Canonical Wnt signaling is well understood for its ability to regulate cell-cell adhesion and cell cycle control. Wnt ligands and β-catenin/ T cell factor (Tcf) signalling are also potent initiators of human oncogenesis such that mutation in regulatory molecules (Mulholland DJ et al. 2005)
Extracellular Wnt binding of the transmembrane Frizzled receptor results in receptor kinase action, phosphorylation of the cytoplasmic mediator: Dishevelled (Dsh) and inhibition of the multifunctional serine/threonine glycogen synthase kinase (GSK3β).
Free cytosolic β-catenin levels are strictly controlled by phosphorylation of the NH2-terminal region of the protein by GSK3β. This reaction requires association with axin and the product of the adenomatous polyposis coli (APC) tumor suppressor gene, and targets β-catenin for ubiquitin-mediated degradation by the proteasome.
Interaction of Wnt ligands with their membrane receptors blocks GSK3β, leading to the accumulation of free β-catenin (Palmer HG et al. 2001)
Upon increased cellular levels and nuclear accumulation , in the nucleus β-catenin binds the amino terminus of the high-mobility group binding protein Tcf and promotes its interaction with target DNA sequences (A/T A/T CAAAG), thereby promoting displacement of the Tcf repressors : Groucho and CtBP. This, in turn, leads to a concomitant recruitment of coactivators such as CREB binding protein (CBP)/p300 , Brgl , and CARM1 and an overall de-repression of Tcf transcription.
Activation of the Wnt/β-catenin/Tcf signaling pathway , either by disengagement of the APC/axin/GSK3 complexing or by Wnt activation promotes induction of downstream gene targets such as cyclin D1 , c-myc , PPAR-gamma , Tcf-1 , matrilysin and CD44. Induction of these genes has dramatic effects on cell and tissue development and oncogenesis (Mulholland DJ et al. 2005)
Activation and inactivation of the Wnt pathway. A : Wnt ligands bind to Frizzled to activate Dishevelled (Dsh), phosphoinhibition of GSK3
β dissociation from Axin, and binding to frequently rearranged in advanced T cell lymphomas (FRATs). Cytosolic β-catenin accumulates and translocates to the nucleus to activate Tcf/lymphoid enhancer factor (Lef)-1-responsive
genes resulting in gene activation and cell cycle progression. B: Absence of Wnt stimulation results in the formation of an Axin/GSK3/APC complex, phosphorylation of
β-catenin by casein kinase 1 (CK1) and GSK3β, followed by Trcp-mediated proteosome degradation. Wnt target genes are, therefore, not activated. WIF, Wnt inhibitory factor.
