PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation.
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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.
Version of record
PARK2, PI3K/Akt activation
AMP-Activated Protein Kinases
Dose-Response Relationship, Drug
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Mice, Inbred NOD
Nitric Oxide Synthase Type III
Protein Kinase Inhibitors
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
Signalling & Cancer Metabolism
License start date
Mol Cell, 2017, 65 (6), pp. 999 - 1013.e7
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
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