Figure 1.

Canonical Wnt pathway. (A) In the canonical Wnt/β-catenin pathway, binding of the Wnt ligand to the FZD receptor and co-receptor LRP5/6 promotes phosphorylation of LRP5/6 by CKIα and GSK3β kinases and polymerization of the DVL protein. Therefore, the destroyer complex is inactivated (Axin, APC, CKIα and GSK3β) and the β-catenin protein is accumulated in the cytosol. The β-catenin translocates to the nucleus and interacts with the TCF/LEF complex, promoting the recruitment of transcriptional co-activators (CBP/p300, BRG1, BCL9 and Pygo), inducing the expression of target genes. (B) In the absence of the Wnt ligand, the destructor complex phosphorylates and induces ubiquitination of β-catenin by βTrCP for its degradation in the proteosome. The absence of nuclear β-catenin favors the recruitment of HDACs by the TCF/LEF and Groucho/TLE repressor complexes, thus inhibiting the expression of target genes. Non-canonical Wnt pathway. Non-canonical Wnt ligands can activate other non-canonical β-catenin-independent signaling pathways, such as the Wnt/PCP and Wnt/Ca²⁺. In the Wnt/Ca²⁺ pathway, the Wnt ligand binds to FZD and ROR1/2 and promotes PLC activation via G proteins in a DVL-dependent way. PLC catalyzes the formation of IP3 and DAG, which results in an increase of Ca²⁺ in the cytosol and activation of kinases such as PKC, Calcineurin and CAMKII. These kinases can modify the cytoskeleton through the small GTPase CDC42 and/or regulate transcription of target genes through NFAT, NFκβ and CREB, among others. In the Wnt/PCP pathway, binding of the Wnt ligand to the FZD receptor and co-receptors, such as ROR1/2, favors the activation of small GTPases of the Rho family (RHOA, RAC) by DVL. RHOA and RAC activate JNK kinases and ROCK kinases, which are involved in the reorganization of the cytoskeleton and/or activation of gene expression via Jun/ATF2, among others. Dashed arrows indicate an indirect activation.