Wnt/β-catenin signaling pathway: a comprehensive overview

author: Binod GC

Introduction to Wnt/β-catenin signaling pathway

this Wnt/β-catenin signaling pathwayalso known as Standardized Wnt pathwaysis a highly conservative cellular communication cascade Embryo development,,,,, Organizational steady stateand Disease Pathology. Imbalances in this pathway are associated with many diseases, including Colorectal cancer,,,,, Osteoporosisand Neurodegenerative disease.

This paper provides an in-depth review of the molecular components, activation mechanisms, intracellular effectors and clinical significance of the pathway, emphasizing its correlation in human health and disease.

Pathway Overview: Wnt/β-catenin Signaling Mechanism

When started Wnt proteina family of secreted lipid-modified glycoproteins that bind to specific receptors on the cell surface:

• Curly (FZD) receptor: Seven-transmembrane domain G-protein coupled receptor with domains of extracellular cysteine ​​(CRD) for Wnt binding.

• LRP5/6 co-receptor: Low-density lipoprotein receptor-associated proteins are essential for signal transduction.

Other regulators include:

These proteins fine-tune the interactions between receptors and affect signaling specificity between tissues.

Cartoons from: PAI, SG, Carneiro, BA, Mota, JM, etc. (2017). Wnt/β-catenin pathway: regulates anti-cancer immune response. Journal of Hematology and Oncology,,,,, 10(101). https://doi.org/10.1186/s13045-017-0471-6

Inactive state: lack of Wnt ligand and β-catenin degradation

No ligand binding Cytoplasmic β-catenin It is for degradation β-catenin disruption complexwhich includes:

• APC (Adenomatous polyps E. coli)

• axis

• GSK3β (glycogen synthase kinase 3β)

• CK1α (casein kinase 1α)

• PP2A (Protein Phosphatase 2a)

• β-trcp (E3 ubiquitin ligase adapter)

Phosphorylation sequence:

1. CK1α phosphorylates β-catenin at Ser45.

2. GSK3β phosphorylates Thr41, Ser37 and Ser33.

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

4. Polyubiquitinated beta-catenin is degraded by the proteasome.

A strict regulation process prevents the accumulation of β-catenin nuclei and Repress Wnt target gene transcription In the absence of signals.

Active state: Wnt ligand binding and β-catenin stabilization

In the presence of the wnt ligand:

• Wnt binds FZD and LRP5/6 CRD to form a receptor complex.

• Dress (DVL) Recruited to the membrane.

• DVL inhibits the destruction of complexes by promoting phosphorylated LRP5/6 tails, resulting in complex disassembly.

• GSK3β activity was inhibited; axe level was reduced.

• β-catenin stabilizes and accumulates In the cytoplasm, then translocate to the nucleus.

Inside the core:

• β-catenin binding TCF/LEF Transcription factor.

• Joint suppressors like Groucho are displaced.

• Co-activator, e.g. CBP/P300,,,,, Bcl9,,,,, pygoand BRG1 Recruited.

• Transcriptional Wnt target gene Activated.

Wnt ligands and receptors

• The mammalian Wnt family includes 19 ligandsmainly activate canonical pathways using Wnt1 classes (Wnt1, Wnt3, Wnt3a, Wnt8a, Wnt8b).

• FZD receptor (FZD1-10) Binding of Wnt protein by CRD.

• Regulatory modulators include:

  • Nolin and Tetraspan membrane protein 12: Active regulatory agencies.

  • SFRPS (secreted curl-related protein): Suppress Wnt signaling.

  • DKK Protein (DKK1-4): Block LRP5/6 to suppress signaling.

  • Sclerostin: Fight against LRP5.

  • Pig (porcupine): An ER enzyme necessary for palmitoylation and secretion of Wnt ligands.

Intracellular signaling molecules

Key intracellular components include:

• β-catenin: The domain where central effector interacts with phosphorylation and proteins.

• Axin: Scaffolding that destroys the complex.

• Clothes are neveled (DVL): Multifunctional cytoplasmic protein with DIX, PDZ and DEP domains.

• GSK3β and CK1α: Kinase phosphorylates β-catenin.

• β-trcp: Ubiquitin ligase adapter.

• pp2a: phosphatase that modulates the activity of the complex.

Nuclear components and target genes

β-catenin activates transcription by

• Replace repressors such as Groucho.

• Recruiting co-activators (CBP/P300, BCL9, PYGO, BRG1).

Famous Wnt target gene:

• Cell cycle regulator: Cyclin D1, C-Myc

• Intrusion/Transfer Tags: MMP7, UPAR, CD44

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

• Others include Cox2, pecin, PPAR-δ, fibronectin, laminin 5γ2 chains.

Other intracellular regulators

• APC: Tumor inhibitors connecting β-catenin and β-TRCP.

• Tank enzyme (TNKS1/2): PARP enzyme degradation axis; inhibitory stabilization axis and downregulate Wnt.

• Chibby and ICAT: Nuclear β-catenin inhibitor.

• axin2: Negative feedback regulator.

• WIF1: isolator ligand.

• Notum: Palmitate acid is removed from Wnt, antagonizing signaling.

Pathway dynamics and feedback mechanisms

• Positive feedback: LRP6, induction of FZD receptor.

• Negative feedback: Upregulation of AXIN2, DKK1 and SFRP.

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

Biological and clinical importance

Development and homeostasis

• Integrated in embryonic formation (axis formation, limb development).

• Stem cells that maintain intestinal crypts and hematopoietic walls.

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

cancer

• Mutations in APC, CTNNB1 and Axin cause Colorectal cancer.

• Abnormal signaling is associated with hepatocellular carcinoma, breast cancer, prostate and lung cancer.

• Constitutive activation promotes proliferation, survival, and metastasis.

Therapeutic target

• Pig inhibitors (LGK974) block wnt secretion.

• Tank enzyme inhibitor Stabilize axis.

• CBP/β-catenin antagonist Disrupt transcription.

• Monoclonal antibodies target FZD or Wnt ligands.

• These are in clinical trials of WNT-driven cancer and fibrotic diseases.

in conclusion

this Wnt/β-catenin signaling pathway It is a key regulator of cell fate, proliferation and differentiation. Its precise control depends on the complex interactions between extracellular ligands, membrane receptors, intracellular scaffolds and nuclear transcription machinery. Irregulation contributes to a variety of diseases, especially cancer, and positions pathways as a priority for therapeutic development.

Ongoing research continues to reveal the complexity of this pathway, providing promising avenues for targeted clinical interventions.

refer to

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

2. Xue, C., Chu, Q., Shi, Q. wait. (2025). Wnt signaling pathways in biology and disease: mechanisms and treatment progression. Signal transduction and targeted therapy10, 106.

3. Maurice, MM, Angers, S. (2025). Mechanical insight into Wnt-β-catenin pathway activation and signal transduction. Nature Review Molecular Cell Biology26, 371–388.