mTORC1 promotes metabolic reprogramming by suppression of GSK3-dependent Foxk1 phosphorylation

Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression.

Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits 14-3-3 interaction, a reduction of DNA binding and nuclear exclusion. Mechanistically, this occurs by mTORC1-dependent suppression of nuclear signaling by the Foxk1-kinase, Gsk3. This pathway then regulates the expression of multiple genes associated with glycolysis and downstream anabolic pathways directly modulated by Foxk1 and/or by Foxk1-regulated expression of Hif-1.