# Naked cuticle

Naked cuticle (Nkd) is a conserved family of intracellular proteins encoded in most animal genomes. The original mutants were discovered by 1995 Nobel laureates Christiane Nüsslein-Volhard and Eric F. Wieschaus and colleagues in their genetic screens for pattern-formation mutants in the fruit fly Drosophila melanogaster. The Nkd gene family was first cloned in the laboratory of Matthew P. Scott. Like many cleverly named fly mutants, the name "naked cuticle" derives from the fact that mutants lack most of the hair-like protrusions from their ventral cuticle and thus appear "naked".
In Drosophila, nkd is a segment–polarity class gene that limits the spatial extent of Wnt signaling pathway activity, similar to how the Patched (Ptc) gene regulates the Hedgehog signaling pathway; i.e., Nkd and Ptc shape tissue gradients of Wnt and Hedgehog signaling. Nkd was linked to Wnt signaling based on expansion of Wnt signaling in nkd mutants, by overexpression of Nkd mimicking loss of Wnt signaling, and by the binding of Nkd protein to the Wnt signal transducing protein Dishevelled (Dsh).
Nkd proteins consist of at least four well-conserved blocks of amino acid sequence interspersed by variable regions. The conserved sequence blocks, from N-terminal to C-terminal, are as follows: 1) a N-terminal membrane anchoring motif, which in mammals is subject to myristoylation; 2) a single, extended EF hand motif (called "EFX" or "NH2") that binds Dsh/Dvl proteins; 3) a thirty amino acid amphipathic alpha helix motif that in the fly Nkd protein mediates nuclear translocation and that in the human Nkd1 protein interferes with the interaction between the EF-hand motif and Dvl proteins; and 4) a C-terminal Histidine-rich sequence of unknown function. Vertebrate (and invertebrate) Nkd proteins have additional regions of homology that presumably mediate specific protein functions. For example, Nkd2 but not Nkd1 associates with the secreted EGF-family ligand TGF alpha via a sequence between the third and fourth block that is only in Nkd2, and a sequence between the third and fourth block that is highly conserved in Drosophila species but is neither present in the more distantly related mosquito Anopheles gambiae Nkd nor in any known vertebrate Nkds mediates nuclear import via binding to the nuclear import factor importin-alpha3.
There are two Nkd proteins (Nkd1 and Nkd2) in most vertebrates including humans, but some lower vertebrates have additional Nkd proteins (e.g. Nkd3 in zebrafish). Mice with a mutant Nkd1 protein had a mild sperm maturation defect, but mice lacking both Nkd1 and Nkd2 were viable without obvious sperm defects. In zebrafish, Nkd genes regulate Wnt signaling.
The mRNA transcription of Nkd genes is inducible by Wnt signaling in diverse animals, such that nkd expression is a readout of Wnt activity. Since Nkd inhibits Wnt signaling, the Nkd genes comprise a negative feedback mechanism.

