Nkd1

Nkd1 is the paralog of mammalian Nkd2 and an ortholog of insect Naked cuticle (Nkd). In Drosophila, Nkd is an inducible negative regulator of Wnt/β-catenin signaling during segmentation in the early embryo. Similarly, Nkd1 can be induced by Wnt/β-catenin signaling in cultured cells and vertebrate embryonic node and somites, but its regulation by Notch signaling in the somites hints that the situation in mammals is more complex than in flies. Although the mechanism by which Nkd1 inhibits Wnt signaling is not known, inferences about the mechanism can be made based on known binding partners and gain- and loss-of-function assays. Fly or mouse Nkd can bind and specifically inactivate Dishevelled (Dsh) or the mammalian homologs Dvl1, Dvl2 and Dvl3, a family of scaffolding proteins that act as crucial intermediates in canonical Wnt/β-catenin signaling as well as in non-canonical Wnt signaling pathways. Nkd1 can also bind to PR72 and PR130, regulatory B′′ subunits of the trimeric protein phosphatase 2A (PP2A). PR72 is required for the inhibitory action of Nkd1 on overactive canonical Wnt signaling, and PR130 overexpression activates canonical Wnt signaling by inhibiting the negative regulatory activity of Nkd1, but whether Nkd1/PP2A association facilitates dephosphorylation of Dsh/Dvl or other substrates that are phosphorylated during Wnt signaling is not known. A role for Nkd1 and canonical Wnt signaling in the maturation of mouse sperm was revealed by a targeted mutation in nkd1. Since then, viable mice with severe mutations in both nkd1 and nkd2 genes have been reported, indicating that Nkd activity is not required for murine development. Finally, overproduction of Nkd1 in cultured cells activated Jun-kinase (JNK) activity, which is thought to be a consequence of non-canonical Wnt signaling in flies and in vertebrates, suggesting that Nkd1 regulates non-canonical Wnt signaling. However, no defects in non-canonical Wnt signaling have been documented in nkd-mutant flies or nkd1-mutant mice.