Wnt/β-Catenin Signaling

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

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-3β-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 (Dvl) is activated by phosphorylation and poly-ubiquitination, which in turn recruits GSK-3β away from the degradation complex. This allows for stabilization of β-catenin levels, Rac1-dependent nuclear translocation 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, point-mutations in β-catenin lead to its deregulated stabilization. APC and Axin mutations also have been documented in some tumors, underscoring the deregulation of this pathway in human cancer. 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, 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:

• Angers S, Moon RT (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10(7), 468–77.
• Barker N, Clevers H (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5(12), 997–1014.
• Fearon ER (2009) PARsing the phrase "all in for Axin"- Wnt pathway targets in cancer. Cancer Cell 16(5), 366–8.
• MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17(1), 9–26.
• Mosimann C, Hausmann G, Basler K (2009) Beta-catenin hits chromatin: regulation of Wnt target gene activation. Nat. Rev. Mol. Cell Biol. 10(4), 276–86.
• Nusse, R. (2009) The Wnt Homepage. http://www.stanford.edu/~rnusse/wntwindow.html.
• Petersen CP, Reddien PW (2009) Wnt signaling and the polarity of the primary body axis. Cell 139(6), 1056–68.
• van Amerongen R, Nusse R (2009) Towards an integrated view of Wnt signaling in development. Development 136(19), 3205–14.

We would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for contributing to this diagram.