Global redox proteome and phosphoproteome analysis reveals redox switch in Akt

Su, Zhiduan, Burchfield, James G., Yang, Pengyi, Humphrey, Sean J., Yang, Guang, Francis, Deanne, Yasmin, Sabina, Shin, Sung-Young, Norris, Dougall M., Kearney, Alison L., Astore, Miro A., Scavuzzo, Jonathan, Fisher-Wellman, Kelsey H., Wang, Qiao-Ping, Parker, Benjamin L., Neely, G. Gregory, Vafaee, Fatemeh, Chiu, Joyce, Yeo, Reichelle, Hogg, Philip J., Fazakerley, Daniel J., Nguyen, Lan K., Kuyucak, Serdar, and James, David E. (2019) Global redox proteome and phosphoproteome analysis reveals redox switch in Akt. Nature Communications, 10. 5486.

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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.

Item ID: 73621
Item Type: Article (Research - C1)
ISSN: 2041-1723
Copyright Information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Funders: National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: NHMRC project grant GNT112020, ARC Discovery Project DP180103482, ARC Discovery Early Career Researcher Award DE170100759
Date Deposited: 03 Aug 2022 02:28
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310103 Cell metabolism @ 25%
31 BIOLOGICAL SCIENCES > 3109 Zoology > 310910 Animal physiology - systems @ 25%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310109 Proteomics and intermolecular interactions (excl. medical proteomics) @ 50%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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