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、存活和迁移中起着重要作用，并且在癌症中经常被激活。在这里，我们展示了信号网络的活动作为协调波传播，受生长因子的影响，驱动人类上皮细胞中基于肌动蛋白的突起。该网络表现出生化兴奋性的标志：相反方向的波的湮灭、全有或全无的反应性和耐火性。Ras、PI(4,5)P2、PI(3,4)P2、ERK 和 TORC2 的突然扰动会改变阈值，即定义网络内正反馈和负反馈循环的观察结果。致癌转化显着增加了波活动、ERK 脉冲的频率和对 EGF 刺激的敏感性。在一系列转移性越来越强的乳腺癌细胞系中，波活动逐渐增强。致癌转化是由各种遗传损伤组合引起的可兴奋性 Ras/PI3K/ERK 网络向较低阈值的转变的观点，可以促进对癌症严重程度和干预措施有效性的评估。