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

10.15252/msb.20167258

Projects: WP1: Integration of Epo-induced Signal Transduction, WP2: Link of Signal Transduction to Gene Regulatory Network, WP3: Cell Fate Decisions of Erythroid Progenitor Cells, WP5: Translational Application for the Characterization and ex vivo Expa...

Mol Syst Biol
24th Jan 2017

Lorenz Adlung, Sandip Kar, Marie-Christine Wagner, Bin She, Sajib Chakraborty, Jie Bao, Susen Lattermann, Melanie Boerries, Hauke Busch, Patrick Wuchter, Anthony D Ho, Jens Timmer, Marcel Schilling, Thomas Höfer, Ursula Klingmüller

Abstract:

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.

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Marcel Schilling

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