Metabolic control of YAP and TAZ by the mevalonate pathway
Metabolic control of YAP and TAZ by the mevalonate pathway
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DOI：
10.1038/ncb2936
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发表时间：
2014-04-01
影响因子：
21.3
通讯作者：
Del Sal, Giannino
中科院分区：
文献类型：
--
作者：
Sorrentino, Giovanni;Ruggeri, Naomi;Del Sal, Giannino
Hippo 途径的 YAP 和 TAZ 介质（以下称为 YAP/TAZ）促进组织增殖和器官生长。然而，它们的生物学特性如何与细胞代谢相交叉仍不清楚。在这里，我们表明 YAP/TAZ 活性受 SREBP/甲羟戊酸途径控制。他汀类药物对该途径的限速酶（HMG-CoA 还原酶）的抑制会阻碍 YAP/TAZ 核定位和转录反应。从机制上讲，甲羟戊酸级联产生的香叶基香叶基焦磷酸是激活 Rho GTPases 所必需的，而 Rho GTPases 反过来又通过抑制 YAP/TAZ 的磷酸化和促进其核积累来激活 YAP/TAZ。甲羟戊酸-YAP/TAZ 轴是乳腺癌细胞增殖和自我更新所必需的。在黑腹果蝇中，甲羟戊酸生物合成和香叶基香叶基化的抑制会减弱 YAP/TAZ 直系同源物 Yorkie 诱导的眼睛过度生长。在肿瘤细胞中，SREBP 转录活性产生的甲羟戊酸水平增加，促进 YAP/TAZ 激活，而甲羟戊酸是由其致癌辅因子突变体 p53 诱导的。这些发现揭示了代谢线索对 YAP/TAZ 的额外调节。
The YAP and TAZ mediators of the Hippo pathway ( hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway ( HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate-YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In Drosophila melanogaster, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.