  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.
