MAPK signaling cascade: multi-stability and dynamic information transfer

About This Grant

PROJECT SUMMARY/ABSTRACT Inflammation is a natural physiological process that initiates and orchestrates the immune response, but an overreaction in magnitude or time can have serious health consequences, including death. Inflammation is initiated when immune sentinel cells, especially macrophages, sense the presence of pathogen or tissue damage and produce inflammatory cytokines. Recipient cells respond to those cytokines by adapting their functions via induced gene expression programs. The signaling pathways associated with inflammation are NFκB and MAPK. The NFκB pathway controls the cellular response to inflammation signals: our recent studies have revealed that the dynamics of NFκB activity is stimulus-specific and robustly distinguishes between different ligands and doses (Immunity 2021; 54:916, Science 2021; 372:1349). In contrast, whether inflammatory cytokines are secreted by macrophages is controlled by MAPK activities p38 and ERK (Cell Syst 2017; 4:330, Genes Dev 2014; 28:2120). Our recent studies found that MAPK p38 activation shows remarkably high heterogeneity (MSB 2024; 9:898), suggesting that the functional role of high MAPK heterogeneity is to limit the production of inflammatory cytokines to a minority of cells, thereby reducing the risk of inflammatory overload. However, what controls the heterogeneity of MAPK signaling remains unclear. An overarching hypothesis of this proposal is that the heterogeneity of MAPK p38 and ERK signaling is the result of the topology and mechanism of the biochemical network that controls activation of these kinases. Specifically, we hypothesize that the two layers of dual-phosphorylation kinase cascades generate a complex multi-stability landscape that can exacerbate molecular noise to generate cell-to-cell heterogeneity. To address this hypothesis, we will investigate both noise exacerbation and buffering emerging from intrinsic characteristics such as the number and relative position of the available stationary states, determined by the kinetic parameters of each pathway and strength of external signals. This will allow us to characterize, through experimentation and detailed biochemical mechanistic modeling, how stimulus information transmission and stimulus-response activities of MAPK p38 and ERK pathways avoid inflammatory overreaction through cell-to- cell variability. By pursuing both synergistic approaches in parallel we will gain a deep understanding of how noisy cytokine secretion is controlled and identify novel strategies of analysis, diagnostics, therapeutics.