ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.
ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.
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ERK 激活通过磷酸化 Exportin-5 全局下调 miRNA
DOI：
10.1016/j.ccell.2016.10.001
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发表时间：
2016-11-14
期刊：
影响因子：
50.3
通讯作者：
Croce CM
中科院分区：
文献类型：
--
作者：
Sun HL;Cui R;Zhou J;Teng KY;Hsiao YH;Nakanishi K;Fassan M;Luo Z;Shi G;Tili E;Kutay H;Lovat F;Vicentini C;Huang HL;Wang SW;Kim T;Zanesi N;Jeon YJ;Lee TJ;Guh JH;Hung MC;Ghoshal K;Teng CM;Peng Y;Croce CM
MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications. Sun et al. find that ERK phosphorylates XPO5, which induces a Pin1-mediated conformational change that inhibits the ability of XPO5 to load and export pre-miRNA from the nucleus. Phosphorylation of XPO5 is associated with global miRNA downregulation and correlates with poor survival in hepatocellular carcinoma.
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影响因子：
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