WntbetaCatenin

Wnt/β-catenin signaling, also known as canonical Wnt signaling, is a conserved cellular pathway that transduces extracellular Wnt signals into changes in gene expression and cell behavior. It centers on β-catenin, a dual-function protein involved in adherens junctions and transcriptional regulation, and on the Frizzled receptor family with LRP5/6 co-receptors. In the cytoplasm, a destruction complex consisting of Axin1/2, APC, GSK-3β, and CK1 phosphorylates β-catenin, marking it for ubiquitination and proteasomal degradation. In the absence of Wnt ligands, this keeps cytoplasmic and nuclear β-catenin levels low, preventing activation of Wnt target genes.

When Wnt ligands bind to Frizzled receptors and LRP5/6, Dishevelled is recruited and the destruction complex is inhibited, leading to stabilization and accumulation of β-catenin. Stabilized β-catenin translocates to the nucleus, where it interacts with TCF/LEF transcription factors to activate target genes involved in proliferation, differentiation, and stem cell maintenance. A negative feedback loop through AXIN2 helps tune signaling. At the cell membrane, β-catenin also associates with E-cadherin to support cell–cell adhesion, linking signaling to tissue architecture.

Biological and clinical relevance: The pathway governs embryonic development, tissue homeostasis, and stem cell biology. It is frequently dysregulated in cancer; activating mutations in CTNNB1 (β-catenin) or loss of APC can cause constitutive signaling and tumorigenesis, notably in colorectal cancer. Therapeutic strategies aiming to modulate Wnt signaling are under investigation, but selective targeting remains challenging due to the pathway’s roles in normal physiology.