Naked cuticle (Nkd)
Encyclopedia
Naked cuticle is a conserved family of intracellular proteins encoded in the genome
s of diverse animals, including nearly all insects and vertebrates studied to date. 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 embryos of the fruit fly Drosophila melanogaster
. Members of the Nkd gene family were 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
activation in a manner analogous to the way that the Patched
(Ptc) gene regulates the Hedgehog signaling pathway
; Nkd and Ptc shape the tissue gradient
s of Wnt and Hedgehog signaling. Nkd was shown to regulate Wnt signaling based on the increased level and expanded distribution of Wnt signaling in nkd mutants, by the Nkd protein's ability when overexpressed to mimic phenotypes caused by loss of Wnt signaling , and by the direct 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 more 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 Drosophila 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. Similarly, 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 appear to 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, the Nkd genes regulate Wnt-signaling related processes .
The transcription of Nkd genes seems to be inducible by the activity of the Wnt signaling pathway in diverse animals, meaning that the expression of the nkd gene can serve as a readout of signaling activity. Since the action of Nkd proteins is to inhibit Wnt signaling activity, the Nkd proteins are part of a negative feedback
mechanism.
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s of diverse animals, including nearly all insects and vertebrates studied to date. The original mutants were discovered by 1995 Nobel laureates Christiane Nüsslein-Volhard
Christiane Nüsslein-Volhard
Christiane Nüsslein-Volhard is a German biologist who won the Albert Lasker Award for Basic Medical Research in 1991 and the Nobel Prize in Physiology or Medicine in 1995, together with Eric Wieschaus and Edward B...
and Eric F. Wieschaus
Eric F. Wieschaus
-External links:***, excellent profile**...
and colleagues in their genetic screens for pattern-formation mutants in embryos of the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. Members of the Nkd gene family were first cloned in the laboratory of Matthew P. Scott
Matthew P. Scott
Matthew P. Scott is a developmental biologist and HHMI investigator at Stanford University studying how embryonic and later development is governed by proteins that control gene activity and cell signaling processes....
. 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
Segment polarity gene
A segmentation gene is a generic term for a gene whose function is to specify tissue pattern in each repeated unit of a segmented organism. In the fruit fly Drosophila melanogaster, segment polarity genes help to define the anterior and posterior polarities within each embryonic parasegment by...
class gene that limits the spatial extent of Wnt signaling pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
activation in a manner analogous to the way that the Patched
Patched
Patched is a conserved 12-pass transmembrane protein receptor that plays an obligate negative regulatory role in the Hedgehog signaling pathway in insects and vertebrates. The original mutations in the ptc gene were discovered in the fruit fly Drosophila melanogaster by 1995 Nobel Laureates Eric F...
(Ptc) gene regulates the Hedgehog signaling pathway
Hedgehog signaling pathway
In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The hedgehog signaling pathway gives cells information that they need to make the embryo develop properly....
; Nkd and Ptc shape the tissue gradient
Gradient
In vector calculus, the gradient of a scalar field is a vector field that points in the direction of the greatest rate of increase of the scalar field, and whose magnitude is the greatest rate of change....
s of Wnt and Hedgehog signaling. Nkd was shown to regulate Wnt signaling based on the increased level and expanded distribution of Wnt signaling in nkd mutants, by the Nkd protein's ability when overexpressed to mimic phenotypes caused by loss of Wnt signaling , and by the direct binding of Nkd protein to the Wnt signal transducing protein Dishevelled
Dishevelled
Dishevelled is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors...
(Dsh).
Nkd proteins consist of at least four well-conserved blocks of amino acid sequence interspersed by more 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
Myristoylation
Myristoylation is an irreversible, co-translational protein modification found in animals, plants, fungi, protozoans and viruses. In this protein modification, a myristoyl group is covalently attached via an amide bond to the alpha-amino group of an N-terminal amino acid of a nascent polypeptide...
; 2) a single, extended EF hand
EF hand
The EF hand is a helix-loop-helix structural domain 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 which the Ca2+ ions are coordinated by ligands within the loop...
motif (called "EFX" or "NH2") that binds Dsh/Dvl proteins; 3) a thirty amino acid amphipathic alpha helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
motif that in the Drosophila 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
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
-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
EGF
EGF can refer to several things:*Epidermal growth factor, a growth factor in biology*Exponential generating function, a function in mathematics*European Gendarmerie Force, a European intervention force...
-family ligand TGF alpha
TGF alpha
Transforming growth factor alpha is upregulated in some human cancers. It is produced in macrophages, brain cells, and keratinocytes, and induces epithelial development. It is closely related to EGF, and can also bind to the EGF receptor with similar effects...
via a sequence between the third and fourth block that is only in Nkd2. Similarly, 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
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...
Anopheles gambiae
Anopheles gambiae
Anopheles gambiae is a complex of at least seven morphologically distinguishable species of mosquitoes in the genus Anopheles. This complex was recognised in the 1960s and includes the most important vectors of malaria in sub-Saharan Africa and the most efficient malaria vectors known.This species...
Nkd nor in any known vertebrate Nkds mediates nuclear import via binding to the nuclear import factor importin
Importin
Importin is a type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the nuclear localization signal . Importin is classified as a karyopherin....
-alpha3.
There are two Nkd proteins (Nkd1 and Nkd2) in most vertebrates including humans, but some lower vertebrates appear to 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, the Nkd genes regulate Wnt-signaling related processes .
The transcription of Nkd genes seems to be inducible by the activity of the Wnt signaling pathway in diverse animals, meaning that the expression of the nkd gene can serve as a readout of signaling activity. Since the action of Nkd proteins is to inhibit Wnt signaling activity, the Nkd proteins are part of a negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
mechanism.