|Figure 1: Schema of TGF-β1 effects on the balance between the canonical WNT/β-catenin pathway
In the presence of the WNT ligands, WNT receptor binds both FZD and LRP5/6 receptors
to initiate LRP phosphorylation and DSH-mediated Frizzled internalization. This leads
to dissociation of the AXIN/APC/GSK-3 β destruction complex. Phosphorylation of β-catenin
is inhibited which inhibits its degradation in the proteasome. Thus, β-catenin accumulates
in the cytosol and then translocates to the nucleus to bind TCF-LEF co-transcription
factors. This induces the WNT-response gene transcription (PDK, MCT-1, MYC, and CYCLIN
D1). PPARγ inhibits the β-catenin/TCF-LEF-induced activation of WNT target genes.
TGF-β also enhances WNT signaling through the inhibition of DKK1. PPARγ activates
DKK1. Abbreviations: adenomatous polyposis coli (APC); Dickkopf-1 (DKK1); Dishevelled
(DSH); Frizzled (FZD); glycogen synthase kinase-3β (GSK-3β); lactate dehydrogenase
(LDH); low-density lipoprotein receptor-related protein 5/6 (LRP5/6); monocarboxylate
lactate transporter-1 (MCT-1); peroxisome proliferator-activated receptor gamma (PPARγ);
pyruvate dehydrogenase kinase (PDK); T-cell factor/lymphoid enhancer factor (TCF/LEF);
Transforming Growth Factor (TGF).