PT  - JOURNAL ARTICLE
AU  - Heberle, Alexander Martin
AU  - Razquin Navas, Patricia
AU  - Langelaar-Makkinje, Miriam
AU  - Kasack, Katharina
AU  - Sadik, Ahmed
AU  - Faessler, Erik
AU  - Hahn, Udo
AU  - Marx-Stoelting, Philip
AU  - Opitz, Christiane A
AU  - Sers, Christine
AU  - Heiland, Ines
AU  - Schäuble, Sascha
AU  - Thedieck, Kathrin
TI  - The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
AID  - 10.26508/lsa.201800257
DP  - 2019 Apr 01
TA  - Life Science Alliance
PG  - e201800257
VI  - 2
IP  - 2
4099  - http://www.life-science-alliance.org/content/2/2/e201800257.short
4100  - http://www.life-science-alliance.org/content/2/2/e201800257.full
SO  - Life Sci. Alliance2019 Apr 01; 2
AB  - 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.