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 an...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-01-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.20167258 |
| _version_ | 1797279859971457024 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lorenz Adlung |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T16:32:05Z |
| format | Article |
| id | doaj.art-f4655425dbe749a68a27fd0cddb98e78 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T16:32:05Z |
| publishDate | 2017-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-f4655425dbe749a68a27fd0cddb98e782024-03-03T10:18:18ZengSpringer NatureMolecular Systems Biology1744-42922017-01-01131n/an/a10.15252/msb.20167258Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferationLorenz Adlung0Sandip Kar1Marie‐Christine Wagner2Bin She3Sajib Chakraborty4Jie Bao5Susen Lattermann6Melanie Boerries7Hauke Busch8Patrick Wuchter9Anthony D Ho10Jens Timmer11Marcel Schilling12Thomas Höfer13Ursula Klingmüller14Division of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Theoretical Systems Biology German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanySystems Biology of the Cellular Microenvironment Group IMMZ ALU Freiburg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanySystems Biology of the Cellular Microenvironment Group IMMZ ALU Freiburg GermanySystems Biology of the Cellular Microenvironment Group IMMZ ALU Freiburg GermanyDepartment of Medicine V University of Heidelberg Heidelberg GermanyDepartment of Medicine V University of Heidelberg Heidelberg GermanyCenter for Biological Signaling Studies (BIOSS) Institute of Physics, University of Freiburg Freiburg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Theoretical Systems Biology German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Systems Biology of Signal Transduction German Cancer Research Center (DKFZ) Heidelberg GermanyAbstract 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.https://doi.org/10.15252/msb.2016725832D‐EpoRBaF3‐EpoRCFU‐EMAPKPI3K |
| spellingShingle | 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 Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation Molecular Systems Biology 32D‐EpoR BaF3‐EpoR CFU‐E MAPK PI3K |
| title | Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation |
| title_full | Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation |
| title_fullStr | Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation |
| title_full_unstemmed | Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation |
| title_short | Protein abundance of AKT and ERK pathway components governs cell type‐specific regulation of proliferation |
| title_sort | protein abundance of akt and erk pathway components governs cell type specific regulation of proliferation |
| topic | 32D‐EpoR BaF3‐EpoR CFU‐E MAPK PI3K |
| url | https://doi.org/10.15252/msb.20167258 |
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