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.
Organ Systems
digestive
musculoskeletal
nervous
integumentary
Pathway Steps
no Wnt — β-catenin → destruction complex (APC + Axin + GSK-3β + CK1α) — via CK1α priming Ser45 → GSK-3β phosphorylating S33/S37/T41 → β-TrCP ubiquitination. In the OFF state the destruction complex (APC, Axin, GSK-3β, CK1α) constitutively captures β-catenin: CK1α primes Ser45, then GSK-3β phosphorylates S33/S37/T41 for β-TrCP ubiquitination. APC mutations (in nearly all colorectal cancers) break this brake, driving constitutive Wnt signaling.
ubiquitinated β-catenin → proteasomal degradation — via baseline OFF state; cytoplasmic β-catenin half-life minutes. Continuous degradation keeps cytoplasmic β-catenin’s half-life to minutes, holding the pathway off. β-catenin also has a separate, Wnt-independent structural role at adherens junctions (binding E-cadherin) — only the free cytoplasmic pool is signaling-competent.
Wnt ligand binding → Frizzled + LRP5/6 co-receptor signalosome — via palmitoylated Wnt secreted via Wntless (porcupine acyltransferase required). Wnt ligands must be palmitoylated by porcupine (PORCN) and secreted via Wntless to bind the Frizzled/LRP5/6 co-receptor pair — so PORCN inhibitors are a therapeutic strategy. LRP5 gain/loss-of-function mutations cause high-bone-mass and osteoporosis-pseudoglioma, underscoring Wnt’s role in bone.
Frizzled-LRP5/6 → Dishevelled (Dvl) recruitment → destruction complex disassembly — via Axin sequestered to membrane; CK1α primes LRP5/6 PPPSPxS motifs. Receptor engagement recruits Dishevelled and sequesters Axin to the membrane, where CK1α/GSK-3β now phosphorylate LRP5/6’s PPPSPxS motifs instead of β-catenin — disabling the destruction complex. This switch of GSK-3β’s target is the core ON mechanism.
destruction complex off → β-catenin stabilization + nuclear translocation — via half-life rises from minutes to hours. With the complex disabled, β-catenin escapes degradation (half-life rises from minutes to hours), accumulates, and enters the nucleus. The amount of stabilized β-catenin sets the strength of the transcriptional response.
nuclear β-catenin → TCF/LEF — Groucho/TLE displacement — via recruits BCL9 + Pygopus + p300/CBP coactivators. β-catenin converts TCF/LEF from repressors to activators by displacing Groucho/TLE corepressors and recruiting BCL9, Pygopus, and the p300/CBP histone acetyltransferases — the molecular switch turning a silenced enhancer into an active one.
β-catenin-TCF complex → Axin2 + c-Myc + cyclin D1 + LGR5 transcription — via Axin2 is the negative-feedback target gene. Target genes include proliferation drivers (c-Myc, cyclin D1), the stem-cell marker LGR5 (intestinal and cancer stem cells), and Axin2 — a negative-feedback target that rebuilds the destruction complex to limit the response, an off-switch that APC-loss tumors override.