The Ras-ERK cascade is activated by countless external cues that stimulate diverse receptors. Therefore, the mechanisms by which distinct receptors dictate different cellular outcomes by activating the same signaling module has long fascinated many researchers. Initial clues came from observations that the duration of ERK activation is critical to cell-fate decisions. In classical experiments, PC12 cells proliferated after transient ERK activation by epidermal growth factor, but terminally differentiated after more sustained ERK activation by nerve growth factor. Subsequent studies suggested that the duration of ERK signaling is interpreted by cells through a network of immediate-early genes. Nevertheless, it remains ill-defined how the duration and strength of Ras-ERK signaling is established and what genes are differently regulated, thereby translating the response into different biological outcomes. Recent studies with lymphocytes have evoked a new idea that two types of interconnected mechanisms can contribute to the sensitivity and robustness of the ERK activity; (1) interplay between two types of Ras activators (Sos and RasGRP); (2) existence of two subcellular compartments for Ras activation (plasma membrane and Golgi). Moreover, candidate immediate early genes that regulate lymphocyte proliferation and differentiation have emerged.
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