Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Dev Cell. 2020 Sep 14;54(5):608-623.e5. doi: 10.1016/j.devcel.2020.08.001. Epub 2020 Sep 1.
The Ras/PI3K/extracellular signal-regulated kinases (ERK) signaling network plays fundamental roles in cell growth, survival, and migration and is frequently activated in cancer. Here, we show that the activities of the signaling network propagate as coordinated waves, biased by growth factor, which drive actin-based protrusions in human epithelial cells. The network exhibits hallmarks of biochemical excitability: the annihilation of oppositely directed waves, all-or-none responsiveness, and refractoriness. Abrupt perturbations to Ras, PI(4,5)P2, PI(3,4)P2, ERK, and TORC2 alter the threshold, observations that define positive and negative feedback loops within the network. Oncogenic transformation dramatically increases the wave activity, the frequency of ERK pulses, and the sensitivity to EGF stimuli. Wave activity was progressively enhanced across a series of increasingly metastatic breast cancer cell lines. The view that oncogenic transformation is a shift to a lower threshold of excitable Ras/PI3K/ERK network, caused by various combinations of genetic insults, can facilitate the assessment of cancer severity and effectiveness of interventions.
Ras/PI3K/细胞外信号调节激酶（ERK）信号网络在细胞生长、存活和迁移中发挥着基本作用，并且在癌症中经常被激活。在这里，我们表明，信号网络的活性作为协调波传播，由生长因子偏向，从而在人上皮细胞中驱动基于肌动蛋白的突起。该网络表现出生化兴奋性的特征：相反方向波的消除、全或无反应性和不应期。对 Ras、PI(4,5)P2、PI(3,4)P2、ERK 和 TORC2 的突然干扰改变了阈值，这些观察结果定义了网络内的正反馈和负反馈环。致癌转化极大地增加了波活动、ERK 脉冲的频率以及对 EGF 刺激的敏感性。波活动在一系列越来越具有转移性的乳腺癌细胞系中逐渐增强。致癌转化是 Ras/PI3K/ERK 网络兴奋性降低的观点，是由各种遗传损伤的组合引起的，这可以促进对癌症严重程度和干预措施有效性的评估。
