Protein-coding gene in the species Homo sapiens
Ortholog search: PDBe RCSB
1MR1, 1SBX
SKI, SKI proto-oncogene, SGS, SKV
OMIM: 164780 MGI: 98310 HomoloGene: 31124 GeneCards: SKI
Chromosome 1 (human)
1p36.33-p36.32
2,228,319 bp
2,310,213 bp
Chromosome 4 (mouse)
4 E2|4 86.17 cM
155,238,532 bp
155,307,049 bp
Top expressed innipple
urethra
popliteal artery
sural nerve
ascending aorta
lower lobe of lung
saphenous vein
right coronary artery
synovial joint
lactiferous ductTop expressed inascending aorta
aortic valve
secondary oocyte
ankle
vas deferens
molar
cerebellar cortex
lip
somite
superior frontal gyrusMore reference expression data
More reference expression data
Molecular function
transcription corepressor activity
protein domain specific binding
histone deacetylase inhibitor activity
zinc ion binding
protein binding
SMAD binding
protein kinase binding
ubiquitin protein ligase binding
DNA-binding transcription factor activity, RNA polymerase II-specific
Cellular component
PML body
centrosome
nuclear body
nucleus
nucleoplasm
transcription regulator complex
cytoplasm
transcription repressor complex
protein-containing complex
Biological process
roof of mouth development
myotube differentiation
SMAD protein signal transduction
somatic stem cell population maintenance
nose morphogenesis
cell motility
bone morphogenesis
negative regulation of transcription by RNA polymerase II
negative regulation of transforming growth factor beta receptor signaling pathway
BMP signaling pathway
negative regulation of osteoblast differentiation
myelination in peripheral nervous system
protein homotrimerization
negative regulation of BMP signaling pathway
positive regulation of Wnt signaling pathway
negative regulation of activin receptor signaling pathway
neural tube closure
lens morphogenesis in camera-type eye
embryonic limb morphogenesis
skeletal muscle fiber development
retina development in camera-type eye
camera-type eye development
positive regulation of DNA binding
olfactory bulb development
cell population proliferation
anterior/posterior axis specification
negative regulation of fibroblast proliferation
face morphogenesis
camera-type eye morphogenesis
negative regulation of Schwann cell proliferation
negative regulation of cell population proliferation
positive regulation of transcription by RNA polymerase II
transcription, DNA-templated
negative regulation of histone deacetylation
neuron development
transforming growth factor beta receptor signaling pathway
negative regulation of cell differentiation
Sources:Amigo / QuickGO
HumanMouse
6497
20481
ENSG00000157933
ENSMUSG00000029050
P12755
Q60698
NM_003036
NM_011385
NM_001357191
NP_003027
n/a
Chr 1: 2.23 – 2.31 MbChr 4: 155.24 – 155.31 Mb
WikidataView/Edit HumanView/Edit Mouse
The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
SKI negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads and repressing the transcription of TGF-beta responsive genes. This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis, specification, and developmental fate.
The name SKI comes from the Sloan-Kettering Institute where the protein was initially discovered.
The SKI protein has a 728 amino acid sequence, with multiple domains. It is expressed both inside and outside of the nucleus. It is in the same family as the SnoN protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix motif, a cysteine and histidine rich area which gives rise to the zinc finger motif, a basic amino acid region, and leucine zipper. All these domains, including a proline rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins. The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine and phenylalanine amino acid regions. Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.
Function
The SKI oncogene is present in all cells, and is commonly active during development. Specifically, avian fibroblasts depend on the SKI protein as a transcription co-regulator inducing transformation. The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization. Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TGF- β) signaling. TGF- β is a protein which regulates cell growth. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells. It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β. The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3 and CReB-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4 complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell\'s ability to stop growth and division, creating cancerous cells.
SKI has been linked to various cancers including human melanomas, esophageal squamous cell carcinoma, cervical cancer and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein\'s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.
Related research
Other research has identified proteins similar to Ski. The SnoN protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.
Dachshund and SKIDA1 are also in the Ski/Sno/Dac family (InterPro: IPR003380, IPR023216.
Interactions
SKI protein has been shown to interact with:
HIPK2,
MECP2,
Mothers against decapentaplegic homolog 1 and
Mothers against decapentaplegic homolog 2,
Mothers against decapentaplegic homolog 3,
NFIX,
Promyelocytic leukemia protein,
SKIL, and
SNW1.
