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, secreted Frizzled related proteins (sFRPs) are secreted glycoproteins with homology to the Wnt-binding domain of the Frizzled family of transmembrane receptors. sFRPs function as soluble antagonists of Wnt signaling by binding directly to Wnt proteins and preventing their interactions with Frizzled receptors. In contrast, 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.