β-Catenin's Multifaceted Roles: Exploring Physiological Regulation and Disease Mechanisms

β-Catenin (β-catenin) is a multifunctional protein that plays a central role in cell adhesion and the Wnt signaling pathway. It functions both as a cytoskeletal protein (binding to E-cadherin to maintain epithelial structure) and as a transcriptional coactivator (regulating proliferation-related genes). Aberrant activation of β-catenin is closely associated with various cancers (such as colorectal cancer, liver cancer) and developmental disorders. In recent years, targeted therapeutic strategies against β-catenin (such as Wnt inhibitors and PROTAC degraders) have become research hotspots. This article reviews β-catenin's structural characteristics, biological functions, disease associations, and recent research progress, while exploring its potential as a therapeutic target.

Structural Features of β-Catenin

β-Catenin is encoded by the CTNNB1 gene and belongs to the Armadillo protein family. Its structural domains determine its multifunctionality:

Domain Composition

N-terminal Domain (1-140 aa):

Contains GSK-3β phosphorylation sites (Ser33/37/Thr41) that regulate protein stability.

Phosphorylation leads to ubiquitination and degradation mediated by β-TrCP (in the absence of Wnt signaling).

Armadillo Repeat Domain (141-664 aa):

12 Armadillo repeat units form the core structure, mediating protein-protein interactions.

Binds to E-cadherin (cell adhesion), TCF/LEF (transcriptional regulation), and APC/Axin (degradation complex).

C-terminal Domain (665-781 aa):

Contains a transcriptional activation domain that recruits coactivators such as BCL9 and Pygo to enhance gene expression.

Post-Translational Modifications

Phosphorylation:

GSK-3β (degradation signal), CK1 (cooperative phosphorylation), Src (Tyr654 phosphorylation promotes nuclear translocation).

Acetylation (Lys49): Enhances transcriptional activity.

Ubiquitination: β-TrCP-dependent degradation pathway.

Biological Functions of β-Catenin

Cell Adhesion: Binds to E-cadherin to form adherens junctions, maintaining epithelial cell polarity.

Regulation of Epithelial-Mesenchymal Transition (EMT): Nuclear translocation of β-catenin promotes EMT, enhancing cancer cell migration.

Wnt/β-Catenin Signaling Pathway

In the absence of Wnt signaling: β-Catenin is phosphorylated by the degradation complex (APC/Axin/GSK-3β/CK1) and degraded via the ubiquitin-proteasome pathway.

Upon Wnt signaling activation: Wnt ligands (such as Wnt3a) bind to Frizzled/LRP receptors → inhibit the degradation complex → β-Catenin accumulates and translocates to the nucleus. It binds to TCF/LEF transcription factors, activating target genes (such as c-Myc, Cyclin D1, Axin2) and promoting cell proliferation.

Other Functions

Stem Cell Maintenance: Highly expressed in intestinal stem cells, maintaining self-renewal.

Embryonic Development: Regulates axis formation (such as dorsal development in Xenopus embryos).

β-Catenin and Disease

Cancer
Colorectal Cancer (CRC): 80% of cases result from APC mutations leading to stable accumulation of β-catenin (e.g., familial adenomatous polyposis, FAP). CTNNB1 mutations (such as S45F, D32G) directly inhibit degradation, promoting tumorigenesis.
Liver Cancer (HCC): 10-30% of cases exhibit CTNNB1 mutations, leading to sustained Wnt pathway activation.

Breast Cancer: Enhanced Wnt/β-Catenin signaling correlates with metastasis and drug resistance.

Developmental Disorders

Neural Tube Defects (such as spina bifida): Aberrant Wnt/β-Catenin signaling affects neural tube closure.
Osteoporosis: Wnt pathway inhibition promotes osteoblast apoptosis, and β-catenin downregulation leads to bone loss.
Fibrotic Diseases

Liver Fibrosis: β-Catenin activates hepatic stellate cells, promoting collagen deposition.

Research Progress and Targeted Therapeutic Strategies

Drugs Targeting the Wnt/β-Catenin Pathway

Wnt Secretion Inhibitors (such as LGK974): Block PORCN-mediated Wnt lipid modification.

Tankyrase Inhibitors (such as XAV939): Stabilize Axin, promoting β-catenin degradation.

β-Catenin/TCF Interaction Inhibitors (such as PKF118-310): Block transcription complex formation.

PROTAC Degraders: Induce β-catenin ubiquitination and degradation (preclinical research stage).

Immunotherapy and β-Catenin

β-Catenin-high tumors often exhibit a "cold tumor" phenotype (reduced T cell infiltration). Combining with immune checkpoint inhibitors (such as PD-1 antibodies) may enhance efficacy.

New Technologies and Discoveries

Phase Separation Regulating Transcription: β-Catenin forms liquid-liquid phase separation condensates with TCF4, regulating gene expression.

Microbiome Influence: Gut microbiota metabolites (such as butyrate) regulate β-catenin activity through epigenetic modifications.

Single-Cell Sequencing: Reveals heterogeneity of β-catenin+ cells in the tumor microenvironment.

Summary

As a core molecule in cell adhesion and the Wnt signaling pathway, β-catenin's aberrant activation plays a critical role in cancer, developmental disorders, and fibrosis. In recent years, targeted drugs against β-catenin (such as PROTAC degraders and Wnt inhibitors) have shown therapeutic potential but still face challenges such as off-target toxicity and drug resistance. Future research could focus on:

Precision regulation of β-catenin subcellular localization (such as selective inhibition of nuclear translocation)

Combination therapy strategies (such as Wnt inhibitors + immunotherapy)

AI-based drug design to optimize targeting efficiency