Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales

Abstract

The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating critical cell-fate decisions, regulating protein synthesis, and mediating learning and memory. While the steady-state behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over timescales much longer than that of phosphorylation-dephosphorylation processes, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal, even in the absence of any explicit feedback or cross-talk with other pathways. We find that the molecular mechanism underlying this behavior is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the repeated reuse of activated kinases as enzymes when they are released from sequestration in complexes leading to one or more spike events following the removal of the stimulus. The persistent adaptive response reported here, indicative of a cellular "short-term" memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.

Short-term cellular memory tunes the signaling responses of the chemokine receptor CXCR4

“…Because cells under normal physiological conditions signal in the context of multiple signaling inputs, we hypothesized that treatment of cells with a different growth factor would generate a short-term memory (19) that modified subsequent CXCL12-CXCR4 signaling. To test this hypothesis, we conditioned cells for 4 hours with fetal bovine serum (FBS) before adding CXCL12.…”

Learning of Signaling Networks: Molecular Mechanisms

“…Different relaxation rates of cascade components lead to 'post-activation bursts' keeping the cascade in an 'activation-competent' state. This can form a system-level memory of the first activation making later responses faster and more robust [23]. Such a short-term molecular memory was demonstrated in the yeast osmotic stress response, too.…”

Dynamic Self-Reinforcement of Gene Expression Determines Acquisition and Retention of Cellular Mechanical Memory

“…Several mechanistic models have been put forward to explain the relationship between mechanics and cell differentiation (5,(26)(27)(28), but these models do not simultaneously capture 1) the timescale disparity between mechanical signaling / cell adaptation and memory development and 2) the continuous range of memory outcomes. More generally, regulatory gene network models with different topologies can give rise to memory using network motifs such as positive and negative reinforcement (29)(30)(31)(32)(33)(34). However, explicit molecular network models for mechanotransduction are difficult to develop because there is not enough data available to determine the many model parameters or assert which components of the regulatory network are rate-limiting.…”