CTNNB1

CTNNB1 is a gene that encodes beta-catenin, a dual-function protein involved in cell–cell adhesion and transcriptional regulation. In humans, beta-catenin participates in the cadherin–catenin complex at adherens junctions, where it binds the cytoplasmic tail of E-cadherin and links to alpha-catenin and the actin cytoskeleton. In parallel, beta-catenin is a central effector of the canonical Wnt signaling pathway, regulating gene expression during development and tissue homeostasis.

Protein structure and interactions: beta-catenin is approximately 781 amino acids long and contains a central region of 12 armadillo repeats that form the main interaction surface. The N-terminal region contains serine/threonine residues that regulate proteolysis, notably those around Ser33, Ser37, Thr41, and Ser45. The C-terminal region contains a transactivation domain that interacts with transcriptional co-activators.

Regulation and signaling: in the absence of Wnt ligands, beta-catenin is phosphorylated by CK1 and GSK-3β, recognized by the E3 ubiquitin ligase β-TrCP, ubiquitinated, and degraded by the proteasome, keeping cytoplasmic/nuclear levels low. Wnt signaling inhibits this destruction complex, leading to stabilization and accumulation of beta-catenin in the cytoplasm and nucleus, where it partners with TCF/LEF transcription factors to activate target genes such as MYC and CCND1 (cyclin D1).

Clinical relevance: CTNNB1 mutations are found in several cancers, frequently involving exon 3, which disrupts phosphorylation and degradation and yields constitutively active beta-catenin. These mutations are observed in hepatoblastoma, hepatocellular carcinoma, desmoid tumors, and colorectal cancer, among others, and can occur with or without APC mutations. Therapeutic approaches aim to inhibit Wnt/beta-catenin signaling, including strategies targeting the beta-catenin–TCF interaction or stabilizing the destruction complex.