Cited by 149PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerFOXO transcription factor regulation

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

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He, Long, Gomes, Ana P., Wang, Xin, Yoon, Sang Oh, Lee, Gina, Nagiec, Michal J., Cho, Sungyun, Chavez, Andre +5 more·2018·Molecular Cell

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.

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Crossref · 10.1016/j.molcel.2018.04.024

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  • mTORC1 influences the protein expression level of several onco-proteins such as HIF1α at post-transcriptional, translational level.

    “Moreover, mTORC1 influences the protein expression level of several onco-proteins such as HIF1α at post-transcriptional, translational level.”

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  1. Bowman CJ Ayer DE Dynlacht BD 2014 Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs Nat Cell Biol 16 12 1202 1214 25402684 PMC4250422

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Authors
He, L., Gomes, A. P., Wang, X., Yoon, S. O., Lee, G., Nagiec, M. J., Cho, S., Chavez, A., Islam, T., Yu, Y., Asara, J. M., Kim, B. Y., & Blenis, J.
Affiliations
  • Harvard University (US)
  • City University of Hong Kong (HK)
  • Weill Cornell Medicine (US)
  • Beth Israel Deaconess Medical Center (US)
  • Korea Research Institute of Bioscience and Biotechnology (KR)
Corresponding author
Blenis, John
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2018-06
Volume
70
Issue
5
Pages
949-960.e4
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2805815575
Cited by
145
References
32
Citations by year
2026: 11 · 2025: 17 · 2024: 17 · 2023: 18 · 2022: 21 · 2021: 27 · 2020: 19 · 2019: 12 · 2018: 3
FWCI
5.43
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • KRIBB Repository (submittedVersion)
Funders
  • WCI-KRIBB Foundation
  • Susan G. Komen Postdoctoral Fellowship ((PDF17481555)
  • Pathway to Independence Award from NCI (K99CA218686-01)
  • LAM Foundation (LAM00100F01-14)
  • Tuberous Sclerosis Alliance
  • NIH NRSA (F32GM106582)
  • KRIBB Research Initiative Program
  • NIH (GM51405, HL121266)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
Keywords
mTORC1 signaling, FOXK1, glycogen synthase kinase-3, nuclear exclusion, glycolysis, metabolic reprogramming, HIF-1α, transcriptional regulation, metabolic disorders
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Animals, Binding Sites, Energy Metabolism, Humans, Phosphorylation, Protein Binding, Signal Transduction, Down-Regulation, Active Transport, Cell Nucleus, Glycogen Synthase Kinase 3, 14-3-3 Proteins, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Forkhead Transcription Factors, HEK293 Cells, Cellular Reprogramming

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