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Review
. 2013 Mar 1;5(3):a015081.
doi: 10.1101/cshperspect.a015081.

Secreted and transmembrane wnt inhibitors and activators

Cristina-Maria Cruciat  1 , Christof Niehrs
Affiliations
Review

Secreted and transmembrane wnt inhibitors and activators

Cristina-Maria Cruciat et al. Cold Spring Harb Perspect Biol. .

Abstract

Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand-receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease.

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Figures

Figure 1.
Figure 1.
Domain structure of Wnt antagonists and agonists. Signal peptides are shown in red. NTR, Netrin-related motif; WIF, Wnt-inhibitory factor 1 domain; EGF, epidermal growth factor-like domain; CT, cystine knot-like domain; IB, insulin growth factor binding protein domain; TY, thyroglobulin type-1 domain; TM, transmembrane domain; L, leucine-rich repeats; TSP, thrombospondin type-1 domain.
Figure 2.
Figure 2.
Models of Wnt signaling inhibition. (A,B) Dkk1 binding to LRP6 disrupts the Wnt-induced Fz–LRP6 complex formation (A) and/or induces LRP6 endocytosis in the presence of its coreceptor Kremen (B). (C) sFRPs, WIF-1, and Cerberus sequester Wnt, thereby inhibiting both canonical and noncanonical Wnt signaling. (D) sFRPs may also inhibit canonical and noncanonical Wnt signaling by binding to Fz. (E) Wise/SOST binding to LRP6 blocks Wnt-induced Fz–LRP6 complex formation. (F) IGFBP-4 binds to LRP6 and Fz, thereby preventing signal transduction by Wnt.
Figure 3.
Figure 3.
Models of Wnt signaling activation. (A) Rspo binds to ZNRF3 and LGR4 and induces clathrin-mediated receptor endocytosis. Internalized ZNRF3 is unable to ubiquitinate and target Wnt receptors for degradation. As a consequence, Fz and LRP6 accumulate on the plasma membrane and transmit canonical Wnt signals. (B) Rspo3 binding to Sdc4 promotes clathrin-mediated endocytosis of the Wnt receptor complex and thereby activates noncanonical Wnt signaling. (C) TSPAN12 is part of the Norrin/Fz4/LRP5 signaling complex and promotes Norrin/β-catenin signaling.
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References

    1. Adamska M, MacDonald BT, Sarmast ZH, Oliver ER, Meisler MH 2004. En1 and Wnt7a interact with Dkk1 during limb development in the mouse. Dev Biol 272: 134–144 - PubMed
    1. Aguilera O, Fraga MF, Ballestar E, Paz MF, Herranz M, Espada J, Garcia JM, Munoz A, Esteller M, Gonzalez-Sancho JM 2006. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25: 4116–4121 - PubMed
    1. Ahn Y, Sanderson BW, Klein OD, Krumlauf R 2010. Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development 137: 3221–3231 - PMC - PubMed
    1. Ai M, Holmen SL, Van Hul W, Williams BO, Warman ML 2005. Reduced affinity to and inhibition by DKK1 form a common mechanism by which high bone mass-associated missense mutations in LRP5 affect canonical Wnt signaling. Mol Cell Biol 25: 4946–4955 - PMC - PubMed
    1. Aoki M, Mieda M, Ikeda T, Hamada Y, Nakamura H, Okamoto H 2007. R-Spondin3 is required for mouse placental development. Dev Biol 301: 218–226 - PubMed

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