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

Long He, Ana P. Gomes, Xin Wang, Sang Oh Yoon, Gina Lee, Michal J. Nagiec, Sungyun Cho, Andre Chavez, Tasnia Islam, Yonghao Yu, John M. Asara, Bo Yeon Kim, John Blenis

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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. He et al. report that Foxk1 phosphorylation is inhibited by mTORC1 through suppression of GSK3 signaling, resulting in diminished Foxk1 14-3-3 binding. The hypophosphorylated Foxk1 accumulates in the nucleus, and it promotes mTORC1-mediated metabolic reprogramming through direct Foxk1-dependent and Foxk1/Hif1α-dependent gene expression.

Original languageEnglish (US)
Pages (from-to)949-960.e4
JournalMolecular cell
Volume70
Issue number5
DOIs
StatePublished - Jun 7 2018

Keywords

  • Foxk1
  • Foxk2
  • GSK3
  • Hif1α
  • mTOR
  • metabolism
  • phosphorylation
  • transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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