Department of Molecular and Cellular Biology, University of California, Davis, CA, USA.
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Mol Syst Biol. 2020 Oct;16(10):e9518. doi: 10.15252/msb.20209518.
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.
RAS 中的激活突变存在于约 30%的人类肿瘤中，由此导致的 ERK/MAPK 信号传导异常在肿瘤发生中起着核心作用。然而，这些信号改变的形式尚不确定，激活的 RAS 突变体与体内 ERK 的激活增加和减少都有关联。合理靶向该途径的激酶活性需要阐明 RAS 突变的定量效应。在这里，我们使用仅表达一种 RAS 同工型的活细胞成像，以新的精度水平定量 ERK 活性。我们发现，尽管它们的生化活性有很大差异，但细胞内的突变 KRAS 同工型具有相似的 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，这些效应作用于重新调整通路的敏感性，最终在保留对生长因子刺激的反应性的同时，抵抗 ERK 活性动态范围的变化。我们的结果调和了文献中看似不一致的报告，并暗示了致癌作用早期 RAS 突变诱导的信号变化是微妙的。
