Argonaute 2 modulates EGFR-RAS signaling to promote mutant HRAS and NRAS-driven malignancies.
Argonaute 2 modulates EGFR-RAS signaling to promote mutant HRAS and NRAS-driven malignancies.
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ArgAerte 2调节EGFR-RAS信号以促进突变的HRAS和NRAS驱动的恶性肿瘤。
DOI：
10.1093/pnasnexus/pgac084
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Chinnaiyan, Arul M.
中科院分区：
文献类型：
--
作者：
Siebenaler, Ronald F.;Chugh, Seema;Waninger, Jessica J.;Dommeti, Vijaya L.;Kenum, Carson;Mody, Malay;Gautam, Anudeeta;Patel, Nidhi;Chu, Alec;Bawa, Pushpinder;Hon, Jennifer;Smith, Richard D.;Carlson, Heather;Cao, Xuhong;Tesmer, John J. G.;Shankar, Sunita;Chinnaiyan, Arul M.
RAS GTP酶的激活突变驱动了近30%的人类癌症。我们先前的工作描述了Argonaute 2（AGO 2）在突变KRAS驱动的癌症中的重要作用，即RNA诱导的沉默复合物。在这里，我们确定了一种新的内源性AGO 2和RAS之间的相互作用在野生型（WT）和突变型HRAS/NRAS细胞。这种相互作用是通过EGFR介导的Y393-AGO 2磷酸化来调节的，并且利用分子动态模拟，我们鉴定了pY 393-AGO 2蛋白结构的构象变化，导致RAS结合位点的破坏。AGO 2的敲低导致突变型HRAS/NRAS驱动的细胞系而非WT RAS细胞的增殖显著降低。这些细胞表现出癌基因诱导的衰老（OIS），如通过β-半乳糖苷酶染色和多个下游衰老效应物的诱导所证明的。从机制上讲，我们发现衰老表型是通过诱导活性氧介导的。有趣的是，我们进一步确定了AGO 2的缺失促进了一种新的前馈途径，导致PTP 1B磷酸酶的抑制和EGFR-MAPK信号的激活，从而导致OIS。综上所述，我们的研究表明，EGFR-AGO 2-RAS信号轴是维持突变型HRAS和NRAS驱动的恶性肿瘤所必需的。
Activating mutations in RAS GTPases drive nearly 30% of all human cancers. Our prior work described an essential role for Argonaute 2 (AGO2), of the RNA-induced silencing complex, in mutant KRAS-driven cancers. Here, we identified a novel endogenous interaction between AGO2 and RAS in both wild-type (WT) and mutant HRAS/NRAS cells. This interaction was regulated through EGFR-mediated phosphorylation of Y393-AGO2, and utilizing molecular dynamic simulation, we identified a conformational change in pY393-AGO2 protein structure leading to disruption of the RAS binding site. Knockdown of AGO2 led to a profound decrease in proliferation of mutant HRAS/NRAS-driven cell lines but not WT RAS cells. These cells demonstrated oncogene-induced senescence (OIS) as evidenced by β-galactosidase staining and induction of multiple downstream senescence effectors. Mechanistically, we discovered that the senescent phenotype was mediated via induction of reactive oxygen species. Intriguingly, we further identified that loss of AGO2 promoted a novel feed forward pathway leading to inhibition of the PTP1B phosphatase and activation of EGFR–MAPK signaling, consequently resulting in OIS. Taken together, our study demonstrates that the EGFR–AGO2–RAS signaling axis is essential for maintaining mutant HRAS and NRAS-driven malignancies.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
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28.5
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作者：
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通讯作者：
Finkel, T
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4
作者：
Hobbs, G. Aaron;Der, Channing J.;Rossman, Kent L.
通讯作者：
Rossman, Kent L.
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS