PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation

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. [Display omitted] •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.