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

Area of Science:

• Cellular Biology
• Molecular Biology
• Metabolism

Background:

• The Target of Rapamycin Complex 1 (mTORC1) signaling pathway is crucial for cellular homeostasis, integrating various signals.
• Understanding mTORC1 effectors is vital for elucidating its role in disease pathogenesis.

Purpose of the Study:

• To identify and characterize the downstream effectors of mTORC1 signaling.
• To investigate the role of transcription factor forkhead/winged helix family k1 (Foxk1) in mTORC1-mediated gene expression and metabolic regulation.

Main Methods:

• Investigated the interaction between mTORC1 signaling and Foxk1.
• Utilized techniques to assess Foxk1 phosphorylation, DNA binding, and subcellular localization upon mTORC1 modulation.
• Examined the regulation of Gsk3 kinase activity and its impact on Foxk1.
• Analyzed gene expression changes related to glycolysis and anabolic pathways, including Hif-1α.

Main Results:

• Identified Foxk1 as a mediator of mTORC1-regulated gene expression.
• Demonstrated that mTORC1 suppression increases Foxk1 phosphorylation, leading to 14-3-3 interaction, reduced DNA binding, and nuclear exclusion.
• Revealed that mTORC1 controls Foxk1 nuclear signaling by suppressing the kinase Gsk3.
• Showed that this pathway regulates genes involved in glycolysis and anabolic processes, partly via Hif-1α.

Conclusions:

• Foxk1 is a critical mediator of mTORC1-driven metabolic rewiring.
• The identified mTORC1-Gsk3-Foxk1 pathway is important for regulating cellular metabolism.
• Dysregulation of this pathway may contribute to metabolic diseases associated with aberrant mTORC1 signaling.