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. 2019 Nov 18;9:1248. doi: 10.3389/fonc.2019.01248

Figure 3.

Figure 3

WNT/β-catenin, TGF-β1, PI3K-AKT, SMAD, and PPARγ pathways. “On state” canonical WNT: In the presence of WNT ligands, the WNT receptor binds LRP5/6 and FZD receptors and initiates LRP phosphorylation and DSH-mediated Frizzled internalization. Then, the pGSK-3β/AXIN/APC destruction complex is dissociated. Phosphorylation of β-catenin is inhibited and β-catenin increases in the cytosol and then translocates to the nucleus. β-catenin binds the TCF-LEF transcription factors and induces the WNT-response gene transcription (CYCLIN D1, cMYC, PDK, MCT-1, AXIN2, fibronectin). DKK1 is activated by PPARγ and inhibits WNT. TGF-β1 binds the TGF-βR2 receptor, which recruits the TGF-βR1 receptor. This leads to the formation of a heterotetramer that phosphorylates SMAD. The SMAD complex then translocates to the nucleus and regulates the transcription of Smad target genes (CTGF, COL1A). PI3K-AKT pathway is a non-SMAD signaling and inactivates GSK-3β. PTEN inhibits PI3K-AKT and PPARγ inhibits AKT. PPARγ inhibits the β-catenin/TCF-LEF-induced activation of WNT target genes. TGF-β1 enhances the canonical WNT pathway through the inhibition of DKK1, itself an inhibitor of the canonical WNT signaling.