WNT/β-catenin signaling route: a complete description

Author: Binod GC

INTRODUCTION TO THE WINT/β-CATENINE SIGNALING WAY

He WNT/β-catenin signaling routealso known as the Canonical WntIt is a highly preserved essential cell communication waterfall for Embryonic development, Tissue homeostasisand disease pathology. The deregulation of this route is involved in many diseases, including Colorectal cancer, osteoporosisand neurodegenerative disorders.

This article provides an in -depth review of the molecular components of the road, activation mechanisms, intracellular effectors and clinical importance, highlighting their relevance in health and human disease.

General Way Description: WNT/β-Catenin Signaling Mechanism

The canonical WNT route begins when WNT proteinsA family of modified secreted glycoproteins, joins specific receptors on the cell surface:

• Frizz Receptors (FZD): Receptors coupled to the G Domain G of seven transmembrane domain with extracellular domains rich in cysteine ​​(CRD) for the WNT union.

• LRP5/6 co-receptors: Proteins related to the low -density lipoproteins receptor essential for signal transduction.

Additional modulators include:

These proteins interactions with fine adjustment receiver and influence the specificity specificity in the tissues.

Caricature of: Pai, SG, Carneiro, Ba, Mota, JM, et al. (2017). WNT/Beta-Catenin via: Anticancer immune response Modulation. HEMATOLOGY AND ONCOLOGY MAGAZINE, 10(101). https://doi.org/10.1186/S13045-017-0471-6

INACTIVE STATE: ABSENCE OF WNT LIGANDO AND DEGRADATION OF β-CATENINE

Without binding ligand, β-cytoplasmic catenin is aimed at degradation by the β-catenin destruction complexwhich includes:

• APC (adenomatous coli polyposis)

• Axina

• GSK3β (glycogen synthase kinase 3 beta)

• CK1α (Casein kinase 1 alpha)

• PP2A (phosphatase 2a protein)

• β-TRCP (Ligasa E3 Ligasa Ubiquitin Adapter)

Phosphorylation sequence:

1. CK1α phosphoryila β-catenin in being45.

2. GSK3β FOSPHORILA THR41, SER37 AND BE33.

3. β-TRCP recognizes phosphorylated β-catenin and recruits the SCF ubiquitin ligase complex.

4. Polyubiquitinated β-catenin is degraded by proteasome.

This strictly regulated process prevents the nuclear accumulation of β-catenin and Inhibits the transcription of the WNT target gene In the absence of signal.

Active state: WNT ligand union and β-catenin stabilization

After the presence of the WNT ligand:

• WNT joins the FZD and LRP5/6 CRD, forming a receiving complex.

• Desalled (DVL) It is recruited for the membrane.

• DVL inhibits the destruction complex by promoting recruitment of axine to LRP5/6 phosphorylated tails, which leads to complex disassembly.

• GSK3β activity is inhibited; Axine levels decrease.

• Β-catenin stabilizes and accumulates In the cytoplasm, then it is translocated to the nucleus.

Within the nucleus:

• β-catenin binds TCF/LEF Transcription factors.

• Copressores as Groucho are displaced.

• Co-activators like CBP/P300, BCl9, Pygoand BRG1 They are recruited.

• Transcription of WNT objective genes It is activated.

WNT ligands and receptors

• The WNT family of mammals includes 19 ligandsWith the WNT1 class (WNT1, WNT3, WNT3A, WNT8A, WNT8B) mainly activating the canonical route.

• FZD Receptors (FZD1–10) Wint proteins through CRD.

• Regulatory modulators include:

  • Norrín and Tetraspanin-12: Positive regulators.

  • SFRPS (Frizz -related secretinas)): Inhibit WNT signaling.

  • DKK proteins (DKK1–4): Block LRP5/6 to inhibit signaling.

  • Scleratin: ANTAGONIZA LRP5.

  • Pig (porcospine): An essential enzyme for palmmitilation and secretion of the WNT ligand.

Intracellular signaling molecules

Key intracellular components include:

• β-catenin: Central effector with domains for phosphorylation and protein interactions.

• Axin: Scaffolding of the destruction complex.

• Desalized (DVL): Multifunctional cytoplasmic protein with Dix, PDZ and dep.

• GSK3β and CK1α: Fosphorylating kinases β-catenin.

• β-TRCP: Ligasa ubiquitin adapter.

• PP2A: Phosphatase that regulates the activity of the destruction complex.

Nuclear components and objects objective

Β-catenin activates transcription by:

• Displacing the repressors as a groucho.

• Recruitment of coactivators (CBP/P300, BCL9, Pygo, BRG1).

Notable WNT Objective Genes:

• Cell cycle regulators: Cycline D1, C-MYC

• Invasion/metastasis markers: MMP7, UPAR, CD44

• Transcription factors: TCF1, C-Jun, FR-1

• Others include COX2, Gastrina, PPAR -δ, Fibronectin, Laminine Chain 5 γ2.

Additional intracellular regulators

• APC: Tumor suppressor that links β-catenin and β-trcp.

• Tankyrases (TNKS1/2): Axine degradation enzymes; The inhibition stabilizes axine and regulates down WNT.

• Chibby and Icat: Nuclear inhibitors of β-catenin.

• Axin2: Negative feedback regulator.

• WIF1: WNT Ligandos kidnappers.

• Notum: Eliminates WNT palmitol acid, antagonizing signaling.

Way dynamics and feedback mechanisms

• Positive comments: LRP6 induction, FZD receptors.

• Negative comments: Positive regulation of Axin2, DKK1 and SFRP.

• Termination mechanisms include receptor endocytosis and proteasomic β-catenin degradation.

Biological and clinical importance

Development and homeostasis

• Essential in embryogenesis (axis formation, limb development).

• Keep stem cells in intestinal crypts and hematopoietic niches.

• Facilitates tissue repair (skin, liver, bone).

Cancer

• APC, CTNNB1 and Axin mutations lead to Colorectal carcinoma.

• Aberrant signage is involved in hepatecellular carcinoma, breast, prostate and lung cancers.

• Constitutive activation promotes proliferation, survival, metastasis.

Therapeutic orientation

• Porcn inhibitors (LGK974) WNT secretion block.

• Tankyrase inhibitors stabilize axin.

• CBP/β-catenin antagonists Interrupt the transcription.

• Monoclonal antibodies are directed to the FZD or WNT ligands.

• These are in clinical trials for cancers driven by WNT and fibrotic diseases.

Conclusion

He WNT/β-catenin signaling route It is a critical regulator of cell destiny, proliferation and differentiation. Its precise control depends on a complex interaction between extracellular ligands, membrane receptors, intracellular scaffolding and nuclear transcriptional machinery. Deregulation contributes to multiple diseases, especially cancer, positioning the road as a key approach to therapeutic development.

Ongoing research continues to unravel the complexities of the road, offering promising pathways for specific clinical interventions.

References

1. Liu, J., Xiao, Q., Xiao, J., et al. (2022). WNT/β-catenin signaling: function, biological mechanisms and therapeutic opportunities. Signal transduction and directed therapy7, 3. https://doi.org/10.1038/s41392-021-00762-6

2. Xue, C., Chu, Q., Shi, Q., et al. (2025). WNT signaling routes in biology and disease: mechanisms and therapeutic advances. Signal transduction and directed therapy10, 106. https://doi.org/10.1038/s41392-025-02142-w

3. Maurice, MM, Angers, S. (2025). Mechanistic knowledge about the activation of the WNT-β-catenin route and signal transduction. Nature magazines Biology of molecular cells26, 371–388. https://doi.org/10.1038/s41580-024-00823-y