PI3K/AKT/mTOR - vitamin D3 signaling (WP4141)

Pathway representation of the model proposed by Ferreira et al. in the Figure 7 C of their article: "Proposed model for the mechanism of action of 1,25(OH)2D3 in human-monocyte-derived DCs. We hypothesize that VDR-bound 1,25(OH)2D3 activates the PI3K-Akt-mTOR pathway via either forming a complex and phosphorylating the regulatory subunit of PI3K, or by other unknown mechanisms. This releases and activates the catalytic subunit, which unleashes the PI3K downstream pathway. Among other functions, activation of this pathway promotes the expression of different key glycolytic enzymes, which induces glycolysis. Control of surface marker expression and cytokine production by 1,25(OH)2D3 might arise from its impact on the PI3K pathway, which can control essential transcription factors (e.g., GSK-3β and NF-κB nuclear translocation) or from the direct regulation of transcription factors, key metabolic bifunctional enzymes, and RNA binding proteins. In the absence of glucose or glycolysis, an increase in the AMP/ATP ratio will be sensed by AMPK, which, in turn, phosphorylates TSC2 and blocks activation of the mTOR complex and its downstream processes. We further consider that the increase in OXPHOS also seen in 1,25D3-DCs is derived from the excess pyruvate generated during induced glycolysis, in addition to the control of metabolic enzymes from the oxidative branch by 1,25(OH)2D3". Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4141 CPTAC Assay Portal]

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