- β-Catenin is a multifunctional protein that plays central roles in both cell–cell adhesion and gene transcription. It is encoded by the CTNNB1 gene and is evolutionarily conserved across metazoans.
- Initially identified as a component of the cadherin–catenin complex in adherens junctions, β-catenin later gained prominence for its pivotal role in the Wnt/β-catenin signaling pathway, a pathway frequently dysregulated in cancer.
- Structurally, β-catenin is a 781-amino acid protein composed of three major domains: the N-terminal domain, the central armadillo (ARM) repeat domain, and the C-terminal transactivation domain. The N-terminal domain (residues 1–131) contains critical phosphorylation sites—Ser33, Ser37, Thr41, and Ser45—which are targeted by casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β). Phosphorylation at these sites marks β-catenin for ubiquitination and subsequent proteasomal degradation in the absence of Wnt signaling.
- The central portion of β-catenin (residues ~132–666) consists of 12 armadillo repeats, which are responsible for the majority of its protein–protein interactions. These repeats form a superhelical structure that acts as a flexible scaffold, facilitating binding to a variety of proteins including cadherins, APC (adenomatous polyposis coli), Axin, TCF/LEF transcription factors, and others. This domain plays dual roles: it mediates β-catenin’s adhesive function by binding to the cytoplasmic tail of E-cadherin at adherens junctions, and it also supports nuclear signaling by binding to transcriptional regulators.
- The C-terminal domain (residues ~667–781) is intrinsically disordered and contains a transactivation domain essential for initiating gene transcription. This region interacts with coactivators such as CBP/p300 and BCL9, amplifying the transcription of Wnt target genes like MYC, CCND1, and AXIN2. Although this domain contributes little to structural stability, it is vital for transcriptional activation and is a therapeutic target in Wnt-driven cancers.
- In the canonical Wnt pathway, β-catenin’s stability is tightly regulated by the destruction complex, which includes APC, Axin, CK1, and GSK3β. In the absence of Wnt ligands, β-catenin is continuously phosphorylated, ubiquitinated, and degraded. When Wnt ligands bind to Frizzled and LRP5/6 receptors, the destruction complex is inhibited, leading to β-catenin stabilization, nuclear accumulation, and activation of Wnt-responsive genes.
- Besides its signaling role, β-catenin is essential in maintaining epithelial integrity via its interaction with cadherins. In adherens junctions, β-catenin links E-cadherin to α-catenin, which connects to the actin cytoskeleton. Loss of E-cadherin or β-catenin mutations that impair this interaction can lead to epithelial-to-mesenchymal transition (EMT), a hallmark of cancer progression.
- Mutations in CTNNB1 are frequent in several cancers, including colorectal, hepatocellular, and endometrial carcinomas. These often involve the N-terminal phosphorylation sites, rendering β-catenin resistant to degradation and constitutively active. Such mutations promote aberrant Wnt signaling, uncontrolled cell proliferation, and tumorigenesis.
- In conclusion, β-catenin is a versatile and tightly regulated protein at the crossroads of adhesion and transcriptional regulation. Its structural adaptability allows it to coordinate diverse cellular processes, while its dysregulation is a key driver of multiple cancers. Understanding its structure–function relationship is fundamental for therapeutic targeting in Wnt-driven pathologies.
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