A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained–but not pulsatile–ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.

中文翻译：

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MAPK 活性动态调节癌基因表达的非细胞自主效应

很大一部分人类癌症在丝裂原激活蛋白激酶 (MAPK) 信号网络中含有基因改变，从而促进不可预测的表型。先前的研究表明，MAPK 活性的时间模式（即信号动力学）差异性地调节细胞行为。然而，信号动力学在介导癌症驱动突变的影响中的作用尚未得到系统探索。在这里，我们表明癌基因表达导致脉冲或持续的 ERK 活性，这与相反的细胞行为（即分别增殖与细胞周期停滞）相关。此外，持续但非脉动的 ERK 活性会在未受干扰的邻近细胞中触发 ERK 活性波，这些细胞依赖于膜金属蛋白酶 ADAM17 和 EGFR 活性。有趣的是，ADAM17-EGFR 信号轴协调邻近细胞向致癌细胞迁移，并且是致癌细胞挤出所必需的。总体而言，我们的数据表明 MAPK 活性的时间模式差异调节癌基因表达的细胞自主和非细胞自主效应。