Ryk: another heretical Wnt receptor defies the canon.

The number of proteins that serve as Wnt receptors is growing, and Ryk is one of the newest members of this group. Understanding how extracellular Wnt ligands interact with transmembrane receptors to activate intracellular signaling cascades is of broad importance to biology and to human disease because of the roles for Wnt in embryogenesis, cancer, and neural development and plasticity. The functions and properties of Ryk, a receptor tyrosine kinase-like protein, in canonical and noncanonical Wnt signaling are beginning to be uncovered. Biochemical and genetic studies reveal that the extracellular regions of Ryk and Fz can form a mutual ligand-binding domain. It remains to be seen whether Ryk can form similar complexes with other Wnt-binding proteins. If divergent transmembrane proteins can combine interchangeably to form heteromeric Wnt receptor complexes, then a stunning diversity of signaling responses might be mediated through differential expression and localization of these proteins in target cells.