PI3K/AKT/mTOR - VitD3 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]
last edited

Authors

Madeomuga, Marvin M2, AlexanderPico, Susan, DeSl, Khanspers, Egonw, MaintBot, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: mTOR signaling pathway phosphatidylinositol 3-kinase-Akt signaling pathway vitamin D signaling pathway

Participants

Label Type Compact Identifier
TCA Cycle Pathway wikipathways:WP78
mTOR GeneProduct ensembl:ENSG00000198793
PDHA1 GeneProduct ensembl:ENSG00000131828
Glucose-6-P Metabolite chebi:4170
HLA-DRA GeneProduct ensembl:ENSG00000204287
Pyruvate Metabolite chebi:15361
AMP Metabolite hmdb:HMDB0003540
HK3 GeneProduct ensembl:ENSG00000160883
AKT GeneProduct ensembl:ENSG00000142208
PI3K GeneProduct ensembl:ENSG00000121879
Fructose Bisphosphate Metabolite chebi:65056
PFKFB4 GeneProduct ensembl:ENSG00000114268
LDHA GeneProduct ensembl:ENSG00000134333
CD80 GeneProduct ensembl:ENSG00000121594
GSK-3b GeneProduct ensembl:ENSG00000082701
TSC1 GeneProduct ensembl:ENSG00000165699
GLUT3 GeneProduct ensembl:ENSG00000059804
VDR GeneProduct ensembl:ENSG00000111424
ROS Metabolite wikidata:Q424361
RXR GeneProduct ensembl:ENSG00000186350
Lactate Metabolite chebi:24996
AMPK GeneProduct ensembl:ENSG00000162409
Fructose-6-P Metabolite chebi:16084
C-MYC GeneProduct ensembl:ENSG00000136997
1,25-(OH)2-D3 Metabolite chebi:17823
CD86 GeneProduct ensembl:ENSG00000114013
CYP24A1 GeneProduct ensembl:ENSG00000019186
C-MYC GeneProduct ensembl:ENSG00000136997
C-MYC GeneProduct ensembl:ENSG00000136997
C-MYC GeneProduct ensembl:ENSG00000136997
ATP Metabolite chebi:15422
PFKFB4 GeneProduct ensembl:ENSG00000114268
VDR GeneProduct ensembl:ENSG00000111424
1,25-(OH)2-D3 Metabolite chebi:17823
RXR GeneProduct ensembl:ENSG00000186350
TSC2 GeneProduct ensembl:ENSG00000103197
Cell cycle Pathway wikipathways:WP179
p65 GeneProduct ensembl:ENSG00000173039
IL10 GeneProduct ensembl:ENSG00000136634
IL12A GeneProduct ensembl:ENSG00000168811
ATP Metabolite chebi:15422

References

  1. Ferreira GB, Vanherwegen A-S, Eelen G, Gutiérrez ACF, Van Lommel L, Marchal K, et al. Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways. Cell Rep. 2015 Feb 10;10(5):711–25. PubMed Europe PMC Scholia