Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation.


Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell cycle progression, is poorly understood. Here, we study different hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell type-specific proliferation. First, cell type-specific protein abundance patterns cause differential signal flow along the AKT and ERK pathways. Second, downstream regulators of both pathways have differential effects on proliferation, suggesting that protein synthesis is rate-limiting for faster cycling cells while slower cell cycles are controlled at the G1-S progression. The integrated mathematical model of Epo-driven proliferation explains cell type-specific effects of targeted AKT and ERK inhibitors and faithfully predicts, based on the protein abundance, anti-proliferative effects of inhibitors in primary human erythroid progenitor cells. Our findings suggest that the effectiveness of targeted cancer therapy might become predictable from protein abundance.


PubMed ID: 28123004

Projects: SBEpo - Systems Biology of Erythropoietin

Publication type: Journal

Journal: Mol Syst Biol

Citation: Mol Syst Biol. 2017 Jan 24;13(1):904. doi: 10.15252/msb.20167258.

Date Published: 24th Jan 2017

Registered Mode: Not specified

Authors: L. Adlung, S. Kar, M. C. Wagner, B. She, S. Chakraborty, J. Bao, S. Lattermann, M. Boerries, H. Busch, P. Wuchter, A. D. Ho, J. Timmer, M. Schilling, T. Hofer, U. Klingmuller

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Created: 31st Jan 2017 at 14:05

Last updated: 3rd Aug 2020 at 18:42

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