The complexity of Wnt intracellular signaling pathways parallels the complexity observed in the diversity of Wnt receptors. Wnt receptors include the Frizzled family, Low Density Lipoprotein Receptor-related Proteins-5/6 (LRP-5/6), Receptor Tyrosine Kinase-like Orphan Receptor-1/2 (ROR1/2), and related to tyrosine (Y) kinase (Ryk).
Frizzled receptors are seven transmembrane G protein-coupled receptors for the Wnt family of glycoproteins. This receptor family contains at least ten different members that mediate distinct, tissue-specific effects. Structurally, all members of the Frizzled family are similar. Each contains a divergent N-terminal signal peptide, a highly conserved extracellular cysteine-rich domain (CRD), a variable length linker region, a seven-pass transmembrane domain, and a variable length C-terminal end. Wnt ligands bind to Frizzled receptors through the CRD, and may also require a co-receptor, such as LRP-5, LRP-6, ROR, or Ryk, to activate downstream signaling pathways. LRP-5 and LRP-6 are orthologs of the Drosophila receptor Arrow, and are associated with the canonical beta-Catenin-dependent signaling pathway. ROR1/2 and Ryk are additional Wnt co-receptors that are associated with non-canonical Wnt signaling pathways. Since Wnt ligands have different affinities for different Frizzled receptors, activation of a given Wnt/Frizzled signaling cascade is dependent on the Wnt ligand and the cellular context of the interaction. Wnt signaling is involved in a variety of developmental processes including cell fate determination, cell polarity, tissue patterning, and control of cell proliferation. In addition, it plays a role in the maintenance of adult tissue homeostasis.
Low-Density Lipoprotein Receptor-Related Proteins (LRPs)
| LRP-1 | LRP-1 Cluster II | LRP-1 Cluster III | LRP-1 Cluster IV | LRP-1B |
| LRP-3 | LRP-4 | LRP-5 | LRP-6 | LRP-10 |
| LRP-11 | LRPAP | Megalin/LRP2 | ST7/LRP12 |
Other Wnt Receptors
| Cripto | MuSK | PTK7/CCK4 |
| Ryk | Vang-like Protein 1/VANGL1 | Vang-like Protein 2/VANGL2 |
Wnt Signaling Modulators
Given that Wnt signaling underlies a diverse range of complex biological functions, modulators of Wnt signaling are of great interest. A number of proteins can either enhance or inhibit Wnt signaling, including Glypicans, R-Spondin proteins, Kremen-1, Kremen-2, Norrin, Sclerostin (SOST), and MESDC2. Glypicans are a family of six heparan sulfate proteoglycans that are anchored to the plasma membrane by a glycosylphosphatidylinositol linkage. These proteins enhance Wnt signaling by stabilizing the interaction between Wnt proteins and Frizzled receptors. Members of the R-Spondin family of proteins (Rspo1-4) also function as positive regulators of Wnt/beta-Catenin-dependent signaling by interfering with Dkk-1-mediated internalization of the Wnt co-receptor, LRP-6. In contrast, Kremen-1 and Kremen-2 antagonize Wnt signaling by forming a complex with Dkk proteins and LRP-5/6 that stimulates LRP-5/6 internalization. MESDC2 and SOST also regulate Wnt signaling through LRP-5/6. MESDC2 is required for proper folding and expression of LRP-5/6, while SOST binds LRP-5/6 and inhibits its ability to function as a co-receptor. Other proteins may regulate Wnt signaling by directly binding to Wnt ligands or Wnt receptors. For example, Norrin is a secreted protein associated with the extracellular matrix that is not related to the Wnt family, but binds to Frizzled-4/LRP and activates the canonical Wnt signaling pathway.
Other Wnt Signaling Modulators
Related Information
- An Overview of Wnt Signaling Pathways
- BIObrief: An Overview of Wnt Signaling Pathways
- Mini-review: The Wnt Family of Secreted Proteins
- Wnt Signaling and sFRPs
- LRP Signaling
- Wnt Inhibitors
- Mini-review: Wnt Receptors & Pathways
- Ryk: A Wnt Co-receptor at the Intersection of Frizzled & Dishevelled
- Wnt: A polarizing factor in early mouse development