Fig. 1.

Schematic depiction of the canonical and non-canonical Wnt pathways. a When the canonical Wnt pathway is inactive, a cytosolic destruction complex consisting of Axin, APC, GSK3 and CK1 is formed. By phosphorylating β-catenin, this complex marks β-catenin for ubiquitination and subsequent degradation by the proteasome. The Wnt transcription factors TCF/LEF remain repressed by Groucho. b Upon binding of a canonical Wnt ligand to the Fzd receptor and LRP5/6 co-receptor, the canonical pathway becomes activated. Dvl is recruited to the receptor complex and subsequently recruits Axin-GSK3, thereby disrupting the destruction complex. Cytosolic levels of β-catenin stabilize and translocate to the nucleus. Here, β-catenin associates with the transcriptional machinery, transcriptional co-factors, and binds to TCF/LEF. This allows for active transcription of Wnt target genes. c, d Non-canonical Wnt ligands bind to Fzd and other transmembrane proteins such as Ryk and Ror, resulting in the recruitment of Dvl. c In the PCP pathway, this can result in activation of the small GTPases RhoA, Rac, and CDC42, which influence cytoskeleton function. RhoA and Rac can also activate JNK, and subsequent AP-1 and NFAT-mediated transcriptional programs. d In the Ca²⁺ pathway, Dvl activates heterotrimeric G proteins, resulting in a cytosolic calcium flux. This activates calcium-dependent signaling molecules including PKC, CamKII, and CaN. Both PKC and CamKII can also promote NFAT transcriptional activity