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The mitogen-activated protein kinase (MAPK) signaling cascade, anevolutionarily conserved motif present in all eukaryotic cells, is involved incoordinating critical cell-fate decisions, regulating protein synthesis, andmediating learning and memory. While the steady-state behavior of the pathwaystimulated by a time-invariant signal is relatively well-understood, we showusing a computational model that it exhibits a rich repertoire of transientadaptive responses to changes in stimuli. When the signal is switched on, theresponse is characterized by long-lived modulations in frequency as well asamplitude. On withdrawing the stimulus, the activity decays over timescalesmuch longer than that of phosphorylation-dephosphorylation processes,exhibiting reverberations characterized by repeated spiking in the activatedMAPK concentration. The long-term persistence of such post-stimulus activitysuggests that the cascade retains memory of the signal for a significantduration following its removal, even in the absence of any explicit feedback orcross-talk with other pathways. We find that the molecular mechanism underlyingthis behavior is related to the existence of distinct relaxation rates for thedifferent cascade components. This results in the imbalance of fluxes betweendifferent layers of the cascade, with the repeated reuse of activated kinasesas enzymes when they are released from sequestration in complexes leading toone or more spike events following the removal of the stimulus. The persistentadaptive response reported here, indicative of a cellular "short-term" memory,suggests that this ubiquitous signaling pathway plays an even more central rolein information processing by eukaryotic cells.

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