Genes: APC (Adenomatous polyposis coli)

Wnt signaling in the small intestine
Wnt signaling in the small intestine
  • Loss of function can contribute to the development of Familial adenomatous polyposis (FAP)
  • Together with GSK-3β and axin Apc builds the β-catenin destruction complex, which playes a key role in the wnt-signalling pathway.
  • In colonic crypts, Apc negatively controls the levels of β-catenin, which governs the proliveration of the enterocytes in the crypt:
    • Cells are produced at the bottom of the crypt and migrate upward to the villus.
    • β-catenin levels decrease coninously from the lower crypt to the upper villus. This is because the migrating cells increase the expression of APC which, in the absence of Wnts, is able to break down β-catenin.
    • The absence of β-catenin drives cells to differentiation.
    • If APC is mutated and therefore not able to build the β-catenin destruction complex, β-catenin levels stay high and prevent cells from differentiation.
    • Continuous proliferation and the formation of polyps is the consequence.

The Wnt- β-catenin / -canonical pathway

Wnt Pathway
Wnt Pathway
  • Ligand: Wnt factors, Receptor: Frizzled
  • Cascade:
    1. Wnt activates Frizzled receptor.
    2. Glycogen synthase kinase-3β (GSK-3β) is suppressed (via dishevelled).
    3. GSK-3β cannot phosphorylate β-catenin.
      • without active frizzled, β-catenin will form a multiprotein complex with Apc and axin. This protein complex helps to bring β-catenin together with GSK-3β for phosphorylation.
      • When β-catenin is phosphorylated, it subsequently is ubiquitylated, what leads to rapid degradation of β-catenin.
    4. β-catenin is not degraded
    5. β-catenin accumulates in cytoplasm and nucleus
    6. Two distinct effects:
      • in nucleus, β-catenin associates with Tcf/Lef transcription factors which enable the expression of genes (e.g. Cyclin D1, Myc), that drive increased proliferation and prevent differentiation. This way the canonical wnt pathway mainly contributes to the stem-cell phenotype.
      • At the cell membrane, β-catenin in involved in the formation of adherens junction, since β-catenin together with p120 and alpha-catenein establishes the linkage between cadherin and the actin cytosceleton.