## Sources

* ↑ Jurgens, G., Wieschaus, E., Nusslein-Volhard, C., Kluding H. 1984. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster. II. Zygotic loci on the third chromosome. Wilhelm Roux’s Arch. Dev. Biol. 193, 283–295, 1984.
* 1 2 Zeng W, Wharton KA Jr, Mack JA, Wang K, Gadbaw M, Suyama K, Klein PS, Scott MP. naked cuticle encodes an inducible antagonist of Wnt signalling. Nature. 2000 Feb 17;403(6771):789-95. PMID 10693810
* ↑ Rousset R, Mack JA, Wharton KA Jr, Axelrod JD, Cadigan KM, Fish MP, Nusse R, Scott MP. Naked cuticle targets dishevelled to antagonize Wnt signal transduction. Genes Dev. 2001 Mar 15;15(6):658-71.PMID 11274052
* 1 2 Wharton KA Jr, Zimmermann G, Rousset R, Scott MP. Vertebrate proteins related to Drosophila Naked Cuticle bind Dishevelled and antagonize Wnt signaling. Dev Biol. 2001 Jun 1;234(1):93-106.PMID 11356022
* ↑ Katoh M. Molecular cloning, gene structure, and expression analyses of NKD1 and NKD2. Int J Oncol. 2001 Nov;19(5):963-9.PMID 11604995
* 1 2 Li C, Franklin JL, Graves-Deal R, Jerome WG, Cao Z, Coffey RJ. Myristoylated Naked2 escorts transforming growth factor alpha to the basolateral plasma membrane of polarized epithelial cells. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5571-6. Epub 2004 Apr 2.PMID 15064403
* ↑ Chan CC, Zhang S, Cagatay T, Wharton KA Jr. Cell-autonomous, myristyl-independent activity of the Drosophila Wnt/Wingless antagonist Naked cuticle (Nkd). Dev Biol. 2007 Nov 15;311(2):538-53. Epub 2007 Sep 15.PMID 17942091
* ↑ Yan D, Wallingford JB, Sun TQ, Nelson AM, Sakanaka C, Reinhard C, Harland RM, Fantl WJ, Williams LT. Cell autonomous regulation of multiple Dishevelled-dependent pathways by mammalian Nkd. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3802-7. PMID 11274398
* ↑ Waldrop S, Chan CC, Cagatay T, Zhang S, Rousset R, Mack J, Zeng W, Fish M, Zhang M, Amanai M, Wharton KA Jr. An unconventional nuclear localization motif is crucial for function of the Drosophila Wnt/wingless antagonist Naked cuticle. Genetics. 2006 Sep;174(1):331-48. Epub 2006 Jul 18.PMID 16849595
* ↑ Guo J, Cagatay T, Zhou G, Chan CC, Blythe S, Suyama K, Zheng L, Pan K, Qian C, Hamelin R, Thibodeau SN, Klein PS, Wharton KA, Liu W. Mutations in the human naked cuticle homolog NKD1 found in colorectal cancer alter Wnt/Dvl/beta-catenin signaling. PLoS One. 2009 Nov 24;4(11):e7982.PMID 19956716
* ↑ Chan CC, Zhang S, Rousset R, Wharton KA Jr. Drosophila Naked cuticle (Nkd) engages the nuclear import adaptor Importin-alpha3 to antagonize Wnt/beta-catenin signaling. Dev Biol. 2008 Jun 1;318(1):17-28. Epub 2008 Mar 18.PMID 18423435
* 1 2 Schneider I, Schneider PN, Derry SW, Lin S, Barton LJ, Westfall T, Slusarski DC. Zebrafish Nkd1 promotes Dvl degradation and is required for left-right patterning. Dev Biol. 2010 Dec 1;348(1):22-33. Epub 2010 Sep 19.PMID 20858476
* ↑ Li Q, Ishikawa TO, Miyoshi H, Oshima M, Taketo MM. A targeted mutation of Nkd1 impairs mouse spermatogenesis. J Biol Chem. 2005 Jan 28;280(4):2831-9. Epub 2004 Nov 16.PMID 15546883
* ↑ Viable mice with compound mutations in the Wnt/Dvl pathway antagonists nkd1 and nkd2. Zhang S, Cagatay T, Amanai M, Zhang M, Kline J, Castrillon DH, Ashfaq R, Oz OK, Wharton KA Jr. Mol Cell Biol. 2007 Jun;27(12):4454-64. Epub 2007 Apr 16.PMID 17438140
* ↑ Van Raay TJ, Coffey RJ, Solnica-Krezel L. Zebrafish Naked1 and Naked2 antagonize both canonical and non-canonical Wnt signaling. Dev Biol. 2007 Sep 15;309(2):151-68. Epub 2007 Apr 21.PMID 17689523
* ↑ Chang JL, Chang MV, Barolo S, Cadigan KM. Regulation of the feedback antagonist naked cuticle by Wingless signaling. Dev Biol. 2008 Sep 15;321(2):446-54. Epub 2008 Jun 6.PMID 18585374