RT Journal Article
SR Electronic
T1 The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800257
DO 10.26508/lsa.201800257
VO 2
IS 2
A1 Alexander Martin Heberle
A1 Patricia Razquin Navas
A1 Miriam Langelaar-Makkinje
A1 Katharina Kasack
A1 Ahmed Sadik
A1 Erik Faessler
A1 Udo Hahn
A1 Philip Marx-Stoelting
A1 Christiane A Opitz
A1 Christine Sers
A1 Ines Heiland
A1 Sascha Schäuble
A1 Kathrin Thedieck
YR 2019
UL https://www.life-science-alliance.org/content/2/2/e201800257.abstract
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.