The way Wnt works: components and mechanism

Abstract

The canonical Wnt/β-catenin pathway is an ancient and evolutionarily conserved signaling pathway that is required for the proper development of all metazoans, from the basal demosponge Amphimedon queenslandica to humans. Misregulation of Wnt signaling is implicated in many human diseases, making this pathway an intense area of research in industry as well as academia. In this review, we explore our current understanding of the molecular steps involved in the transduction of a Wnt signal. We will focus on how the critical Wnt pathway component, β-catenin, is in a "futile cycle" of constant synthesis and degradation and how this cycle is disrupted upon pathway activation. We describe the role of the Wnt pathway in major human cancers and in the control of stem cell self-renewal in the developing organism and in adults. Finally, we describe well-accepted criteria that have been proposed as evidence for the involvement of a molecule in regulating the canonical Wnt pathway.

Figure 1

The current model of Wnt/β-catenin signaling. (Left panel) In the absence of Wnt, cytoplasmic β-catenin forms a complex with APC, Axin, GSK3, and CK1α. β-Catenin is phosphorylated by CK1α and subsequently phosphorylated by GSK3. The phosphorylated form of β-catenin is recognized by the E3 ubiquitin ligase SCF^β-TRCP, which targets β-catenin for proteasomal degradation. In the absence of nuclear β-catenin, Wnt target genes are repressed. APC, adenomatous polyposis coli; GSK3, glycogen synthase kinase 3; CK1α, casein kinase 1 alpha. (Right panel) In the presence of Wnt ligand, a receptor complex forms between Fz, LRP5/6, and Wnt. The recruitment of Dsh by Fz leads to LRP5/6 phosphorylation by CK1α and GSK3 followed by recruitment of Axin to LRP5/6. The latter disrupts Axin-mediated phosphorylation/degradation of β-catenin, leading to accumulation of β-catenin in the cytoplasm and its translocation to the nucleus, where it acts as a transcriptional co-activator with TCF to activate Wnt-responsive target genes. Fz, Frizzled; Dsh, Dishevelled; TCF, T-cell factor.

Figure 2

Synthesis and export of Wnt ligand. Wnt ligand undergoes multiple posttranslational modifications in the ER. Glycosylation and palmitoylation of Wnt ligand (the latter mediated by the transmembrane protein Porc) are required for its translocation to the Golgi apparatus. Palmitoylation of Wnt allows it to bind Wls, which provides a mechanism for transportation to the plasma membrane. The retromer complex recycles Wls from the plasma membrane back to the Golgi.

Figure 3

Nuclear TCF/β-catenin transcriptional complexes. Upon Wnt/β-catenin signaling, DNA-bound TCF/β-catenin recruits many other transcriptional complexes to Wnt target genes. Dotted lines represent interactions between the transcriptional complexes and β-catenin. During active Wnt target gene transcription, the co-repressor Gro/TLE cycles on and off of β-catenin in an XIAP-dependent manner with the other transcriptional complexes. Gro/TLE, Groucho/transducin-like enhancer of split.