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

TY - JOUR

T1 - Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation

AU - Adlung, Lorenz

AU - Kar, Sandip

AU - Wagner, Marie-Christine

AU - She, Bin

AU - Chakraborty, Sajib

AU - Bao, Jie

AU - Lattermann, Susen

AU - Boerries, Melanie

AU - Busch, Hauke

AU - Wuchter, Patrick

AU - Ho, Anthony D

AU - Timmer, Jens

AU - Schilling, Marcel

AU - Höfer, Thomas

AU - Klingmüller, Ursula

N1 - © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2017/1/24

Y1 - 2017/1/24

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Cell Cycle

KW - Cell Proliferation

KW - Cells, Cultured

KW - Erythroid Cells/cytology

KW - Erythropoietin/metabolism

KW - Humans

KW - MAP Kinase Signaling System

KW - Mice

KW - Models, Theoretical

KW - Proto-Oncogene Proteins c-akt/metabolism

U2 - 10.15252/msb.20167258

DO - 10.15252/msb.20167258

M3 - SCORING: Journal article

C2 - 28123004

VL - 13

SP - 904

IS - 1

ER -