Global redox proteome and phosphoproteome analysis reveals redox switch in Akt

Zhiduan Su, James G. Burchfield, Pengyi Yang, Sean J. Humphrey, Guang Yang, Deanne Francis, Sabina Yasmin, Sung-Young Shin, Dougall M. Norris, Miro A. Astore, Jonathan Scavuzzo, Kelsey H. Fisher-Wellman, Qiao Ping Wang, Benjamin L. Parker, G. Gregory Neely, Fatemeh Vafaee, Joyce Chiu, Reichelle Yeo, Philip J. Hogg, Daniel J. FazakerleyLan K. Nguyen, Serdar Kuyucak, David E. James

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63 Citations (Scopus)

Abstract

Protein oxidation sits at the intersection of multiple signalling pathways, yet the magnitude and extent of crosstalk between oxidation and other post-translational modifications remains unclear. Here, we delineate global changes in adipocyte signalling networks following acute oxidative stress and reveal considerable crosstalk between cysteine oxidation and phosphorylation-based signalling. Oxidation of key regulatory kinases, including Akt, mTOR and AMPK influences the fidelity rather than their absolute activation state, highlighting an unappreciated interplay between these modifications. Mechanistic analysis of the redox regulation of Akt identified two cysteine residues in the pleckstrin homology domain (C60 and C77) to be reversibly oxidized. Oxidation at these sites affected Akt recruitment to the plasma membrane by stabilizing the PIP3 binding pocket. Our data provide insights into the interplay between oxidative stress-derived redox signalling and protein phosphorylation networks and serve as a resource for understanding the contribution of cellular oxidation to a range of diseases.

Original languageEnglish
Article number5486
Number of pages18
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2 Dec 2019

Keywords

  • insulin signalling
  • post-translational modifications
  • proteomics

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