An optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells

Wenping Zhou, Wenxue Li, Shisheng Wang, Barbora Salovska, Zhenyi Hu, Bo Tao, Yi Di, Ujwal Punyamurtula, Benjamin E. Turk, William C. Sessa () and Yansheng Liu ()
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Wenping Zhou: Yale University School of Medicine
Wenxue Li: Yale University School of Medicine
Shisheng Wang: Sichuan University
Barbora Salovska: Yale University School of Medicine
Zhenyi Hu: Yale University School of Medicine
Bo Tao: Yale University School of Medicine
Yi Di: Yale University School of Medicine
Ujwal Punyamurtula: Brown University
Benjamin E. Turk: Yale University School of Medicine
William C. Sessa: Yale University School of Medicine
Yansheng Liu: Yale University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The serine/threonine kinase AKT is a central node in cell signaling. While aberrant AKT activation underlies the development of a variety of human diseases, how different patterns of AKT-dependent phosphorylation dictate downstream signaling and phenotypic outcomes remains largely enigmatic. Herein, we perform a systems-level analysis that integrates methodological advances in optogenetics, mass spectrometry-based phosphoproteomics, and bioinformatics to elucidate how different intensity, duration, and pattern of Akt1 stimulation lead to distinct temporal phosphorylation profiles in vascular endothelial cells. Through the analysis of ~35,000 phosphorylation sites across multiple conditions precisely controlled by light stimulation, we identify a series of signaling circuits activated downstream of Akt1 and interrogate how Akt1 signaling integrates with growth factor signaling in endothelial cells. Furthermore, our results categorize kinase substrates that are preferably activated by oscillating, transient, and sustained Akt1 signals. We validate a list of phosphorylation sites that covaried with Akt1 phosphorylation across experimental conditions as potential Akt1 substrates. Our resulting dataset provides a rich resource for future studies on AKT signaling and dynamics.

Date: 2023
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DOI: 10.1038/s41467-023-39514-1

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