Ras effector switching as a developmental strategy.
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Organisms pattern and specify cell fates with remarkably high fidelity and robustness, and cancer may be considered in part to be a disease of fate specification gone awry. During C. elegans vulval development an initial EGF signal prompts Ras to activate its canonical effector pathway, Raf-MEK-ERK, to induce a primary cell, which subsequently signals its 2 neighbors via Notch to develop as secondary cells. We have shown that Ras signaling through an alternate effector pathway, RalGEF-Ral, antagonizes Ras-Raf pro-primary signaling. Ras-RalGEF-Ral instead promotes secondary fate in support of Notch. We validated a previous model that EGF can also contribute to secondary fate, and argue that Ras-RalGEF-Ral mediates this EGF pro-secondary activity. Ras-Raf-MEK-ERK signaling was previously shown to be extinguished from secondary cells by secondary-specific expression of MAP kinase phosphatase, and we found that Ral expression is transcriptionally restricted to secondary cells. Thus during vulval development Ras switches effectors from Raf to RalGEF to promote divergent and mutually antagonistic cell fates, perhaps mirroring divergent effector usage in Ras-dependent tumors with differential pharmacological responsiveness.
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