The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner

Heberle, Alexander Martin; Navas, Patricia Razquin; Langelaar-Makkinje, Miriam; Kasack, Katharina; Sadik, Ahmed; Faessler, Erik; Hahn, Udo; Marx-Stoelting, Philip; Opitz, Christiane A.; Sers, Christine; Heiland, Ines; Schäuble, Sascha; Thedieck, Kathrin

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.

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Heberle, Alexander / Navas, Patricia / Langelaar-Makkinje, Miriam / et al: The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner. 2019.

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