Naked cuticle (Nkd) is a conserved family of intracellular proteins encoded in most animal
genome
A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
s. The original mutants were discovered by 1995 Nobel laureates
Christiane Nüsslein-Volhard
Christiane (Janni) Nüsslein-Volhard (; born 20 October 1942) is a German developmental biologist and a 1995 Nobel Prize in Physiology or Medicine laureate. She is the only woman from Germany to have received a Nobel Prize in the sciences.
NÃ ...
and
Eric F. Wieschaus and colleagues in their genetic screens for pattern-formation mutants in the fruit fly ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
''. 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
In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
activity, similar to how the
Patched (Ptc) gene regulates the
Hedgehog signaling pathway
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...
; i.e., Nkd and Ptc shape tissue
gradient
In vector calculus, the gradient of a scalar-valued differentiable function f of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p gives the direction and the rate of fastest increase. The g ...
s 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,
[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. ] and by the binding of Nkd protein to the Wnt signal transducing protein
Dishevelled
Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh (Dvl in mammals) is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initi ...
(Dsh).
Nkd proteins consist of at least four well-conserved blocks of amino acid sequence interspersed by variable regions.
[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.] 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;
[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.] 2) a single, extended
EF hand
The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins.
The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...
motif (called "EFX" or "NH2") that binds Dsh/Dvl proteins;
3) a thirty amino acid
amphipathic alpha helix
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...
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
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
-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
Mosquitoes, the Culicidae, are a Family (biology), family of small Diptera, flies consisting of 3,600 species. The word ''mosquito'' (formed by ''Musca (fly), mosca'' and diminutive ''-ito'') is Spanish and Portuguese for ''little fly''. Mos ...
Anopheles gambiae
The ''Anopheles gambiae'' complex consists of at least seven morphologically indistinguishable species of mosquitoes in the genus ''Anopheles''. The complex was recognised in the 1960s and includes the most important vectors of malaria in sub- ...
Nkd nor in any known vertebrate Nkds mediates nuclear import via binding to the nuclear import factor
importin
Importin is a type of karyopherin that transports protein molecules from the Eukaryotic Cell, cell's cytoplasm to the cell nucleus, nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).
I ...
-alpha3.
There are two Nkd proteins (
Nkd1 and
Nkd2
Naked cuticle 2 (NKD2) is a human gene that encodes the protein Nkd2, one of the Naked cuticle (Nkd) family of proteins that regulate the Wnt signaling pathway. Both Nkd1 and Nkd2 proteins can bind to Dishevelled proteins (DVL1
Segment polari ...
) in most vertebrates including humans, but some lower vertebrates have additional Nkd proteins (e.g. Nkd3 in zebrafish
[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.]). 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.
[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] Since Nkd inhibits Wnt signaling, the Nkd genes comprise a
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
mechanism.
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Developmental genes and proteins