mTORC3 activity is regulated by GSK3β through the activation of PKCδ that phosphorylates and activates STAT1

Abstract

AbstractThe mechanistic target of rapamycin serine/threonine kinase (mTOR), a critical regulator of cell proliferation, is implicated in many human diseases, including cancer. Our laboratory recently discovered a new mTOR complex, called mTORC3, distinct from the two canonical mTOR complexes, mTORC1, and mTORC2, which causes accelerated proliferation and increased malignancy of cancer cells. Understanding how mTORC3 is controlled is an important approach to designing cancer therapies targeting mTORC3. Having investigated how mTORC3 activity was affected by glycogen synthase kinase-3β (GSK3β), a known regulator of mTOR activity, we found that cells do not assemble mTORC3 upon GSK3β knockout, due to extinguished expression of ETV7, an essential component of the mTORC3 complex. We discovered that the lack of ETV7 expression resulted from reduced phosphorylation of serine 727 (S727) of the Signal Transducer and Activator of Transcription 1 (STAT1), which is required for transcriptional activation of ETV7. Finally, we identified that GSK3β through PKCδ phosphorylates STAT1-S727. Together, we identified a novel GSK3β/PKCδ/ STAT1 pathway in Karpas cells that regulates ETV7 transcription, thus positively regulating mTORC3 activity. The identification of this signaling pathway could benefit the therapeutic design for numerous diseases including cancer.