Figure 1. Differential gene expression responses to ERK signaling.

(A) Differential regulation of EGR1, FOSL1, and FOS expression. In each case, ERK phosphorylates a transcription factor (TF) that binds to the gene promoter. Left: EGR1 protein binds to its own gene promoter, inhibiting further transcription. Middle: ERK initiates FOSL1 transcription and also stabilizes FRA-1 protein. Right: ERK initiates FOS expression, and stabilizes FOS protein through phosphorylation; sustained ERK activation also apparently induces a FOS transcriptional repressor that has not been definitively identified [36]. (B) Sustained signaling generates high concentrations of FRA-1 and FOS protein. Subsequently, the FOS repressor inhibits further expression of FOS. After the initial peak of EGR1 concentration, EGR1 represses its own transcription (auto-inhibition), thus returning to an equilibrium with low baseline expression. (C) Pulsatile signaling generates short bursts of EGR1 accumulation. Since EGR1 transcription is brief and the protein is unstable, auto-inhibition does not persist. This allows EGR1 levels to track closely with ERK activity pulses. Conversely, pulsatile signaling weakly induces FRA-1 and FOS expression because sustained signaling is required for protein stabilization. Figure adapted in part from [24].