PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis.
PRMT5-mediated arginine methylation activates AKT kinase to govern tumorigenesis.
复制标题
DOI：
10.1038/s41467-021-23833-2
复制
发表时间：
2021-06-08
影响因子：
16.6
通讯作者：
Gan W
中科院分区：
文献类型：
--
作者：
Yin S;Liu L;Brobbey C;Palanisamy V;Ball LE;Olsen SK;Ostrowski MC;Gan W
AKT参与许多关键的细胞过程，包括细胞增殖、凋亡和代谢。AKT的过度活化与许多病理状况，特别是癌症相关。新的证据表明精氨酸甲基化参与调节AKT信号通路。然而，精氨酸甲基化是否以及如何直接调节AKT激酶活性仍然未知。在这里，我们报告，蛋白质精氨酸甲基转移酶5（PRMT 5），而不是其他PRMTs，促进AKT的激活，通过催化对称二甲基化AKT 1在精氨酸391（R391）。从机制上讲，AKT 1-R391甲基化与磷脂酰肌醇3，4，5三磷酸（PIP 3）协同作用，以解除普列克底物蛋白同源性（PH）-构象，导致AKT 1膜易位，随后被磷酸肌醇依赖性激酶-1（PDK 1）和雷帕霉素复合物2（mTORC 2）的机制靶点激活。因此，AKT 1-R391甲基化缺陷显著抑制AKT 1激酶活性和肿瘤发生。最后，我们表明PRMT 5抑制剂与AKT抑制剂或化疗药物协同作用以增强细胞死亡。总之，我们的研究表明，R391甲基化是AKT激活及其致癌功能的重要步骤。据报道，精氨酸甲基化调节AKT相关信号传导。在这里，作者表明PRMT 5介导的精氨酸甲基化促进AKT活性并诱导肿瘤发生。
AKT is involved in a number of key cellular processes including cell proliferation, apoptosis and metabolism. Hyperactivation of AKT is associated with many pathological conditions, particularly cancers. Emerging evidence indicates that arginine methylation is involved in modulating AKT signaling pathway. However, whether and how arginine methylation directly regulates AKT kinase activity remain unknown. Here we report that protein arginine methyltransferase 5 (PRMT5), but not other PRMTs, promotes AKT activation by catalyzing symmetric dimethylation of AKT1 at arginine 391 (R391). Mechanistically, AKT1-R391 methylation cooperates with phosphatidylinositol 3,4,5 trisphosphate (PIP3) to relieve the pleckstrin homology (PH)-in conformation, leading to AKT1 membrane translocation and subsequent activation by phosphoinositide-dependent kinase-1 (PDK1) and the mechanistic target of rapamycin complex 2 (mTORC2). As a result, deficiency in AKT1-R391 methylation significantly suppresses AKT1 kinase activity and tumorigenesis. Lastly, we show that PRMT5 inhibitor synergizes with AKT inhibitor or chemotherapeutic drugs to enhance cell death. Altogether, our study suggests that R391 methylation is an important step for AKT activation and its oncogenic function. Arginine methylation has been reported to regulate AKT-associated signalling. Here, the authors show that PRMT5-mediated arginine methylation promotes AKT activity and induces tumourigenesis.
登录
查看更多内容
影响因子：
4.7
作者：
Carnero A;Paramio JM
通讯作者：
Paramio JM
影响因子：
8.8
作者：
Chiang K;Zielinska AE;Shaaban AM;Sanchez-Bailon MP;Jarrold J;Clarke TL;Zhang J;Francis A;Jones LJ;Smith S;Barbash O;Guccione E;Farnie G;Smalley MJ;Davies CC
通讯作者：
Davies CC
影响因子：
4
作者：
Bedford, Mark T.
通讯作者：
Bedford, Mark T.
影响因子：
56.9
作者：
Franke, TF;Kaplan, DR;Toker, A
通讯作者：
Toker, A
DOI：
10.1016/s1387-2656(08)00008-2
发表时间：
2008-01-01
期刊：
BIOTECHNOLOGY ANNUAL REVIEW, VOL 14
影响因子：
--
作者：
Aletta, John M.;Hu, John C.
通讯作者：
Hu, John C.