- Wnt signaling is a highly conserved pathway that plays crucial roles in development, stem cell maintenance, and tissue homeostasis. The pathway exists in three main branches: the canonical (β-catenin-dependent) pathway and two non-canonical pathways (planar cell polarity and calcium pathways).
- In the canonical pathway, the absence of Wnt ligands leads to continuous degradation of β-catenin by a destruction complex containing APC, Axin, GSK3β, and CK1. When Wnt proteins bind to Frizzled receptors and LRP5/6 co-receptors, they trigger the recruitment of Dishevelled proteins and inhibition of the destruction complex. This allows β-catenin to accumulate and translocate to the nucleus, where it partners with TCF/LEF transcription factors to activate target genes.
- The planar cell polarity pathway operates independently of β-catenin and regulates cell polarity and cytoskeletal rearrangements. It involves Frizzled receptors and Dishevelled, but signals through small GTPases like Rho and Rac to affect cell movement and tissue organization. The Wnt/calcium pathway activates calcium-dependent enzymes and affects cell adhesion and movement.
- Regulation of Wnt signaling occurs at multiple levels, including secreted antagonists (like DKKs and SFRPs), receptor turnover, and nuclear import/export of β-catenin. The pathway is also modulated by various post-translational modifications and cellular contexts.
- Aberrant Wnt signaling is linked to numerous diseases, particularly cancer. Mutations in APC or β-catenin are common in colorectal cancer, while altered Wnt signaling contributes to other cancers and developmental disorders. This has made the pathway an attractive target for therapeutic intervention.
