Ski is involved in oncogenic transformation and enhancement of muscle differentiation by blocking TGF-beta signaling [, ]. Ski binds directly to the Smad3/4 complex and negatively regulates TGF-beta signaling [, , ]. It plays a role in terminal differentiation of skeletal muscle cells, but not in the determination of cells to the myogenic lineage []. Ski is a component of the histone deacetylase complex (HDAC) complex and is required for the transcriptional repression mediated by this complex []. This entry includes v-ski (viral oncogene ski) from the avian Sloan-Kettering retroviruses and its homologue from animals, c-ski []. c-ski can promote cancer progression and is highly expressed in some of solid cancers including leukemia, melanoma, colorectal cancer, gastric cancer and pancreatic cancer []. However, it can also act as a tumour suppressor in some cases [].
Ski family transcriptional corepressor 1 (SKOR1), also known as ladybird homeobox corepressor 1 or fussel-15 homologue, belongs to Ski family. Like the other members, it is characterised by a Ski homologue domain and a SAND domain - a domain found in some nuclear proteins involved in chromatin-dependent transcriptional regulation. Fussel-15 is mainly expressed in the central nervous system (CNS). The Ski family of nuclear oncoproteins is known to repress transforming growth factor-beta (TGF-beta) signalling through inhibition of transcriptional activity of Smad proteins. Fussel-15 interacts with Smad1, Smad2 and Smad3 molecules and suppresses mainly BMP signalling pathway, but it has only minor effects on TGF-beta signalling [].
The Ski family of nuclear oncoproteins represses transforming growth factor-beta (TGF-beta) signaling through inhibition of transcriptional activity of Smad proteins. This entry represents Ski family transcriptional corepressor 2 (also known as Fussel-18), which acts as a TGF-beta antagonist. Its expression is restricted to the nervous system [].
This entry includes superkiller protein 3 (Ski3) from yeasts and plants and tetratricopeptide repeat protein 37 (TTC37) from animals. They are a component of the Ski complex required for exosome-mediated RNA surveillance []. In budding yeasts, the SKI complex (Ski2-Ski3-Ski8) is a helicase complex functioning with the RNA-degrading exosome to mediate the 3'-5' messenger RNA (mRNA) decay in turnover and quality-control pathways []. Ski3 has also been shown to repress dsRNA virus propagation by specifically blocking translation of viral mRNAs []. In humans, TTC37 is also a component of the SKI complex. However, unlike yeast SKI, which is cytoplasmic, human SKI is both nuclear and cytoplasmic []. Mutations in the TTC37 gene cause Syndromic diarrhea/Trichohepatoenteric (SD/THE) syndrome [].
This group represents a group of ATP-dependent RNA helicases and their homologues, including Ski complex protein Ski2 and RNA helicase Mtr4 (also known as Dob1). Ski2 is a putative RNA helicase that forms ski complex, which participates in many cytoplasmic pathways of the exosome in both yeast and metazoan cells, including 3'-to-5' mRNA turnover []. Mtr4 is a ATP-dependent 3'-5' RNA helicase involved in nuclear RNA processing and degradation [, ]. This entry also includes Arabidopsis AtMTR4 (AT1G59760) and HEN2 (AT2G06990), which target specific subsets of nuclear transcripts for degradation by the nuclear exosome [].
SKIP (SKI-interacting protein) is an essential spliceosomal component and transcriptional coregulator, which may provide regulatory coupling of transcription initiation and splicing []. SKIP was identified in a yeast 2-hybrid screen, where it was shown to interact with both the cellular and viral forms of SKI through the highly conserved region on SKIP knownas the SNW domain []. SKIP is now known to interact with a number of other proteins as well. SKIP potentiates the activity of important transcription factors, such as vitamin D receptor, CBF1 (RBP-Jkappa), Smad2/3, and MyoD. It works with Ski in overcoming pRb-mediated cell cycle arrest, and it is targeted by the viral transactivators EBNA2 and E7 [].
This domain is about 100 amino acids long and contains a conserved CLPQ motif. The c-ski proto-oncogene has been shown to influence proliferation, morphological transformation and myogenic differentiation []. Sno, a Ski proto-oncogene homologue, is expressed in two isoforms and plays a role in the response to proliferation stimuli. Dachshund also contains this domain. It is involved in various aspects of development [, ].
This domain is the N-terminal extended region found in the Ski2 protein. The Ski complex is a conserved multiprotein assembly required for the cytoplasmic functions of the exosome, including RNA turnover, surveillance, and interference []. Ski2, Ski3, and Ski8 assemble in a tetramer with 1:1:2 stoichiometry.
SKIP (SKI-interacting protein) is an essential spliceosomal component and transcriptional coregulator, which may provide regulatory coupling of transcription initiation and splicing []. SKIP was identified in a yeast 2-hybrid screen, where it was shown to interact with both the cellular and viral forms of SKI through the highly conserved region on SKIP known as the SNW domain []. SKIP is now known to interact with a number of other proteins as well. SKIP potentiates the activity of important transcription factors, such as vitamin D receptor, CBF1 (RBP-Jkappa), Smad2/3, and MyoD. It works with Ski in overcoming pRb-mediated cell cycle arrest, and it is targeted by the viral transactivators EBNA2 and E7 [].This entry represents the SNW domain.
