Wnt/β-Catenin Signaling

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• Reviews
• Pathway Key
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Pathway Description:

The Wnt/β-Catenin pathway regulates cell fate decisions during development of vertebrates and invertebrates. The Wnt-ligand is a secreted glycoprotein that binds to Frizzled receptors, which triggers a cascade resulting in displacement of the multifunctional kinase GSK-3β from the APC/Axin/GSK-3 β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral cell-cell adhesion adaptor protein as well as transcriptional co-regulator, is targeted for degradation by the APC/Axin/GSK-3β-complex. Appropriate phosphorylation of β-catenin by coordinated action of CK1 and GSK-3β leads to its ubiquitination and proteasomal degradation through the β-TrCP/SKP complex. In the presence of Wnt binding (On-state), Dishevelled (Dsh) is activated, seemingly at least in part by phosphorylation, which in turn recruits GSK-3β away from the degradation complex. This allows for stabilization of β-catenin levels, nuclear import and recruitment to the LEF/TCF DNA-binding factors where it acts as an activator for transcription by displacement of Groucho-HDAC co-repressors. Additionally, in complex with the homeodomain factor Prop1, β-catenin has also been shown to act in context-dependent activation as well as repression complexes. Importantly, some human cancers harbor point-mutations in β-catenin leading to its deregulated stabilization, and APC as well as axin mutations have also been documented, underscoring the involvement of abnormal activation of this pathway in human tumors. During development the Wnt/β-catenin pathway integrates signals from many other pathways including Retinoic acid, FGF, TGF-β and BMP in many different cell-types and tissues. In addition, the component GSK-3β is also involved in glycogen metabolism and other key pathways, which has made its inhibition relevant to diabetes and neurodegenerative disorders.

Selected Reviews:

• Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5(12), 997–1014.
• Bienz M (2005) beta-Catenin: a pivot between cell adhesion and Wnt signalling. Curr. Biol. 15(2), R64–7.
• Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127(3), 469–80.
• Gordon MD, Nusse R (2006) Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J. Biol. Chem. 281(32), 22429–33.
• Nelson WJ, Nusse R (2004) Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303(5663), 1483–7.
• Nusse R (2005) The Wnt gene homepage. http://www.stanford.edu/~rnusse/wntwindow.html
• Schulte G, Bryja V (2007) The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol. Sci. 28(10), 518–25.
• Stoick-Cooper CL, Moon RT, Weidinger G (2007) Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine. Genes Dev. 21(11), 1292–315.
• Willert K, Jones KA (2006) Wnt signaling: is the party in the nucleus? Genes Dev. 20(11), 1394–404.

CST would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, for contributing to these diagrams.