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Journal Article

Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis

MPS-Authors
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Karayel,  Özge
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Bludau,  Isabell
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Schulman,  Brenda A.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Alpi,  Arno F.
Schulman, Brenda / Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

Fulltext (public)

msb.20209813.pdf
(Publisher version), 5MB

Supplementary Material (public)

msb20209813.reviewer_comments.pdf
(Supplementary material), 881KB

Citation

Karayel, Ö., Xu, P., Bludau, I., Velan Bhoopalan, S., Yao, Y., Ana Rita, F., et al. (2020). Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis. Molecular Systems Biology, 16(12): e9813. doi:10.15252/msb.20209813.


Cite as: http://hdl.handle.net/21.11116/0000-0007-9B31-3
Abstract
Human erythropoiesis is an exquisitely controlled multistep developmental process, and its dysregulation leads to numerous human diseases. Transcriptome and epigenome studies provided insights into system-wide regulation, but we currently lack a global mechanistic view on the dynamics of proteome and post-translational regulation coordinating erythroid maturation. We established a mass spectrometry (MS)-based proteomics workflow to quantify and dynamically track 7,400 proteins and 27,000 phosphorylation sites of five distinct maturation stages of in vitro reconstituted erythropoiesis of CD34+ HSPCs. Our data reveal developmental regulation through drastic proteome remodeling across stages of erythroid maturation encompassing most protein classes. This includes various orchestrated changes in solute carriers indicating adjustments to altered metabolic requirements. To define the distinct proteome of each maturation stage, we developed a computational deconvolution approach which revealed stage-specific marker proteins. The dynamic phosphoproteomes combined with a kinome-targeted CRISPR/Cas9 screen uncovered coordinated networks of erythropoietic kinases and pinpointed downregulation of c-Kit/MAPK signaling axis as key driver of maturation. Our system-wide view establishes the functional dynamic of complex phosphosignaling networks and regulation through proteome remodeling in erythropoiesis. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.