WNTS and WNT receptors as therapeutic tools and targets in human disease processes

Abstract

The body of scientific literature linking Wnts and Wnt-associated proteins to human disease processes continues to grow in parallel with new discoveries from basic science laboratories that further characterize the elaborate cellular events following the binding of Wnts to their receptors. While Wnt-mediated signaling has long been known to play a major role in human carcinogenesis, accumulating evidence indicates that Wnts are also important mediators of inflammation and recovery from injury. The binding of secreted Wnt ligands to their receptors offers an attractive and accessible target for therapeutic regulation of these signaling pathways. Several promising preliminary studies have already addressed potential avenues for the manipulation of Wnt signaling in disease processes. This review will focus on disease processes involving the regulation of Wnt signaling at the level of Wnt binding to its target receptors. Wnt proteins, Wnt receptors, and secreted Wnt inhibitors are attractive as potential therapeutic agents and targets due to their extracellular location. In addition, since Wnt signaling results in a diverse array of downstream intracellular events, many of which are not fully understood, the targeting of this pathway at the most upstream site of pathway activation also provides a strategic advantage for therapy. As the list of Wnt-related diseases continues to grow, advances in our understanding of the biochemical and molecular mechanisms underlying Wnt signaling may ultimately translate into innovative ways to treat Wnt-related disease processes in patients.

Figure 1

A summary of the extracellular interactions between Wnts, Wnt receptors and Wnt regulatory proteins. This simplified representation of the known extracellular interactions governing Wnt signaling depicts how secreted Wnt ligands can interact with receptors that trigger either the Wnt/beta-catenin pathway or other pathways like the Wnt/Ca pathway that act via other signaling mediators. As indicated in the figure, activation of Wnt/Ca receptors can inhibit the Wnt/beta-catenin pathway. The portrayal of RYK reflects data suggesting that this receptor may be able to activate both the Wnt/beta-catenin as well as beta-catenin-independent Wnt signaling cascades (17). Extracellular levels of Wnt ligand are titrated by binding to sFRPs, which exhibit homology to the cysteine-rich Wnt-binding domains of the FZD receptor. The secreted protein DKK antagonizes Wnt signaling via binding to the canonical Wnt co-receptor LRP5/6.