Wnt/β-catenin/ Tcf signalling pathway

Author: monica mangioni
Date: 24/01/2008


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.

2010-04-01T16:22:02 - chiara grasso

The cell signalling transduction pathway mediated by the Wingless-type (Wnt) proteins is highly conserved between species. It influences embryonic development, cell polarity and adhesion, apoptosis and tumorigenesis, and interacts with other cell signalling pathways.
The Wnt signalling transduction pathway is essentially a network of a number of separate but interacting pathways.
In this pathway a specific Wnt ligand binds to its target ‘frizzled’ transmembrane receptor (Fz) with downstream activation of gene transcription by b-catenin. This results from interference with the multiprotein b-catenin destruction complex.
In the presence of Wnt, the activated Fz transduces the signal to a cytoplasmic protein, the dishevelled protein (Dvl), which inhibits GSK-3b (the serine/threonine kinase glycogen synthase-3b). The Wnt signal leads to functional inactivation and dissociation of a multi-protein b-catenin destruction complex, which is made up of the tumour suppressor protein adenomatous polyposis coli (APC), GSK-3b and Axin; this results in dephosphorylation and dissociation of b-catenin. Unphosphorylated b-catenin is stabilised and accumulates in the cytoplasm of cells. The b-catenin then associates with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors in the nucleus leading to the eventual transcription and expression of target genes such as c-myc, c-jun, Fra and cyclin D1.
In the absence of the Wnt signalling, GSK-3b phosphorylates b-catenin. Phosphorylated b-catenin is recognised by b-TrCP, which is a component of an E3 ubiquitin ligase. This factor associates with the b-catenin and activates the ubiquination mechanism, leading in its degradation in proteasome.
The significance of the Wnt pathway in the pathology of human cancers 2004

This scheme shows the role of APC in Wnt pathway: In the absence of Wnt or with the presence of wild-type APC protein (on the left), ß-catenin is degraded. In the presence of Wnt (right scheme), or in the absence of APC (as occurs in many colon cancers), ß-catenin target genes (including c-myc) are expressed. Myc expression, in turn, leads to the expression of other genes, included the polyamine ornithine decarboxylase (ODC), which is a proto -oncogene. Then, The APC gene product indirectly regulates transcription of a number of critical cell-proliferation genes; loss of APC function increases transcription of ß-catenin targets.
Molecular causes of colon cancer 2002

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