Taken together, these data demonstrate that PARK2 depletion contributes to the activation of Akt signaling through promoting S-nitrosylation and ubiquitination of the tumor suppressor PTEN. Notably, our data also highlight a previously unexplored mechanism contributing to AMPK-mediated activation of PI3K/Akt involving the inhibition of PTEN by S-nitrosylation, which appears to be critical for the proliferative capacity and survival of PTEN-proficient cancer cells under conditions of energy stress. Here, PTEN is linked to neoplasm.