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oai:repisalud.isciii.es:20.500.12105/204182024-11-29T02:59:27Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967
Repisalud author Gupta, Amit author Anjomani-Virmouni, Sara author Koundouros, Nikos author Dimitriadi, Maria author Choo-Wing, Rayman author Valle, Adamo author Zheng, Yuxiang author Chiu, Yu-Hsin author Agnihotri, Sameer author Zadeh, Gelareh author Asara, John M author Anastasiou, Dimitrios author Arends, Mark J author Cantley, Lewis C author Poulogiannis, George 2024-07-11T09:07:42Z 2024-07-11T09:07:42Z 2017-03-16 Gupta A, Anjomani-Virmouni S, Koundouros N, Dimitriadi M, Choo-Wing R, Valle A, et al. PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation. Mol Cell. 2017 Mar 16;65(6):999-1013.e7. 10.1016/j.molcel.2017.02.019 1097-4164 1097-2765 Molecular Cell http://hdl.handle.net/20.500.13003/9903 28306514 L614882907 2-s2.0-85015319383 http://hdl.handle.net/20.500.12105/20418 396431900008 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. eng PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation research article