Activating mutations in RAS are present in ~ 30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative effects of RAS mutations. Here, we use live‐cell imaging in cells expressing only one RAS isoform to quantify ERK activity with a new level of accuracy. We find that despite large differences in their biochemical activity, mutant KRAS isoforms within cells have similar ranges of ERK output. We identify roles for pathway‐level effects, including variation in feedback strength and feedforward modulation of phosphatase activity, that act to rescale pathway sensitivity, ultimately resisting changes in the dynamic range of ERK activity while preserving responsiveness to growth factor stimuli. Our results reconcile seemingly inconsistent reports within the literature and imply that the signaling changes induced by RAS mutations early in oncogenesis are subtle.

中文翻译：

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致癌突变的 RAS 信号活性被 ERK/MAPK 通路重新调整

大约 30% 的人类肿瘤中存在 RAS 中的激活突变，由此产生的 ERK/MAPK 信号异常在肿瘤发生中起着核心作用。然而，这些信号变化的形式是不确定的，激活 RAS 突变体与体内ERK 激活的增加和减少有关. 合理地靶向该途径的激酶活性需要阐明 RAS 突变的定量影响。在这里，我们在仅表达一种 RAS 亚型的细胞中使用活细胞成像，以更高的准确度量化 ERK 活性。我们发现，尽管它们的生化活性存在很大差异，但细胞内的突变 KRAS 同种型具有相似的 ERK 输出范围。我们确定了通路水平效应的作用，包括反馈强度的变化和磷酸酶活性的前馈调节，其作用是重新调整通路敏感性，最终抵抗 ERK 活性动态范围的变化，同时保持对生长因子刺激的反应性。