Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer

Figure 1 Schematic representation of the Wnt/β-catenin signaling in epithelial cells. The Wnt signaling pathway can be subdivided into a “canonical” or β-catenin-dependent and “non-canonical” or β-catenin-independent. A: In the absence of Wnt ligands, a multi-subunit destruction complex, composed by adenomatous polyposis coli (APC), Axin, GSK3β, CKI, binds and phosphorylates β-catenin tagging for ubiquitination and subsequent proteasomal degradation (βTrCP). The “canonical” Wnt signaling is initiated by the binding of one of 19 Wnt ligands to one of 10 Frizzled receptors (Fzd), in the presence of the co-receptor LRP5 or 6. This leads to recruitment of Disheveled and inhibition of the APC destruction complex. Accumulation of β-catenin in the cytoplasm leads to its translocation to the nucleus where it interacts with TCF/LEF to drive transcription of Wnt target genes including c-myc, cyclin D1, axin2 and others; B: The “non-canonical” Wnt signaling is initiated by the binding of Wnt5a to ROR2, alone or in combination, with a Frizzled receptor leading to the activation of the planar-cell polarity (PCP) pathway through Rock2, RhoA, Rac or JNK. Alternatively, Wnt11 can bind a Frizzled receptor alone and activate the Wnt/calcium pathway that involves the calcium/calmodulin dependent Kinase II (CamKII), protein-kinase-C (PKC) and nuclear factor of activated T cells (NFAT). Importantly, the “non-canonical” Wnt pathway inhibits the “canonical“ one either impairing β-catenin accumulation in the cytoplasm or the β-catenin/TCF/LEF complex formation.