Stimulus-Coupled Spatial Restriction of Extracellular Signal-Regulated Kinase 1/2 Activity Contributes to the Specificity of Signal-Response Pathways

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Abstract
Current understanding of cell regulatory systems suggests a diverse array of extracellular stimuli commonly recruit a limited cadre of core signal transduction modules to drive discrete stimulus-specific responses. One such module is the Raf-MEK-extracellular signal-regulated kinase (ERK) kinase cascade. Little information exists about how this pathway can be appropriately coupled to discrete cell biological processes. Contributing factors may include regulation of the duration, amplitude, and/or subcellular compartmentalization of active ERK1/2. To define properties of ERK1/2 that may help mediate stimulus-selective signal propagation, we have examined the dynamic behavior of native ERK1/2 activation at the single-cell level. In primary human cell cultures, ERK1/2 activation is not an all-or-none response. Instead, the amount of active ERK1/2 in individual cells accumulated in proportion to the concentration of external stimulus. The variable degree of ERK1/2 activation correlated well with the degree of ERK1/2 effector activation. Therefore, the relative amplitude of ERK1/2 activation within a cell can be modulated and may contribute to the generation of stimulus-specific biological responses. Importantly, we also found that the capacity of active ERK1/2 to accumulate in the nucleus and drive immediate-early gene expression is dependent upon the nature of the inductive signal, but independent of the amplitude of ERK1/2 activation. Therefore, nuclear accumulation of active ERK1/2 is a discrete regulated step that can direct the function of the kinase in response to specific stimuli.