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

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

Author information

1
Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
2
Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
4
Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
5
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
6
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
7
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea.
8
Meyer Cancer Center and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Cheongwon, Korea. Electronic address: jblenis@med.cornell.edu.

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.

KEYWORDS:

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

PMID:
29861159
PMCID:
PMC6591025
DOI:
10.1016/j.molcel.2018.04.024
[Indexed for MEDLINE]
Free PMC Article

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