Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis

Karayel, O.; Xu, P.; Bludau, I.; Bhoopalan, S. V.; Yao, Y.; Freitas Colaco, A. R.; Santos Delgado, A.; Schulman, B. A.; Alpi, A. F.; Weiss, M. J.; Mann, M.

doi:10.1101/2020.05.18.102178

bioRxiv · 10.1101/2020.05.18.102178

Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis

Karayel, O.·Xu, P.·Bludau, I.·Bhoopalan, S. V.·Yao, Y.·Freitas Colaco, A. R.·Santos Delgado, A.·Schulman, B. A.·Alpi, A. F.·Weiss, M. J.·Mann, M.

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Abstract

Human erythropoiesis is exquisitely controlled at multiple levels and its dysregulation leads to numerous human diseases. Despite many functional studies focused on classical regulators, we lack a global, system-wide understanding of post-translational mechanisms coordinating erythroid maturation. Using the latest advances in mass spectrometry (MS)-based proteomics we comprehensively investigate the dynamics of protein and post-translational regulation of in vitro reconstituted CD34+ HSPC-derived erythropoiesis. This quantifies and dynamically tracks 7,400 proteins and 27,000 phosphorylation sites. Our data reveals differential temporal protein expression encompassing most protein classes and numerous post-translational regulatory cascades. Drastic cell surface remodeling across erythropoiesis include numerous orchestrated changes in solute carriers, providing new stage-specific markers. The dynamic phosphoproteomes combined with a kinome-targeting CRISPR/Cas9 screen reveal coordinated networks of erythropoietic kinases and downregulation of MAPK signaling subsequent to c-Kit attenuation as key drivers of maturation. Our global view of erythropoiesis establishes a central role of post-translational regulation in terminal differentiation.

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Karayel, O., Xu, P., Bludau, I., Bhoopalan, S. V., Yao, Y., Freitas Colaco, A. R., Santos Delgado, A., Schulman, B. A., Alpi, A. F., Weiss, M. J., Mann, M.. 2020-05-19. Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis. https://doi.org/10.1101/2020.05.18.102178

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