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

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.

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

“…Previous studies have identified a crucial role of FOXK1 in cancers [33][34][35]. To explore whether HUMT exerted its function through FOXK1-mediated cell proliferation and vascular endothelial growth factor (VEGFC) signaling, which was a previously reported key lymphangiogenesis pathway [36,37], we analyzed the effect of HUMT-KO by western blot.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…transcriptional activity under hypoxic conditions [75]. mTORC1 promotes HIF1α transcription through Foxk1 [76]. By mTORC1-mediated inhibition of GSK3, Foxk1 phosphorylation is repressed and allows its accumulation in the nucleus to induce HIF1α transcription.…”

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

“…However, further investigation of the mechanisms underlying the opposite actions of GSK3 in different types of tumors, also related to mTOR inhibition, should provide opportunities to better understand the processes controlled by GSK3 and to identify those that may safely benefit from administration of selective drugs. Moreover, this kind of studies could provide insights toward other molecules, controlled by GSK3, that would serve as targets more amenable to a therapeutic intervention, as we have seen in the works of Momcilovic et al [121] and He et al [69,102]. These studies could also lead to the development of substrate-competitive GSK3 inhibitors with a high specificity for one of the two paralogs, as already demonstrated in some studies [136][137][138].…”

“…Therefore, Akt upregulates these targets indirectly via the inhibition of GSK3. These substrates include, among the others, the prosurvival B-cell lymphoma 2 (Bcl-2) family member myeloid cell leukemia 1 (Mcl-1) [64] or transcription factors such c-Myc [65], sterol regulatory element binding protein 1c (SREBP1c) [66], nuclear factor E2-related factor 2 (Nfr2) [67], Hypoxia-inducible transcription factor 1α (Hif-1α) [68], and forkhead/winged helix family k1 (Foxk1) [69]. Several targets of GSK3 are positively involved in the control of neoplastic cell proliferation, survival, and metabolism.…”

“…two conditions that result in mTORC1 inhibition) promoted nuclear translocation of GSK3β [22]. mTORC1 is capable to downmodulate GSK3α activity, thereby resulting in suppressed phosphorylation of the forkhead/winged helix family k1 (Foxk1) transcription factor, a critical mediator of mTORC1dependent expression of multiple genes associated with glycolysis and downstream anabolic pathways, mainly via the transcriptional upregulation of Hif-1α [69]. It was shown that these events occur through an mTORC1-mediated reduction of nuclear GSK3α signaling, whereas, when mTORC1 is inactivated by rapamycin treatment, Foxk1 is phosphorylated by GSK3α at multiple amino acidic residues (Ser402/406/ 427/431), binds 14-3-3 proteins, and is excluded from the nucleus.…”