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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.