University of Hertfordshire


  • Amit Gupta
  • Sara Anjomani-Virmouni
  • Nikos Koundouros
  • Maria Dimitriadi
  • Rayman Choo-Wing
  • Adamo Valle
  • Yuxiang Zheng
  • Yu-Hsin Chiu
  • Sameer Agnihotri
  • Gelareh Zadeh
  • John M Asara
  • Dimitrios Anastasiou
  • Mark J Arends
  • Lewis C Cantley
  • George Poulogiannis
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Original languageEnglish
Pages (from-to)999-1013.e7
JournalMolecular Cell
Journal publication date16 Mar 2017
Publication statusPublished - 16 Mar 2017


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.


This is an Open Access article, Open Access funded by Wellcome Trust Under a Creative Commons license.

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