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PARK2 Depletion Connects Energy and Oxidative Stress to PI3K/Akt Activation via PTEN S-Nitrosylation
Authors
Adamo Valle
Agnihotri
+71 more
Amit Gupta
Aquilano
Bernardini
Broniowska
Burns
Carracedo
Corti
Dawson
Di Cristofano
Dimitrios Anastasiou
Dimmeler
Efeyan
Fallon
Fujiwara
Gelareh Zadeh
George Poulogiannis
Glessner
Gong
Green
Gupta
Hedrich
Ismail
Itier
John M. Asara
Kim
Kitada
Kovacs
Kwak
Lee
Leonard
Lewis C. Cantley
Lin
Lücking
Manning
Manzanillo
Maria Dimitriadi
Mark J. Arends
Mira
Mookherjee
Nikos Koundouros
Numajiri
Ocana
Ong
Periquet
Picchio
Podsypanina
Poulogiannis
Rayman Choo-Wing
Saal
Sameer Agnihotri
Sara Anjomani-Virmouni
Schulz
Siddiqui
Song
Song
Stevens
Szász
Tay
Trachootham
Trotman
Unoki
Veeriah
Wang
Wongseree
Xiao
Yeo
Yu-Hsin Chiu
Yuan
Yuan
Yuxiang Zheng
Zhang
Publication date
1 March 2017
Publisher
'Elsevier BV'
Doi
Abstract
© 2017 The Authors. PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely un-known. Here we show that PARK2is 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 nitricoxide synthase (eNOS), enhanced levels of reactiveoxygen species, and a concomitant increase inoxidized nitric oxide levels, thereby promoting theinhibition 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-nitrosylationin supporting cell survival and proliferation under conditions of energy deprivation.NIH P01-CA120964 (J.M.A. and L.C.C.) and R01-GM041890; Ministry of Education, Culture and Sport under the Program for Promoting and Hiring of Talent and its Employability (Subprogram for Mobility) of the Spanish Government; ICR; MRC grant MC_UP_1202/1
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