2012 Group 5 Project
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Wnt/Beta-catenin Signalling Pathway
- Wnt proteins encompass a network of secreted glycolipoproteins
- Wnt signalling best known for playing a variety roles in embryogenesis, control of cellular proliferation and the resulting birth defects, cancers and other diseases arising from mutations in the pathway 
- Beta-catenin commonly exists as a subunit making up the cadherin protein complex
- Cadherin proteins play an integral role in the formation of adhesion junctions between cells
- Beta-catenin also acts to help anchor the actin cytoskeleton within the cell
- Beta-catenin plays a vital role in the Wnt signalling pathway by directly affecting the control of protein synthesis within the cell. The interaction of beta-catenin with the TCF/LEF family of transcription factors on the template DNA strand converts them from repressors to activators, triggering downstream transcription of Wnt target genes and synthesis of their encoded proteins. 
- This interaction is reliant on an intracellular cascade which ultimately dictates the amount of Beta-catenin present in the cytoplasm which is then able to reach the nucleus and effect transcription.
- In the absence of Wnt (“off state”), beta-catenin is targeted for proteasomal degradation. Intracellular Axin, GSK-3β (glycogen synthase kinase 3β) and APC (Adenomatous polyposis coli – coded for by the APC tumour suppressor gene) form a “destruction complex” leading to phosphorylation of β-catenin by the coordinated action of CK1 and GSK-3β and subsequent ubiquination. 
- In the presence of Wnt (“on state”) an extracellular “Wnt signal” binds to a cell surface G-protein coupled receptor of the “Frizzled” (FRZ) family. This results in the activation (phosphorylation and poly-ubiquination) of proteins of the “Dishevelled” (DSH) family implicated in the inactivation of the “destruction complex” by the recruitment of GSK-3β away from the complex. With the complex now interrupted, an increased amount of beta-catenin is able to reach the nucleus where it can promote transcription of Wnt target genes. 
- Low-density lipoprotein receptor-related protein (LRP) family functions as a transmembrane co-receptor for Frizzled. It functions to recruit axin to the membrane, leading to axin degradation upon the initiation of the Wnt signalling cascade and the dissociation of beta-catenin into the cytoplasm without degradation by the “destruction complex”. 
- The Beta-catenin gene can be said to function as an oncogene given that the promotion of transcription of Wnt target genes by beta-catenin has been shown to be involved in the development of basal cell carcinoma, colorectal cancer and breast cancer. 
Caught up in a Wnt storm: Wnt signaling in cancer 
- The Wnt signaling pathway, named for its most upstream ligands, the Wnts, is involved in various differentiation events during embryonic development and leads to tumor formation when aberrantly activated. Molecular studies have pinpointed activating mutations of the Wnt signaling pathway as the cause of approximately 90% of colorectal cancer (CRC), and somewhat less frequently in cancers at other sites, such as hepatocellular carcinoma (HCC).
- Greater than 90% of all CRCs will have an activating mutation of the canonical Wnt signaling pathway, ultimately leading to the stabilization and accumulation of β-catenin in the nucleus of a cell.
- Fig. Schematic representation of a colon crypt and proposed model for polyp formation. At the bottom third of the crypt, the progenitor proliferating cells accumulate nuclear β-catenin. Consequently, they express β-catenin/TCF target genes. An uncharacterized source of WNT factors likely resides in the mesenchymal cells surrounding the bottom of the crypt, depicted in red. As the cells reach the mid-crypt region, β-catenin/TCF activity is downregulated and this results in cell cycle arrest and differentiation. Cells undergoing mutation in APC or β-catenin become independent of the physiological signals controlling β-catenin/TCF activity. As a consequence, they continue to behave as crypt progenitor cells in the surface epithelium giving rise to aberrant crypt foci.
Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases 
- Signaling by the Wnt family of secreted glycolipoproteins is one of the fundamental mechanisms that direct cell proliferation, cell polarity, and cell fate determination during embryonic development and tissue homeostasis (Logan and Nusse, 2004). As a result, mutations in the Wnt pathway are often linked to human birth defects, cancer, and other diseases (Clevers, 2006). A critical and heavily studied Wnt pathway is the canonical Wnt pathway, which functions by regulating the amount of the transcriptional coactivator β-catenin, which controls key developmental gene expression programs.
- Given the critical roles of Wnt/b-catenin signaling in development and homeostasis, it is no surprise that mutations of the Wnt pathway components are associated with many hereditary disorders, cancer, and other diseases (Table 1).
- Association of deregulated Wnt/β-catenin signaling with cancer has been well documented, particularly with colorectal cancer (Polakis, 2007) (Table 1). Constitutively activated β-catenin signaling, due to APC deficiency or β-catenin mutations that prevent its degradation, leads to excessive stem cell renewal/proliferation that predisposes cells to tumorigenesis.
- Mutations of β-catenin at and surrounding these serine and threonine residues are frequently found in cancers, generating mutant β-catenin that escapes phosphorylation and degradation (Table 1).
- Frizzled receptor
- Frizzled proteins
Glossary of Terms
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