns that selectively regulate intracellular processes based on their dynamics (18).…”

“…For example, circadian oscillations occur once per day, synaptic firing happens multiple times per second, and various hormones, including blood insulin, exhibit unique temporal patterns that selectively regulate intracellular processes based on their dynamics (18). These physiological changes that cells experience are not always acute and they could happen in smooth and slow patterns over time or space (17). This mismatch between traditional experimental conditions and the dynamic reality of physiological environments has created a gap in our understanding of how signaling behaves within complex natural settings.…”

“…Emerging studies demonstrate that different cell stimulations that vary over time or space can dramatically affect intracellular signaling dynamics (17, 19). As a result, qualitatively distinct dynamics of the same signaling molecule such as signals with different amplitudes, durations, rates, or oscillations can lead to altered gene expression or create entirely distinct cell phenotypes (7, 15, 16, 18–32).…”

“…Our studies have demonstrated that gradual cell stress yield superior results compared to conventional approaches when constructing predictive mathematical models of cell signaling (15, 16). Furthermore, we and other pioneering studies have investigated the impact of varying the rate of osmotic stress over time on signaling activation and cellular survival (17, 19, 23, 26–29, 44–46). However, our understanding of how cells integrate dynamic signal features continuedly over time, such as the rate of change in stress, along with the stress concentration itself, remains unknown.…”