Naked cuticle encodes an inducible antagonist of Wnt signalling

Department of Developmental Biology, Howard Hughes Medical Institute, Beckman Center, Stanford University School of Medicine, California 94305, USA.
Nature (Impact Factor: 41.46). 03/2000; 403(6771):789-95. DOI: 10.1038/35001615
Source: PubMed


During animal development, cells have to respond appropriately to localized secreted signals. Proper responses to Hedgehog, transforming growth factor-beta, epidermal growth factor and fibroblast growth factor/Ras signals require cognate inducible antagonists such as Patched, Dad, Argos and Sprouty. Wnt signals are crucial in development and neoplasia. Here we show that naked cuticle (nkd), a Drosophila segment-polarity gene, encodes an inducible antagonist for the Wnt signal Wingless (Wg). In fly embryos and imaginal discs nkd transcription is induced by Wg. In embryos, decreased nkd function has an effect similar to excess Wg; at later stages such a decrease appears to have no effect. Conversely, overproduction of Nkd in Drosophila and misexpression of Nkd in the vertebrate Xenopus laevis result in phenotypes resembling those of loss of Wg/Wnt function. nkd encodes a protein with a single EF hand (a calcium-binding motif) that is most similar to the recoverin family of myristoyl switch proteins. Nkd may therefore link ion fluxes to the regulation of the potency, duration or distribution of Wnt signals. Signal-inducible feedback antagonists such as nkd may limit the effects of Wnt proteins in development and disease.

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    • "Therefore Nkd should not interact with Arm in a yeast two-hybrid assay. Furthermore, it has been demonstrated that Nkd requires active Wg signaling in Drosophila, but the requirement for Nkd activity induced by Wg has not been tested, or at least reported (Zeng et al., 2000; Rousset et al., 2001). Finally , fly Nkd was found to interact with Importin α3, which promoted the nuclear localization of Nkd (Chan et al., 2008). "
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    ABSTRACT: Misregulation of Wnt signaling is at the root of many diseases, most notably colorectal cancer and while we understand the activation of the pathway, we have a very poor understanding of the circumstances under which Wnt signaling turns itself off. There are numerous negative feedback regulators of Wnt signaling but two stand out as constitutive and obligate Wnt induced regulators: Axin2 and Nkd1. While Axin2 behaves similar to Axin in the destruction complex, Nkd1 is more enigmatic. Here we use zebrafish blastula cells that are responsive Wnt signaling to demonstrate that Nkd1 activity is specifically dependent on Wnt ligand activation of the receptor. Furthermore, our results support the hypothesis that Nkd1 is recruited to the Wnt signalosome with Dvl2 where it becomes activated to move into the cytoplasm to interact with β-catenin inhibiting its nuclear accumulation. Comparison of these results with Nkd function in Drosophila generates a unified and conserved model on the role of this negative feedback regulator in the modulation of Wnt signaling. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 04/2015; 26(12). DOI:10.1091/mbc.E14-12-1648 · 4.47 Impact Factor
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    • "There are 3 branches of Wnt signaling pathway: canonical Wnt pathway, the planar cell polarity pathway and Wnt/Ca 2? pathway (Hlsken and Behrens 2000). Nkd was identified as inducible antagonist Wnt pathway (Zeng et al. 2000), which was later proved to bind to Dishevelled (Wharton et al. 2001; Yan et al. 2001). Dishevelled (Dvl) is a very important component of Wnt signaling pathway, relaying the signal from receptor to downstream effctors. "
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    ABSTRACT: Frequent amplification and abundant expression of Nkd2 has been identified in malignant peripheral nerve sheath tumors (MPNSTs), dominant for genomic instability, who is involved in both Wnt pathway and EGFR signaling pathway. As a negative regulator of Wnt pathway, Nkd2 suppresses Wnt signaling by binding to Dvl1 and causing its ubiquitination followed by 26S proteasome degradation. On the other hand, it interacts with TGF-α for its transportation to basolateral plasma membrane in polarized epithelial cells. It is of interest to determine if Nkd2 over-expression contributes to tumorigenesis and genomic instablity. In this paper, we found that cells expressing NKD2 delayed mitotic exit stage after double thymidine block synchronization, but aneuploidy was not detected in these cells. This was further confirmed by Western blotting. In nocodazole-synchronised cells, Cyclin B1 degradation was delayed with Nkd2 over-expression compared to control group. Given many previous publications showed that Wnt pathway components are involved in mitotic progression. Further investigation on Nkd2’s function in mitosis might give more clues on MPNSTs pathological progression.
    Genes & genomics 10/2013; 35(5). DOI:10.1007/s13258-013-0104-6 · 0.60 Impact Factor
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    • "In flies, absence of Nkd results in a naked cuticle phenotype (hence its name) at larval stages, but even though nkd is expressed at multiple other stages of development in domains of active Wnt signaling, its loss of function does not appreciably affect these other Wnt signaling events [21]. Double knockout of nkd1 and nkd2 in mouse results in subtle alterations in cranial bone morphology, but are otherwise normal and fertile [22] and ubiquitous overexpression of Nkd1 in the mouse or in the fly embryo does not have any obvious consequences [15,17,21]. These results are consistent with our analysis of Nkd1 function in zebrafish. "
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    ABSTRACT: Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1's ability to antagonize canonical Wnt/β-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/β-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized.
    PLoS ONE 08/2013; 8(8):e74666. DOI:10.1371/journal.pone.0074666 · 3.23 Impact Factor
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