Personalized phosphoproteomics identifies functional signaling

Elise J Needham, Janne Rasmuss Hingst, Benjamin L Parker, Kaitlin R Morrison, Guang Yang, Johan Dejgaard Onslev, Jonas Møller Kristensen, Kurt Højlund, Naomi X Y Ling, Jonathan S Oakhill, Erik A. Richter, Bente Kiens, Janni Petersen, Christian Pehmøller, David E James*, Jørgen Wojtaszewski*, Sean J Humphrey*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

46 Citations (Scopus)

Abstract

Protein phosphorylation dynamically integrates environmental and cellular information to control biological processes. Identifying functional phosphorylation amongst the thousands of phosphosites regulated by a perturbation at a global scale is a major challenge. Here we introduce 'personalized phosphoproteomics', a combination of experimental and computational analyses to link signaling with biological function by utilizing human phenotypic variance. We measure individual subject phosphoproteome responses to interventions with corresponding phenotypes measured in parallel. Applying this approach to investigate how exercise potentiates insulin signaling in human skeletal muscle, we identify both known and previously unidentified phosphosites on proteins involved in glucose metabolism. This includes a cooperative relationship between mTOR and AMPK whereby the former directly phosphorylates the latter on S377, for which we find a role in metabolic regulation. These results establish personalized phosphoproteomics as a general approach for investigating the signal transduction underlying complex biology.

Original languageEnglish
JournalNature Biotechnology
Volume40
Issue number4
Pages (from-to)576-584
Number of pages9
ISSN1087-0156
DOIs
Publication statusPublished - 2022

Bibliographical note

© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

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