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 conserved Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. This developmental cascade integrates signals from other pathways, including retinoic acid, FGF, TGF-β, and BMP, within different cell types and tissues. The Wnt ligand is a secreted glycoprotein that binds to Frizzled receptors, which triggers displacement of the multifunctional kinase GSK-3β from a regulatory APC/ Axin/GSK-3β-complex. In the absence of Wnt-signal (Off-state), β-catenin, an integral E-cadherin cell-cell adhesion adaptor protein and transcriptional co-regulator, is targeted by coordinated phosphorylation by CK1 and the APC/Axin/GSK-3β-complex leading to its ubiquitination and proteasomal degradation through the β-TrCP/SKP pathway. In the presence of Wnt ligand (On-state), the co-receptor LRP5/6 is brought in complex with Wnt-bound Frizzled. This leads to activation of Dishevelled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3β from APC/Axin through an unclear mechanism that may involve substrate trapping and/ or endosome sequestration. The transcriptional effects of Wnt ligand is mediated via Rac1-dependent nuclear translocation of β-catenin and the subsequent recruitment of LEF/ TCF DNA-binding factors as co-activators for transcription, acting partly by displacing Groucho-HDAC co-repressors. Additionally, β-catenin has also been shown to cooperate with the homeodomain factor Prop1 in context-dependent activation as well as repression complexes. Importantly, researchers have found β-catenin point mutations in human tumors that prevent GSK-3β phosphorylation and thus lead to its aberrant accumulation. E-cadherin, APC, and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Furthermore, GSK-3β is involved in glycogen metabolism and other signaling 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.
• Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149(6), 1192–205.
• 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.
• Metcalfe C, Bienz M (2011) Inhibition of GSK3 by Wnt signalling--two contrasting models. J. Cell. Sci. 124(Pt 21), 3537–44.
• 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 (2010) The Wnt Homepage.
• Petersen CP, Reddien PW (2009) Wnt signaling and the polarity of the primary body axis. Cell 139(6), 1056–68.
• Sokol SY (2011) Maintaining embryonic stem cell pluripotency with Wnt signaling. Development 138(20), 4341–50.
• 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.