Schematic of the canonical Wnt signaling pathway. A) In the absence of Wnt ligands, β-cat is sequestered in the cytoplasm by the destruction complex consisting of APC, axin, GSK-3, and CK-1α, leading to its degradation by the proteasome. TCF and Groucho bind to the promoters of Wnt target genes and repress their expression. B) Upon binding of a Wnt ligand to the Frizzled receptor and LRP-5/6 co-receptor, the destruction complex is disrupted by Dvl. In turn, β-cat enters the nucleus where it forms the bipartite transcription factor β-cat/TCF and stimulates Wnt target gene expression. GPCR, G-protein coupled receptor. Dvl, dishevelled. APC, adenomatous polyposis coli. GSK-3, glycogen synthase kinase-3. CK-1α, casein kinase 1α. IR, insulin receptor. HDAC, histone deacetylase. CtBP-1, C-terminal binding protein-1. H/N, hormone/neurotransmitter. PKA, protein kinase A. Ins, insulin. CBP, cAMP response element-binding (CREB) binding protein.