Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover.
Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover.
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DOI：
10.15252/embj.201489385
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发表时间：
2014-11-03
期刊：
影响因子：
--
通讯作者：
Cohen SM
中科院分区：
文献类型：
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作者：
Hong X;Nguyen HT;Chen Q;Zhang R;Hagman Z;Voorhoeve PM;Cohen SM
癌症基因组积累了许多遗传和表观遗传修饰。然而，人类细胞转化可以通过一些遗传定义的元素来完成。这些元件激活支持复制永生和锚定非依赖性生长所需的关键途径，这是体内肿瘤发生的预测因子。在这里，我们提供的证据表明，海马肿瘤抑制途径是一个关键的障碍Ras介导的细胞转化。Hippo途径通过βTrCP-SCF泛素连接酶复合物靶向YAP 1降解。相反，Ras途径起相反作用，通过下调泛素连接酶复合物底物识别因子SOCS 5/6来促进YAP 1稳定性。SOCS 5/6的缺失或YAP 1的上调可以绕过体外锚定非依赖性生长和体内肿瘤形成中对致癌Ras的需要。通过YAP 1靶点双调蛋白，Ras激活内源性EGFR途径，这是转化所必需的。因此，RasV 12的致癌活性取决于其抵消Hippo通路活性的能力，从而产生正反馈回路，这取决于YAP 1的稳定性。
Cancer genomes accumulate numerous genetic and epigenetic modifications. Yet, human cellular transformation can be accomplished by a few genetically defined elements. These elements activate key pathways required to support replicative immortality and anchorage independent growth, a predictor of tumorigenesis in vivo. Here, we provide evidence that the Hippo tumor suppressor pathway is a key barrier to Ras-mediated cellular transformation. The Hippo pathway targets YAP1 for degradation via the βTrCP-SCF ubiquitin ligase complex. In contrast, the Ras pathway acts oppositely, to promote YAP1 stability through downregulation of the ubiquitin ligase complex substrate recognition factors SOCS5/6. Depletion of SOCS5/6 or upregulation of YAP1 can bypass the requirement for oncogenic Ras in anchorage independent growth in vitro and tumor formation in vivo. Through the YAP1 target, Amphiregulin, Ras activates the endogenous EGFR pathway, which is required for transformation. Thus, the oncogenic activity of RasV12 depends on its ability to counteract Hippo pathway activity, creating a positive feedback loop, which depends on stabilization of YAP1.
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DOI：
10.1126/science.1199010
发表时间：
2011-04-22
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Heallen T;Zhang M;Wang J;Bonilla-Claudio M;Klysik E;Johnson RL;Martin JF
通讯作者：
Martin JF
影响因子：
64.5
作者：
Kapoor A;Yao W;Ying H;Hua S;Liewen A;Wang Q;Zhong Y;Wu CJ;Sadanandam A;Hu B;Chang Q;Chu GC;Al-Khalil R;Jiang S;Xia H;Fletcher-Sananikone E;Lim C;Horwitz GI;Viale A;Pettazzoni P;Sanchez N;Wang H;Protopopov A;Zhang J;Heffernan T;Johnson RL;Chin L;Wang YA;Draetta G;DePinho RA
通讯作者：
DePinho RA
影响因子：
64.5
作者：
Dong, Jixin;Feldmann, Georg;Pan, Duojia
通讯作者：
Pan, Duojia
影响因子：
6.4
作者：
Iwatsuki, Masaaki;Mimori, Koshi;Mori, Masaki
通讯作者：
Mori, Masaki
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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