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FLASH GENE

Symbol

SKI

contributors: mct/shn - updated : 02/02/2013

HGNC name	v-ski sarcoma viral oncogene homolog (avian)
HGNC id	10896

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003036 7 - 5707 NP_003027 - 728 - 2009 19341714

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Skin/Tegument skin       highly Urinary bladder       highly   kidney       highly

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	gastrula, autonomous neural axis formation

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal region (most likely from AA 261 to 491) appeared to be responsible for its ability to bind to SIAH2 and stabilize HDAC3 and RARA
	conserved CLPQ motif
	R-SMAD binding domain
	C-terminal SKI (491–728) protein could not bind to SIAH2 and had no effect on the self-degradation of SIAH2, but this region – including the coiled-coil domain – appears to be required for SKI localization to the centrosomes and for SKI interaction with Aurora A

secondary structure

C-terminal region, with a alpha-helix coiled-coil domain (AA536–710) that has been shown to be important for either homo-dimerization or dimerization

HOMOLOGY

interspecies	homolog to avian sarcoma viral (v-ski) oncogene
	ortholog to Ski, Mus musculus
	ortholog to Ski, Rattus norvegicus

Homologene

FAMILY

SKI family

CATEGORY

protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,centromere
text	localized at the centrosomes and mitotic spindle during mitosis

basic FUNCTION	involved in terminal differentiation of skeletal muscle cells
	may play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage
	role in the morphogenesis of craniofacial structures and the central nervous system
	participate in dorsal-ventral specification of both neuroectoderm and mesoderm
	inhibits both TGF-beta-induced transcriptional activation and repression
	a crucial signal in Schwann cell development and myelination
	act as a transcriptional corepressor by multiple direct and indirect interactions with several distinct repression complexes
	having a repressive effect on RA signaling pathway which might also apply to the other signaling pathways inhibited by the SKI protein
	acts as a transcriptional co-repressor by multiple direct and indirect interactions with several distinct repression complexes
	inhibits SIAH2-mediated proteasomal degradation of HDAC3
	increases the levels of HDAC3 (and/or RARA indirectly) by interacting with SIAH2 and inhibiting SIAH2 ubiquitin ligase activity
	negative regulator of the transforming growth factor-beta and other signalling pathways
	in the maintenance of the neural stem cell pool and the specification of callosal neurons
	required for transcriptional repression of Ctip2 in callosal neurons
	a central role for Ski-Satb2 interactions in regulating transcriptional mechanisms of callosal neuron specification
	ability of SKI to enhance UBE2I activity is essential for its transforming function
	can enhance MDM2-mediated TP53 ubiquitination and thus proteasomal degradation, which likely results in a decreased TP53 level
	may predominantly be required in the very proximal aorta at early stages of development for the proper regulation of TGFB signaling within the arterial media

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

TGF-beta signaling pathway

a component

INTERACTION

DNA	TGGC/ANNNNNT/GCCAA of the nuclear factor I (NFI) and TCCCNNGGGA of the binding site of Olf-1/EBF

RNA

small molecule

protein	Ski Interacting Protein, SKIP
	SnoN
	retinoblastoma protein, Rb
	promyelocytic leukemia, PML
	MeCP2
	Smad2/3
	c-Jun
	Smad3
	Gli3
	homeodomain-interacting protein kinase 2, HIPK2
	Smad1, Smad2, Smad3, Smad4 and Smad5
	DNA-binding domain of c-Myb
	GATA1
	PU.1
	Arkadia
	SKI is necessary for muscle terminal differentiation and it exerts this role, at least in part, through its association with SIX1 and EYA3 to regulate the MYOG transcription
	histone deacetylase 3, HDAC3 and protein arginine methyltransferase 5, PRMT5
	PRDM16 (MID:19049980
	RARalpha
	SMAD4
	retinoic acid receptor ALPHA, RARA
	SPI1
	SIAH2
	TGF-beta type I receptor
	TP53
	can increase MDM2 sumoylation to enhance TP53 degradation
	can enhance UBE2I-mediated cellular sumoylation, possibly through direct interaction with UBE2I

cell & other

REGULATION

activated by

AURKA that is able to phosphorylate SKI

Phosphorylated by

Akt/PKB kinase

Other

regulated during the cell cycle by ubiquitylation and subsequent proteasomal degradation

ASSOCIATED DISORDERS

corresponding disease(s)

DEL1P36 , SGS2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   deletion     in facial clefting (and/or neural tube defect) tumoral     --over   in a variety of human cancers, including melanoma, leukemia, colorectal, pancreatic, esophageal, and gastric cancers

Susceptibility

to orofacial defect

Variant & Polymorphism SNP	(257C>G)associated with a decreased risk for orofacial defects

Candidate gene	for facial clefting in 1p36 deletion
Marker
Therapy target

ANIMAL & CELL MODELS

	defects in neurulation, craniofacial, patterning, and skeletal muscle development in ski -/- mice
	ski-deficient heterozygous mice display susceptibility to tumorigenesis
	Ski-deficient callosal neurons lose their identity and ectopically express the transcription factor Ctip2
	Ski-/- mice display a lethal phenotype with associated midline facial cleft, a depressed nasal bridge, eye anomalies, skeletal muscle defects, and digital anomalies