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

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

    OnderzoeksoutputAcademicpeer review

    15 Citaten (Scopus)
    169 Downloads (Pure)

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    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.

    Originele taal-2English
    Artikelnummer201800257
    Aantal pagina's22
    TijdschriftLife science alliance
    Volume2
    Nummer van het tijdschrift2
    DOI's
    StatusPublished - apr-2019

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