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.