Category: signaling
Canonical Wnt/β-catenin signaling controls stem-cell self-renewal, embryonic patterning, tissue regeneration, and is hijacked in ~90% of colorectal cancers + many others. Core logic: β-catenin level is the binary signal. OFF state (no Wnt): cytoplasmic β-catenin captured by a destruction complex (APC + Axin + GSK-3β + CK1α) → CK1α primes Ser45 → GSK-3β phosphorylates Ser33/37/Thr41 → β-TrCP ubiquitination → proteasomal destruction. ON state (Wnt ligand present): Wnt binds Frizzled + LRP5/6 co-receptor → recruits Dishevelled → disassembles destruction complex (Axin sequestered) → β-catenin accumulates + translocates to nucleus → displaces Groucho/TLE corepressor on TCF/LEF → drives Wnt target genes (Axin2, c-Myc, cyclin D1, LGR5, etc.). Disease drivers: APC loss-of-function (germline = FAP; somatic = ~80% sporadic CRC); β-catenin gain-of-function S33/S37/T41/S45 mutations (hepatocellular carcinoma, desmoid); RNF43/ZNRF3 loss (pancreas); R-spondin overexpression. Therapeutics: lithium chronic inhibits GSK-3β → β-catenin stabilization (anti-suicidal + neurogenic action — partial overlap); porcupine inhibitors (LGK974 — Wnt secretion) and tankyrase inhibitors (Axin stabilization) trialed for tumors; ICG-001 (β-catenin / CBP). Repurposed agents that dampen Wnt: aspirin (sulindac-active analog; CRC chemoprevention); curcumin + EGCG (pre-clinical). Cross-links: [[pi3k_akt_signaling]] (AKT phosphorylates GSK-3β = shared node), [[cell_cycle_cdk]] (cyclin D1 / c-Myc), [[hedgehog_smoothened]] — parallel developmental morphogen.