Affinage

SKI

Ski oncogene · UniProt P12755

Length
728 aa
Mass
80.0 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/10 claims corpus-supported (90%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SKI (c-Ski) is a nuclear transcriptional co-repressor that functions as a central antagonist of TGF-β-superfamily signaling by directly binding the receptor-activated Smads and recruiting histone-modifying repressor machinery to Smad-regulated promoters (PMID:10485843, PMID:15128733). SKI engages Smad2, Smad3, and Smad4 on TGF-β-responsive elements and represses transcription by recruiting N-CoR and its associated histone deacetylase complex, thereby blocking TGF-β-induced growth inhibition (PMID:10485843); it similarly represses BMP-specific Smad1/Smad4 complexes to influence neural specification and osteoblast differentiation (PMID:11121043). Structurally, SKI competes with the coactivator CBP for the same SARA-binding surface on Smad2/3 and assembles defined oligomers with R-Smad trimers and R-Smad/Smad4 complexes (PMID:17283070). A defining repression target is the Smad7 gene, which SKI and Smad4 co-occupy and silence through the Smad-binding element in a Smad4-dependent manner (PMID:15128733). SKI extends this co-repressor logic beyond canonical Smad signaling, binding Gli3 to support Shh/Gli repression (PMID:12435627), cooperating with Satb2 to recruit NuRD/HDAC complexes and silence Ctip2 during corpus callosum formation (PMID:22334647), and acting as a genome-wide co-repressor for RUNX1 at myeloid enhancers (PMID:29471413). SKI also restrains Hippo signaling, promoting LATS2-mediated phosphorylation and degradation of TAZ and recruiting NCoR1 to repress TEAD-dependent transcription (PMID:25670202, PMID:33847835). SKI abundance is tightly controlled by regulated proteolysis—via the ubiquitin-conjugating enzyme Cdc34, the E3 ligases Arkadia/RNF111 and (with SnoN) Siah2-related pathways, and Akt-mediated phosphorylation at Thr458—coupling its co-repressor output to cell-cycle and signaling state (PMID:15122324, PMID:19875456, PMID:34473197). In immune differentiation, TGF-β-induced SKI degradation relieves SKI-SMAD4-mediated repression of the Rorc locus to permit Th17 differentiation (PMID:29072299). SKI mutations cause Shprintzen-Goldberg syndrome: disease mutations abolish SKI binding to phospho-SMAD2/3, stabilizing SKI and attenuating TGF-β transcriptional responses (PMID:33416497). Separately, the human SKI complex acts in cytoplasmic RNA surveillance, gating RNA channeling from the 80S ribosome to the exosome through ATP-dependent conformational switching of its helicase (PMID:35120588).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1990 Medium

    Established that c-Ski is a nuclear protein lacking intrinsic sequence-specific DNA binding, requiring partner proteins—framing it from the outset as a complex-dependent regulator rather than an autonomous transcription factor.

    Evidence DNA-cellulose binding and deletion mutagenesis of in vitro-translated Ski

    PMID:2183181

    Open questions at the time
    • Identity of the required partner proteins not determined
    • No physiological target promoter defined
  2. 1998 Medium

    Showed that Ski binds a specific DNA element (GTCTAGAC) only as part of multi-protein nuclear complexes and represses through it, refining how Ski achieves promoter-directed repression.

    Evidence DNA binding-site selection, EMSA, UV cross-linking, and reporter assays

    PMID:9452486

    Open questions at the time
    • Cellular co-factors mediating sequence recognition not all identified
    • Element relevance to endogenous genes unclear
  3. 1999 High

    Identified the TGF-β/Smad axis as the central pathway repressed by SKI, defining its core molecular mechanism: direct R-Smad/Smad4 binding plus N-CoR/HDAC recruitment to block growth inhibition.

    Evidence Reciprocal Co-IP, ChIP, and reporter assays in TGF-β-responsive cells

    PMID:10485843

    Open questions at the time
    • Structural basis of Smad binding not resolved
    • Which target genes drive the growth phenotype not enumerated
  4. 2000 High

    Extended SKI repression to BMP-specific Smad1/4 complexes, establishing it as a pan-TGF-β-superfamily antagonist with developmental consequences.

