PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.
PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.
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DOI：
10.1016/j.molcel.2017.02.019
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发表时间：
2017-03-16
期刊：
影响因子：
16
通讯作者：
Poulogiannis G
中科院分区：
文献类型：
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作者：
Gupta A;Anjomani-Virmouni S;Koundouros N;Dimitriadi M;Choo-Wing R;Valle A;Zheng Y;Chiu YH;Agnihotri S;Zadeh G;Asara JM;Anastasiou D;Arends MJ;Cantley LC;Poulogiannis G
PARK 2是一种与疾病状态有关的基因，在细胞命运决定中具有相反的反应，但其在促生存信号传导中的作用在很大程度上是未知的。在这里，我们发现PARK 2在超过三分之一的人类癌症中发生了改变，其缺失导致磷脂酰肌醇3-激酶/Akt（PI 3 K/Akt）活化增强，并增加了对PI 3 K/Akt/mTOR抑制剂的脆弱性。PARK 2耗竭有助于AMPK介导的内皮型一氧化氮合酶（eNOS）的活化、活性氧水平的增强以及氧化型一氧化氮水平的伴随增加，从而促进S-亚硝基化和泛素化对PTEN的抑制。值得注意的是，在PARK 2缺失的情况下，单独的AMPK活化足以诱导PTEN S-亚硝基化。Park 2缺失和Pten缺失在促进体内肿瘤发生方面也表现出显著的协同性。总之，我们的研究结果揭示了一个重要的缺失机制，可能是PARK 2缺陷肿瘤中PTEN抑制的原因，并且它们突出了PTEN S-亚硝基化在能量剥夺条件下支持细胞存活和增殖的重要性。PARK 2负调节PI 3 K/Akt途径PARK 2耗竭通过S-亚硝基化和泛素化促进PTEN失活AMPK活化在PARK 2耗竭不存在的情况下触发PTEN S-亚硝基化PARK 2损失和PTEN损失显示出显著的协同性以促进体内肿瘤发生Gupta et al.揭示了在控制PI 3 K/Akt激活的动态信号传导和代谢网络中的重要缺失片段。PARK 2失活通过S-亚硝基化通过氧化还原介导的PTEN失活将能量和氧化应激与Akt活化连接起来，以支持能量剥夺条件下的细胞存活。
PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here we show that PARK2 is altered in over a third of all human cancers, and its depletion results in enhanced phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of endothelial nitric oxide synthase (eNOS), enhanced levels of reactive oxygen species, and a concomitant increase in oxidized nitric oxide levels, thereby promoting the inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 loss and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors, and they highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation. PARK2 negatively regulates the PI3K/Akt pathway PARK2 depletion promotes PTEN inactivation by S-nitrosylation and ubiquitination AMPK activation triggers PTEN S-nitrosylation in the absence of PARK2 depletion PARK2 loss and PTEN loss display striking cooperativity to promote tumorigenesis in vivo Gupta et al. reveal an important missing piece in the dynamic signaling and metabolic network governing PI3K/Akt activation. PARK2 inactivation connects energy and oxidative stress to Akt activation via redox-mediated inactivation of PTEN by S-nitrosylation to support cell survival under conditions of energy deprivation.