Gupta, AmitAnjomani-Virmouni, SaraKoundouros, NikosDimitriadi, MariaChoo-Wing, RaymanValle, AdamoZheng, YuxiangChiu, Yu-HsinAgnihotri, SameerZadeh, GelarehAsara, John MAnastasiou, DimitriosArends, Mark JCantley, Lewis CPoulogiannis, George2024-07-112024-07-112017-03-16Gupta 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.e7.1097-2765http://hdl.handle.net/20.500.13003/9903http://hdl.handle.net/20.500.12105/20418PARK2 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.enghttp://creativecommons.org/licenses/by/4.0/Dose-Response Relationship, DrugEnzyme ActivationCell MovementHumansUbiquitin-Protein LigasesTOR Serine-Threonine KinasesMCF-7 CellsProtein Processing, Post-TranslationalCell SurvivalTime FactorsAMP-Activated Protein KinasesOxidation-ReductionProto-Oncogene Proteins c-aktMice, Inbred NODSignal TransductionMice, KnockoutPTEN PhosphohydrolaseGene Expression Regulation, NeoplasticTumor BurdenOxidative StressEnergy MetabolismTransfectionHEK293 CellsHCT116 CellsNitric OxideAntineoplastic AgentsProtein Kinase InhibitorsCell ProliferationNeoplasmsGene Expression ProfilingNitric Oxide Synthase Type IIIAnimalsUbiquitinationPhosphatidylinositol 3-KinaseMice, SCIDRNA Interferenceresearch articleAttribution 4.0 International28306514656999-1013.e710.1016/j.molcel.2017.02.0191097-4164Molecular Cellopen accessUbiquitina-Proteína LigasasRatones SCIDSerina-Treonina Quinasas TORCélulas MCF-7Supervivencia CelularFosfatidilinositol 3-QuinasaUbiquitinaciónAntineoplásicosMetabolismo EnergéticoNeoplasiasInterferencia de ARNÓxido NítricoÓxido Nítrico Sintasa de Tipo IIIPerfilación de la Expresión GénicaTransducción de SeñalAnimalesRegulación Neoplásica de la Expresión GénicaRatones NoqueadosCélulas HCT116Proliferación CelularRatones Endogámicos NODInhibidores de Proteínas QuinasasCélulas HEK293Factores de TiempoCarga TumoralMovimiento CelularRelación Dosis-Respuesta a DrogaActivación EnzimáticaHumanosProteínas Quinasas Activadas por AMPProcesamiento Proteico-PostraduccionalEstrés OxidativoFosfohidrolasa PTENTransfecciónOxidación-ReducciónProteínas Proto-Oncogénicas c-akt2-s2.0-85015319383396431900008L614882907