An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells.
An Excitable Ras/PI3K/ERK Signaling Network Controls Migration and Oncogenic Transformation in Epithelial Cells.
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DOI：
10.1016/j.devcel.2020.08.001
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发表时间：
2020-09-14
影响因子：
11.8
通讯作者：
Devreotes PN
中科院分区：
文献类型：
--
作者：
Zhan H;Bhattacharya S;Cai H;Iglesias PA;Huang CH;Devreotes PN
RAS/PI3K/ERK信号网络在细胞的生长、存活和迁移中起着重要作用，在肿瘤中经常被激活。在这里，我们展示了信号网络的活动以协调波的形式传播，受到生长因子的偏向，生长因子驱动着人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特征：湮灭相反方向的波，要么全有要么全无反应，以及难以捉摸。对RAS、PI(4，5)P2、PI(3，4)P2、ERK和TORC2的突然扰动改变了阈值，这些观测定义了网络内的正反馈回路和负反馈回路。致癌转化显著增加了ERK的波活性、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，波的活性逐渐增强。认为致癌转化是由多种遗传侮辱组合引起的可兴奋的RAS/PI3K/ERK网络向较低阈值的转变，有助于评估癌症的严重性和干预的有效性。詹其雄等人。研究RAS/PI3K/ERK信号网络的兴奋性。他们证明，活动在细胞皮质上以协调波的形式传播，并描绘了导致兴奋性的分子反馈。转化的细胞表现出更多的波动，这表明癌症可以被视为网络的低阈值状态。
The Ras/PI3K/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: 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 which 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 assessment of cancer severity and effectiveness of interventions. Zhan et al. investigate excitability of the Ras/PI3K/ERK signaling network. They demonstrate that activities propagate as coordinated waves on the cell cortex and delineate the molecular feedbacks that cause excitability. Transformed cells display more waves suggesting that cancer can be viewed as a low threshold state of the network.
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影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
13.6
作者：
Bhattacharya, Sayak;Banerjee, Tatsat;Iglesias, Pablo A.
通讯作者：
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影响因子：
7.7
作者：
Hansen SD;Mullins RD
通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1073/pnas.1809039115
发表时间：
2018-09-25
影响因子：
11.1
作者：
Li X;Edwards M;Swaney KF;Singh N;Bhattacharya S;Borleis J;Long Y;Iglesias PA;Chen J;Devreotes PN
通讯作者：
Devreotes PN