LKB1 regulates PRMT5 activity in breast cancer.
LKB1 regulates PRMT5 activity in breast cancer.
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DOI：
10.1002/ijc.31909
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发表时间：
2019-02-01
影响因子：
6.4
通讯作者：
Le Romancer M
中科院分区：
文献类型：
--
作者：
Lattouf H;Kassem L;Jacquemetton J;Choucair A;Poulard C;Trédan O;Corbo L;Diab-Assaf M;Hussein N;Treilleux I;Le Romancer M
蛋白质精氨酸甲基转移酶5（PRMT 5）是负责细胞质和细胞核中靶蛋白上精氨酸残基对称二甲基化的主要酶。虽然它的活性与各种癌症的肿瘤进展有关，但这种癌蛋白在乳腺癌中的表达模式几乎没有研究。在目前的工作中，我们分析了其在一个大型乳腺癌患者队列中的表达，揭示了ERα阳性肿瘤中较高的核PRMT 5水平，以及与延长的无病生存期和总生存期的相关性。有趣的是，高PRMT 5核表达也与较高的核肝激酶B1（LKB 1）相关，表明可能存在功能关系。一致地，几种方法提供了PRMT 5和LKB 1在乳腺上皮细胞的细胞质中直接相互作用的证据。此外，虽然PRMT 5不能甲基化LKB 1，但我们发现PRMT 5是LKB 1的良好褪色底物。我们鉴定了位于PRMT 5的TIM-桶结构域中的T132、139和144残基作为LKB 1磷酸化的靶位点。PRMT 5 T139/144突变为A139/144后，其甲基转移酶活性显著降低，这可能是由于失去了与MEP 50、pICln和RiOK 1等调节蛋白的相互作用。此外，LKB 1表达的调节改变了PRMT 5的活性，突出了一种可能具有临床意义的新的调节机制。
Protein arginine methyltransferase 5 (PRMT5) is the main enzyme responsible for the symmetrical dimethylation of arginine residues on target proteins in both the cytoplasm and the nucleus. Though its activity has been associated with tumor progression in various cancers, the expression pattern of this oncoprotein has been scarcely studied in breast cancer. In the current work, we analyzed its expression in a large cohort of breast cancer patients, revealing higher nuclear PRMT5 levels in ERα-positive tumors and an association with prolonged disease free and overall survival. Interestingly, high PRMT5 nuclear expression was also associated with higher nuclear liver kinase B1 (LKB1), suggesting that a functional relationship may occur. Consistently, several approaches provided evidence that PRMT5 and LKB1 interact directly in the cytoplasm of mammary epithelial cells. Moreover, although PRMT5 is not able to methylate LKB1, we found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. In addition, modulation of LKB1 expression modified PRMT5 activity, highlighting a new regulatory mechanism that could have clinical implications.
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DOI：
10.1074/jbc.m109.015578
发表时间：
2009-08-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Pesiridis GS;Diamond E;Van Duyne GD
通讯作者：
Van Duyne GD
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：
--
作者：
Poulard C;Corbo L;Le Romancer M
通讯作者：
Le Romancer M
影响因子：
4.8
作者：
Friesen, WJ;Wyce, A;Dreyfuss, G
通讯作者：
Dreyfuss, G
影响因子：
21.3
作者：
Jansson, Martin;Durant, Stephen T.;La Thangue, Nicholas B.
通讯作者：
La Thangue, Nicholas B.