mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation

Mol Cell. 2018 Jun 7;70(5):949-960.e4. doi: 10.1016/j.molcel.2018.04.024. Epub 2018 May 31.


The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. 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 a 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-1α. Thus, Foxk1 mediates mTORC1-driven metabolic rewiring, and it is likely to be critical for metabolic diseases where improper mTORC1 signaling plays an important role.

Keywords: Foxk1; Foxk2; GSK3; Hif1α; mTOR; metabolism; phosphorylation; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Active Transport, Cell Nucleus
  • Animals
  • Binding Sites
  • Cell Proliferation
  • Cellular Reprogramming*
  • Down-Regulation
  • Energy Metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Phosphorylation
  • Protein Binding
  • Signal Transduction


  • 14-3-3 Proteins
  • FOXK1 protein, human
  • Forkhead Transcription Factors
  • Foxk1 protein, mouse
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mechanistic Target of Rapamycin Complex 1
  • Glycogen Synthase Kinase 3