Beta-catenin destruction complex, TCF activation, and stem cell regulation
The canonical Wnt/β-catenin pathway controls cell proliferation, stem cell self-renewal, and cell fate decisions throughout development and adult tissue homeostasis. In the OFF state, a destruction complex (APC–Axin–GSK3β–CK1) phosphorylates β-catenin, targeting it for ubiquitination and proteasomal degradation, keeping nuclear levels low and TCF/LEF transcription factors repressed by Groucho. Wnt ligand binding to Frizzled-LRP5/6 co-receptors recruits Dishevelled, disassembling the destruction complex. β-catenin accumulates, translocates to the nucleus, displaces Groucho from TCF/LEF, and activates target genes (c-Myc, Cyclin D1, Axin2, Lgr5). APC truncations (seen in >80% of colorectal cancers) constitutively activate the pathway by abolishing destruction complex function, driving uncontrolled proliferation.