Wnt/β-Catenin Signaling

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, leading to the formation of a larger cell surface complex with LRP5/6. Frizzleds are ubiquitinated by ZNRF3 and RNF43, whose activity is inhibited by R-spondin binding to LGR5/6. In this manner R-spondins increase sensitivity of cells to the Wnt ligand. Activation of the Wnt receptor complex 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. Stablized β-catenin is translocated to the nucleus via Rac1 and other factors, where it binds to LEF/TCF transcription factors, displacing co-repressors and recruiting additional co-activators to Wnt target genes. Additionally, β-catenin cooperates with several other transcription factors to regulate specific targets. 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, R-spondin and Axin mutations have also been documented in tumor samples, underscoring the deregulation of this pathway in cancer. Wnt signaling has also been shown to promote nuclear accumulation of other transcriptional regulator implicated in cancer, such as TAZ and Snail1. 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.
• Cadigan KM, Waterman ML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4(11), .
• Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149(6), 1192–205.
• de Lau W, Peng WC, Gros P, Clevers H (2014) The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes Dev. 28(4), 305–16.
• 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.
• Niehrs C (2012) The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13(12), 767–79.
• 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.
• Valenta T, Hausmann G, Basler K (2012) The many faces and functions of β-catenin. EMBO J. 31(12), 2714–36.

We would like to thank Prof. Kenneth Cadigan, University of Michigan, Ann Arbor, MI, for contributing to this diagram.

created January 2003

revised September 2016