Members of the eye absent (EYA) family were originally characterised in fly eye development. EYA proteins are both transcriptional activators and tyrosine phosphatases [, ], and have been shown to dephosphorylate H2AX, promoting repair and cell survival in the response to DNA damage []. EYA proteins (EYA1-4) are normally expressed early in development [, ]. Their phosphatase activity regulates Six1-Dach-Eya transcriptional effects in precursor cell proliferation and survival in mammalian organogenesis [].EYA3 forms a complex with Six1 and Ski that regulates muscle terminal differentiation [].
This domain of unknown function is found in Focadhesin from animals and RST1 (RESURRECTION 1) from plants. Focadhesin (FOCAD) is a focal adhesion protein with potential tumour suppressor function in gliomas []. RST1 was originally identified in a genetic screen for factors involved in the biosynthesis of epicuticular waxes []. Later, RST1 and RST1 INTERACTING PROTEIN (RIPR) have been shown to act as cofactors of the cytoplasmic exosome and the Ski complex in plants []. RST1 is involved in the suppression of siRNA-mediated silencing of transgenes and certain endogenous transcripts [].
This entry includes a group of leucine rich adaptor proteins, including LURAP1 (LRAP35A), LURAP1L and LRAP25. LURAP1 activates the canonical NF-kappa-B pathway, promotes proinflammatory cytokine production and promotes the antigen presenting and priming functions of dendritic cells []. LRAP25, also known as C184M or MMTV receptor, is a Ski (a transcriptional co-repressor) binding protein that negatively regulates tumour growth factor-beta signaling by sequestering the Smad proteins in the cytoplasm []. LRA25 also serves as an adaptor protein of MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) [].
The c-ski proto-oncogene has been shown to influence proliferation, morphological transformation and myogenic differentiation []. It may play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Sno, a Ski proto-oncogene homologue, is expressed in two isoforms and plays a role in the response to proliferation stimuli.Ski is a multidomain protein that includes a domain bearing high sequence similarity with the retinal determination protein Dachshund []. This conserved domain contains a DNA binding motif [].
This entry includes Focadhesin from animals and RST1 (RESURRECTION 1) from plants. Focadhesin (FOCAD) is a focal adhesion protein with potential tumour suppressor function in gliomas []. RST1 was originally identified in a genetic screen for factors involved in the biosynthesis of epicuticular waxes []. Later, RST1 and RST1 INTERACTING PROTEIN (RIPR) have been shown to act as cofactors of the cytoplasmic exosome and the Ski complex in plants []. RST1 is involved in the suppression of siRNA-mediated silencing of transgenes and certain endogenous transcripts [].
This entry represents the SKI/SnoN family of proteins, which are the products of the oncogenic sno gene. This gene was identified based on its homology to v-ski, the transforming component of the Sloan-Kettering virus. Both Ski and SnoN are potent negative regulators of TGF-beta []. Overexpression of Ski or SnoN results in oncogenic transformation of avian fibroblasts; however it may also result in terminal differentiation and therefore the Ski/SnoN mechanism of action is thought to be complex [].These proteins do not have catalytic or DNA-binding activity and therefore function primarily through interaction with other proteins, acting as transcriptional cofactors. Despite their lack of DNA-binding ability, their primary function is related to transcriptional regulation, in particular the negative regulation of TGF-beta signalling [, ]. Ski/SnoN interact concurrently with co-Smad and R-Smad and in doing so block the ability of the Smad complexes to activate transcription of the TGF-beta target genes []. Binding of Ski/SnoN may additionally stabilise the Smad heteromer on DNA, therefore preventing further binding of active Smad complexes []. As Smad complexes critically mediate the inhibitory signals of TGF-beta in epithelial cells, high levels of SKI/SnoN may promote cell proliferation. They repress gene transcription recruiting diverse corepressors and histone deacetylases and stablish cross-regulatory mechanisms with TGF-beta/Smad pathway that control the magnitude and duration of TGF-beta signals. The alteration in regulatory processes may lead to disease development [].High levels of SnoN have been shown to stabilise p53 with a resultant increase in premature senescence. SnoN interacts with the PML protein and is then recruited to the PML nuclear bodies, resulting in stabilisation of p53 and premature senescence [].
The SAND domain (named after Sp100, AIRE-1, NucP41/75, DEAF-1) is a conserved ~80 residue region found in a number of nuclear proteins, many of which function in chromatin-dependent transcriptional control. These include proteins linked to various human diseases, such as the Sp100 (Speckled protein 100kDa), NUDR (Nuclear DEAF-1 related), GMEB (Glucocorticoid Modulatory Element Binding) proteins and AIRE-1 (Autoimmune regulator 1) proteins.Proteins containing the SAND domain have a modular structure; the SAND domain can be associated with a number of other modules, including the bromodomain, the PHD finger and the MYND finger. Because no SAND domain has been found in yeast, it is thought that the SAND domain could be restricted to animal phyla. Many SAND domain-containing proteins, including NUDR, DEAF-1 (Deformed epidermal autoregulatory factor-1) and GMEB, have been shown to bind DNA sequences specifically. The SAND domain has been proposed to mediate the DNA binding activity of these proteins [, ]. Structurally, the SAND domain consists of a novel alpha/beta fold, which has a core of three short helices packed against a barrel-like β-sheet; it is structurally similar to the SH3-like fold.Other proteins display domains that are structurally similar to the SAND domain. One such example is the SMAD4-binding domain of the oncoprotein Ski, which is stabilised by a bound zinc atom, and resembles a SAND domain, in which the corresponding I loop is responsible for DNA binding. Ski is able to disrupt the formation of a functional complex between the Co- and R-SMADs, leading to the repression of TGF-beta, Activin and BMP responses, resulting in the repression of TGF-signalling [].
