MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression
MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression
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DOI：
10.7554/elife.60541
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发表时间：
2020-09-17
期刊：
影响因子：
7.7
通讯作者：
Regot, Sergi
中科院分区：
文献类型：
--
作者：
Aikin, Timothy J.;Peterson, Amy F.;Regot, Sergi
大部分人类癌症在促分裂原活化蛋白激酶（MAPK）信号传导网络内含有遗传改变，其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）差异调节细胞行为。然而，信号传导动力学在介导癌症驱动突变的作用中的作用尚未得到系统的研究。在这里，我们表明，癌基因表达导致脉冲或持续ERK活性，与相反的细胞行为（即增殖与细胞周期停滞，分别）。此外，持续的，但不是脉动的ERK活性触发ERK活性波在未受干扰的相邻细胞，这取决于膜金属蛋白酶ADAM 17和EGFR的活性。有趣的是，ADAM 17-EGFR信号轴协调邻近细胞向致癌细胞的迁移，并且是致癌细胞挤出所需的。总的来说，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的影响。
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.