Adlung, Lorenz
[Author];
Wuchter, Patrick
[Author];
Ho, Anthony Dick
[Author];
Schilling, Marcel
[Author];
Höfer, Thomas
[Author];
Klingmüller, Ursula
[Author]
Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation
Description:
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. Synopsis <img class="highwire-embed" alt="Embedded Image" src="http://msb.embopress.org/sites/default/files/highwire/msb/13/1/904/embed/graphic-1.gif"/>Mathematical modeling and quantitative experiments identify the abundance of components of the AKT and ERK signaling pathways as the key determinant of the cell type‐specific regulation of Epo‐induced proliferation. Cell type‐specific dynamics of Epo‐induced signal activation are determined by the different abundance of key signaling proteins.A dynamic pathway model adapted to experimentally measured, cell type‐specific protein abundance can faithfully predict the Epo‐induced dynamics of AKT, ERK, and S6 activation.Based on snapshot measurements of protein abundance, the mathematical model predicts the cell type‐specific impact of AKT and MEK inhibitors on Epo‐induced proliferation in human cells.