The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
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- Alexander Martin Heberle
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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- Patricia Razquin Navas
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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- Miriam Langelaar-Makkinje
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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- Katharina Kasack
- Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
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- Ahmed Sadik
- Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
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- Erik Faessler
- Jena University Language and Information Engineering Lab, Friedrich-Schiller-University Jena, Jena, Germany
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- Udo Hahn
- Jena University Language and Information Engineering Lab, Friedrich-Schiller-University Jena, Jena, Germany
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- Philip Marx-Stoelting
- German Federal Institute for Risk Assessment, Strategies for Toxicological Assessment, Experimental Toxicology and ZEBET, German Centre for the Protection of Laboratory Animals (Bf3R), Berlin, Germany
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- Christiane A Opitz
- Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
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- Christine Sers
- Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany
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- Ines Heiland
- Faculty of Bioscience, Fisheries and Economics, Department of Arctic and Marine Biology, UiT The Arctic University of Norway, Tromsø, Norway
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- Sascha Schäuble
- Jena University Language and Information Engineering Lab, Friedrich-Schiller-University Jena, Jena, Germany
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- Kathrin Thedieck
- Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
抄録
<jats:p>All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.</jats:p>
収録刊行物
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- Life Science Alliance
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Life Science Alliance 2 (2), e201800257-, 2019-03-28
Life Science Alliance, LLC