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Wnt Inhibitors

Wnt signaling can be inhibited by several antagonists that bind either to the Wnt ligand itself, or to Wnt receptors. Known antagonists of Wnt signaling include Dickkopf (Dkk) proteins, Wnt Inhibitory Factor-1 (WIF-1), and secreted Frizzled-Related Proteins (sFRPs). The Dkk family of secreted proteins includes Dkk-1-4 and Soggy, a protein with homology to Dkk-3, but not other Dkk family members. Dkk-1, -2, and -4 function as antagonists of canonical Wnt signaling by either binding to LRP-5/6 and preventing it from interacting with Wnt-Frizzled complexes, or by binding to Kremen-1 or -2 and triggering the internalization of LRP-5/6. In contrast, both WIF-1 and sFRPs antagonize Wnt signaling by binding directly to Wnt proteins and inhibiting their activity. WIF-1 is a secreted protein that can bind to Wnts through its WIF domain. Members of the sFRP family (sFRP-1-5) bind to Wnt proteins through their N-terminal cysteine-rich domains (CRDs), which are homologous to the CRDs found in the Frizzled family of Wnt receptors. Although sFRPs are generally thought to function as Wnt antagonists, they may also enhance Wnt signaling by stabilizing or transporting Wnt ligands. In addition to binding to Wnt proteins, sFRPs can also inhibit Wnt signaling pathways by binding directly to Frizzled receptors. Reduced sFRP expression is associated with aberrant activation of Wnt signaling and tumorigenesis.