Figure 2

Scheme of known Wnt pathways. A Canonical Wnt/β-catenin pathway. In the "off-state" no Wnt proteins are present or are inhibited by factors like WIF, sFRPs and Dkk. Cytosolic β-catenin is targeted to proteolytic degradation through phosphorylation by the APC-Axin-GSK3β-CK1á complex and ubiquitination by the βTrCP-dependent E3 ubiquitin ligase. In the "on-state" stimulation of Fzd receptors and their co-receptors Lrp5/6 by Wnt ligands, leads to recruitment of Dvl and Axin to Fzd, thereby inhibiting the degradation complex. Consequently, β-catenin accumulates in the cytoplasm and enters the nucleus, activating target gene transcription through association with Lef1/TCF. B Non-canonical Wnt/Ca²⁺ pathway. Interaction of non-canonical Wnt ligands with Fzd receptors can lead to G-Protein mediated phosphorylation of Dsh, thereby activating PLC and increasing intracellular calcium levels. These will activate CAMKII and PKC, as well as the transcription factor NFAT. Additionally, Fzd receptors in association with Kny, Ror2 or Ryk receptors can activate JNK, promoting target gene expression through AP-1. C Non-canonical Wnt/PCP pathway. This pathway is characterized by an asymmetric distribution of Fzds, the cadherin Flamingo and VANGL2, resulting in cell polarization. Wnt signaling promoted by either Wnt or an interaction of Fzd with VANGL2 activates RhoA/B, Cdc42 or Rac1. Dsh activates Rac1, while RhoA/B and Cdc42 need the participation of Daam1 downstream of Dsh. Rac1 can also activate JNK, resulting in the NFAT pathway. All three down stream pathways are key players in cytoskeletal rearrangement and cellular polarity. The signaling of the Flamingo/Fzd interaction is still obscure.