Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation
| Autor: | Jens Timmer, Marie Christine Wagner, Anthony D. Ho, Lorenz Adlung, Melanie Boerries, Susen Lattermann, Hauke Busch, Patrick Wuchter, Thomas Höfer, Bin She, Ursula Klingmüller, Sajib Chakraborty, Jie Bao, Marcel Schilling, Sandip Kar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway 32D‐EpoR Cell Apoptosis PI3K Baf3-Epor Mice 0302 clinical medicine Protein biosynthesis CFU‐E Quantitative Biology & Dynamical Systems Cells Cultured Systems Biology Applied Mathematics Cell Cycle Articles Cell cycle Cell biology medicine.anatomical_structure Computational Theory and Mathematics 030220 oncology & carcinogenesis General Agricultural and Biological Sciences Information Systems Signal Transduction Cell type Erythroid-Differentiation Hematopoietic Progenitor Cells Signal-Transduction Phosphoinositide 3-Kinase MAP Kinase Signaling System Erythropoietin Receptor Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Erythroid Cells medicine Animals Humans Label-Free Quantification Cycle Progression 32d-Epor Protein kinase B Erythropoietin PI3K/AKT/mTOR pathway Cell Proliferation General Immunology and Microbiology Cell growth Models Theoretical MAPK Cfu-E BaF3‐EpoR 030104 developmental biology Functional-Analysis Phosphatidylinositol 3-Kinase Proto-Oncogene Proteins c-akt |
| Zdroj: | Molecular Systems Biology |
| ISSN: | 1744-4292 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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