The Wnt signaling transduction is an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, etc. The extra-cellular Wnt signal stimulates several intra-cellular signaling transduction cascades, particularly, the canonical or Wnt/β-catenin dependent pathway and the non-canonical or β-catenin-independent pathway.
In the absence of Wnt, β-catenin is targeted to a multimeric protein complex called destruction complex (consisting of axin, adenomatous polyposis coli (APC), and GSK3β , casein kinase 1 (CK1) and the stabilization of β-catenin) for its phosphorylation. This phosphorylation targets β-catenin for β-Trcp–mediated ubiquitination and its subsequent degradation by the proteasome.
Conversely, a cascade of events initiated by the binding of Wnt to the cysteine-rich domain of Frizzled receptors results in the disassembly of the destruction complex. This process also involves the phosphoprotein dishevelled. Cytoplasmic β-catenin accumulates and is eventually imported into the nucleus, where it serves as a transcriptional coactivator of transcription factors of the TCF/LEF family. TCF/LEF target genes are then involved in regulating cell proliferation, stem cell maintenance, or differentiation (Figure 1).
The non-canonical or β-catenin-independent signaling transduction can be further divided into two distinct branches, the Planar Cell Polarity signaling or PCP signaling and the Wnt/Ca2+ signaling transduction.
Planar Cell Polarity signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dvl. Dvl through Daam1 mediates activation of Rho which in turn activates Rho kinase (ROCK). Dvl also mediates activation of Rac, which in turn activates JNK. The signaling from Rock, JNK and Profilin are integrated for cytoskeletal changes for cell polarization and motility during gastrulation.
Wnt/Ca2+ signaling via Fz mediates activation of Dvl via activation of G-proteins. Dishevelled activates the phosphodiesterase PDE which inhibits PKG and in turn inhibits Ca2+ release. Dvl through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CaMK and calcineurin. CaMK then activates TAK and NLK, which inhibit β-catenin/TCF function to negatively regulate dorsal axis formation. DAG through PKC activates CDC42 to mediate tissue separation and cell movements (Figure 2).
1. Tata Purushothama Rao, Michael Kuhl. An Updated Overview on Wnt Signaling Pathways. Circ Res. 2010; 106:1798-1806.
2. Yuko Komiya, Raymond Habas. Wnt signal transduction pathways. Organogenesis. 2008; 4:2, 68-75.