Wnt/beta-catenin signaling: components, mechanisms, and diseases

Abstract

Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.

Figure 1. Overview of Wnt/β-catenin signaling

A) In the absence of Wnt, cytoplasmic β-catenin forms a complex with Axin, APC, GSK3 and CK1, and is phosphorylated by CK1 (blue) and subsequently by GSK3 (yellow). Phosphorylated β-catenin is recognized by the E3 ubiquitin ligase β-Trcp, which targets β-catenin for proteosomal degradation. Wnt target genes are repressed by TCF-TLE/Groucho and histone deacetylases (HDAC). B) In the presence of Wnt ligand, a receptor complex forms between Fz and LRP5/6. Dvl recruitment by Fz leads to LRP5/6 phosphorylation, and Axin recruitment. This disrupts Axin-mediated phosphorylation/degradation of β-catenin, allowing β-catenin to accumulate in the nucleus where it serves as a co-activator for TCF to activate Wnt responsive genes.

Figure 2. Wnt biogenesis and secretion

Wnts are glycosylated and lipid modified in the ER involving Porcupine, and escorted by Wntless from the Golgi to the plasma membrane for secretion. Wntless is retrieved from endocytic vescicles back to the Golgi by the retromer complex. After secretion mature Wnts bind to HSPGs and lipoprotein particles or form multimers, which can modulate Wnt gradients and facilitate long range Wnt signaling. The number of Wnt molecules bound to the lipoprotein particle and in the multimeric form were drawn arbitrarily.

Figure 3. Secreted Wnt antagonists and agonists

A) Antagonists. WIF and sFRP bind directly to secreted Wnts and/or Fz. DKK and SOST/WISE proteins bind LRP5/6 to prevent Fz-LRP6 complex formation. Shisa proteins trap Fz in the ER. B) Agonists. Wnts are the primary agonists and form a complex with LRP5/6 and Fz to activate signaling. Norrin acts similar to Wnt, but binds specifically to Fz4. R-spondin proteins (Rspo) act via and may bind to LRP5/6 and/or Fz receptors. In the ER, the chaperone MESD is needed for LRP5/6 maturation.

Figure 4. Regulation of Axin complex assembly for β-catenin degradation

The core components of the Axin complex, Axin, APC, GSK3 and CK1 collectively promote β-catenin phosphorylation for degradation by β-Trcp. In addition to phosphorylating β-catenin, GSK3 (yellow) and CK1 (blue) also phosphorylate Axin and APC and enhance their binding to β-catenin and degradation complex stability, further ensuring β-catenin phosphorylation. The inset illustrates β-catenin phosphorylation (by CK1 and GSK3) and dephosphorylation (by PP2A). APC may also act to prevent PP2A dephosphorylation of β-catenin. APC paradoxically facilitates Axin degradation and possibly vise vesa (indicated by dashed line, see text). PP1 dephosphorylates Axin to antagonize CK1 phosphorylation and negatively regulates GSK3-Axin binding resulting in complex disassembly.

Figure 5. Models of Wnt receptor activation

A) Initiation and Amplification. Wnt forms a complex with LRP6 and Fz-Dvl at the membrane. Dvl recruits Axin-GSK3 resulting in the phosphorylation of one or more PPPSP motifs in LRP6 (initiation). Partially phosphorylated LRP6 may be able to recruit and more efficiently bind Axin-GSK3 and promote more PPPSP phosphorylation (amplification). B) Signalsome formation via Dvl polymerization and receptor clustering. The oligiomerization property of Dvl promotes the aggregation of individual Wnt-LRP6-Fz complexes, resulting in Axin recruitment to the membrane and LRP6 phosphorylation by GSK3 and CK1. C) PI4KIIα and PIP5KI kinases, the latter of which binds directly with Dvl, promote PIP₂ production and receptor clustering/phosphorylation. The configurations of receptor clustering in B and C were drawn arbitrarily. In all models, PPPSPxS motifs are sequentially phosphorylated by GSK3 and CK1, probably via CK1γ (membrane-associated) and/or CK1α and CK1ε associated with Axin and Dvl, respectively, and MACF1 may have a role in the translocation of the Axin complex to the receptors,

Figure 6. Nuclear TCF/β-catenin co-activator complexes

Upon Wnt/β-catenin signaling activation, WRE-bound TCF/β-catenin recruits many co-activator complexes to Wnt target genes. For simplicity only a few representative complexes are illustrated. Dotted lines represent their interactions with β-catenin or between complexes. During active Wnt target gene transcription, APC promotes the exchange between β-catenin/co-activators with co-repressors CtBP, TLE and HDAC in a cyclic manner (double-headed red arrow) while TCF remains bound to the WRE. Ac and Me symbolize histone modifications, such as acetylation and methylation.