Negative regulation of TCF-dependent signaling by WNT ligand antagonists

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R-HSA-3772470
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Homo sapiens
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Several unrelated families of secreted proteins antagonize WNT signaling. Secreted frizzled-related proteins (sFRPs) have a cysteine rich domain (CRD) that is also found in FZD and ROR receptors, while WNT inhibitory factor (WIF) proteins contain a WIF domain also present in the WNT-receptor RYK. Both these classes of secreted WNT antagonists inhibit signaling by binding to WNTs and preventing their interaction with the FZD receptors. sFRPs may also able to bind the receptors, blocking ligand binding (Bafico et al, 1999; reviewed in Kawano and Kypta, 2003). The interaction of WIF and sFRPs with WNT ligand may also play a role in regulating WNT diffusion and gradient formation (reviewed in Boloventa et al, 2008).

Dickkopf (DKK) and Sclerostin (SOST) family members, in contrast, antagonize WNT signaling by binding to LRP5/6. There are four DKK family members in vertebrates; the closely related DKK1, 2 and 4 proteins have been shown to have roles in WNT signaling, while the more divergent DKK3 appears not to (Glinka et al, 1998; Fedi et al, 1999; Mao et al, 2001; Semenov et al, 2001; reviewed in Niehrs, 2006). Secreted DKK proteins bind to LRP6 in conjunction with the single-pass transmembrane proteins Kremen 1 and 2, and this interaction is thought to disrupt the WNT-induced FZD-LRP5/6 complex. In some cases, DKK2 has also been shown to function as a WNT agonist (reviewed in N (reviewed in Niehrs, 2006).
Like DKK proteins, SOST binds LRP5/6 and disrupts WNT-dependent receptor activation (Semenov et al, 2005).

Literature References
PubMed ID Title Journal Year
18322270 Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease

Bovolenta, P, Esteve, P, Ruiz, JM, Cisneros, E, Lopez-Rios, J

J. Cell. Sci. 2008
10383463 Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling

Fedi, P, Bafico, A, Nieto Soria, A, Burgess, WH, Miki, T, Bottaro, DP, Kraus, MH, Aaronson, SA

J. Biol. Chem. 1999
12775774 Secreted antagonists of the Wnt signalling pathway

Kawano, Y, Kypta, R

J. Cell. Sci. 2003
11357136 LDL-receptor-related protein 6 is a receptor for Dickkopf proteins

Mao, B, Wu, W, Li, Y, Hoppe, D, Stannek, P, Glinka, A, Niehrs, C

Nature 2001
15908424 SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor

Semënov, M, Tamai, K, He, X

J. Biol. Chem. 2005
9450748 Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction

Glinka, A, Wu, W, Delius, H, Monaghan, AP, Blumenstock, C, Niehrs, C

Nature 1998
10347172 Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling

Bafico, A, Gazit, A, Pramila, T, Finch, PW, Yaniv, A, Aaronson, SA

J. Biol. Chem. 1999
11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6

Semënov, MV, Tamai, K, Brott, BK, Kühl, M, Sokol, S, He, X

Curr Biol 2001
17143291 Function and biological roles of the Dickkopf family of Wnt modulators

Niehrs, C

Oncogene 2006
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