The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
| Autor: | Patricia Razquin Navas, Udo Hahn, Kathrin Thedieck, Erik Faessler, Christine Sers, Katharina Kasack, Ahmed Sadik, Christiane A. Opitz, Miriam Langelaar-Makkinje, Philip Marx-Stoelting, Sascha Schäuble, Ines Heiland, Alexander Martin Heberle |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Arsenites Cell Survival Health Toxicology and Mutagenesis p38 mitogen-activated protein kinases VDP::Mathematics and natural science: 400::Basic biosciences: 470::Cell biology: 471 Plant Science mTORC1 Mechanistic Target of Rapamycin Complex 1 Biology Cytoplasmic Granules Transfection p38 Mitogen-Activated Protein Kinases Biochemistry Genetics and Molecular Biology (miscellaneous) Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Stress granule Stress Physiological Humans Computer Simulation Stress granule assembly Phosphorylation Research Articles PI3K/AKT/mTOR pathway Ecology HEK 293 cells Translation (biology) Cell biology HEK293 Cells 030104 developmental biology Gene Knockdown Techniques 030220 oncology & carcinogenesis MCF-7 Cells biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt Research Article HeLa Cells Signal Transduction VDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Cellebiologi: 471 |
| Zdroj: | Life Science Alliance Life science alliance, 2(2):201800257. Life Science Alliance LLC |
| ISSN: | 2575-1077 |
| Popis: | PI3K and p38 act in a hierarchical manner to enhance mTORC1 activity and stress granule formation; although PI3K is the main driver, the impact of p38 gets apparent as PI3K activity declines. 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. |
| Databáze: | OpenAIRE |
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