title: Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation.
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.
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lorenz
authors.identifier: 0000-0002-0971-2309
authors.initials: L
authors.lastname: Adlung
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|BioQuant Center, University of Heidelberg, Heidelberg, Germany.|Department of Chemistry, Indian Institute of Technology, Mumbai, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Kar
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Wagner
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bin
authors.initials: B
authors.lastname: She
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sajib
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.
authors.forename: Jie
authors.initials: J
authors.lastname: Bao
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Lattermann
authors.affiliation: Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.affiliation: Systems Biology of the Cellular Microenvironment Group, IMMZ, ALU, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hauke
authors.identifier: 0000-0003-4763-4521
authors.initials: H
authors.lastname: Busch
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany.|Institute for Transfusion Medicine and Immunology, University of Heidelberg, Mannheim, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wuchter
authors.affiliation: Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Center for Biological Signaling Studies (BIOSS), Institute of Physics, University of Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marcel
authors.identifier: 0000-0002-9517-5166
authors.initials: M
authors.lastname: Schilling
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany t.hoefer@dkfz.de u.klingmueller@dkfz.de.|BioQuant Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany t.hoefer@dkfz.de u.klingmueller@dkfz.de.|Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Ursula
authors.identifier: 0000-0001-9845-3099
authors.initials: U
authors.lastname: Klingmüller
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D004921:Erythropoietin / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008962:Models, Theoretical; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D004921:Erythropoietin; D051057:Proto-Oncogene Proteins c-akt
keywords: 
  MAPK
  ; 32D‐EpoR; BaF3‐EpoR; CFU‐E; PI3K