    Evidence Co-IP, reporter assays, Xenopus overexpression and mammalian differentiation assays

    PMID:11121043

    Open questions at the time
    • Whether BMP-Smad and TGF-β-Smad repression use identical co-repressor surfaces unresolved
  5. 2002 High

    Broadened SKI's co-repressor role beyond Smads by linking it to Gli3-mediated Hedgehog repression with in vivo genetic epistasis, showing SKI integrates into multiple developmental signaling circuits.

    Evidence Co-IP, reporter assays, Gli3/Ski double-mutant mice, and Ski-deficient fibroblasts

    PMID:12435627

    Open questions at the time
    • Direct contribution of HDAC recruitment to Gli3 repression in vivo not isolated
  6. 2004 High

    Defined Smad7 as a key endogenous SKI target and demonstrated SKI's role in Schwann cell proliferation and myelination, connecting molecular repression to tissue-level phenotypes.

    Evidence ChIP, reporter, and RNAi for Smad7 (15128733); Ski knockout mice, overexpression, and Oct6 Co-IP for myelination (15312649)

    PMID:15128733 PMID:15312649

    Open questions at the time
    • How basal vs signal-induced Smad7 repression is partitioned not fully resolved
    • Direct Oct6 mechanism in myelin gene control incomplete
  7. 2004 Medium

    Revealed that SKI levels are regulated by cell cycle-dependent ubiquitin-mediated degradation, coupling its co-repressor output to proliferative state.

    Evidence In vitro ubiquitination, dominant-negative Cdc34, and cell-cycle synchronization

    PMID:15122324

    Open questions at the time
    • E3 ligase partnering Cdc34 not identified here
    • Degron sequence not mapped
  8. 2007 High

    Provided the biochemical mechanism for SKI repression—competition with CBP for the SARA-binding surface on Smad2/3 and assembly of defined Ski-Smad oligomers—explaining how SKI displaces coactivators.

    Evidence SEC, ITC, and mutational analysis of purified recombinant proteins

    PMID:17283070

    Open questions at the time
    • Full-length SKI-Smad complex structure not determined here
    • Cellular stoichiometry not validated
  9. 2009 Medium

    Showed Akt phosphorylation at Thr458 destabilizes SKI, adding a kinase-driven layer of control over SKI's repression of Smad7 and thereby TGF-β output.

    Evidence In vitro kinase assay, T458 mutagenesis, cycloheximide chase, and reporter assays

    PMID:19875456

    Open questions at the time
    • Link between phosphorylation and a specific degradation machinery not established
  10. 2012 High

    Demonstrated SKI partners with the chromatin remodeler Satb2 to recruit NuRD/HDAC complexes and silence Ctip2, establishing a concrete chromatin-level repression mechanism with a neurodevelopmental phenotype.

    Evidence Co-IP, ChIP, Ski knockout, and in utero electroporation

    PMID:22334647

    Open questions at the time
    • Generality of Satb2-NuRD recruitment to other loci not tested
  11. 2015 High

    Identified SKI as a suppressor of Hippo effectors TAZ/YAP, broadening its tumor-suppressive repressor activity to LATS2 activation and TEAD-NCoR1 transcriptional repression.

    Evidence Co-IP, reporter assays, siRNA/overexpression, and xenografts (25670202); BioID2, LIMD1 interaction, and post-MI model (33847835)

    PMID:25670202 PMID:33847835

    Open questions at the time
    • Why TAZ but not YAP is selectively degraded not fully resolved
    • LATS2-independent degradation pathway mechanism undefined
  12. 2017 High

    Showed that TGF-β-induced proteasomal degradation of SKI relieves SKI-SMAD4 repression of the Rorc locus, mechanistically linking SKI turnover to a T-helper cell fate decision.

    Evidence Proteomics, Co-IP, ChIP, and SMAD4/SKI genetic perturbation with histone-modification assays

    PMID:29072299

    Open questions at the time
    • Identity of the degradation machinery not specified in this study
  13. 2018 High

    Genome-wide mapping established SKI as a co-repressor co-occupying RUNX1 enhancers in AML, defining a chromatin-scale role in myeloid differentiation control.

    Evidence ChIP-seq, RNA-seq, CRISPR/shRNA deletion, and reporter assays

    PMID:29471413

    Open questions at the time
    • Direct RUNX1-SKI contact surface not mapped
    • Whether HDAC recruitment underlies all silenced loci unclear
  14. 2021 High

    Crystallographic and patient-cell work showed Shprintzen-Goldberg syndrome mutations abolish SKI-phospho-SMAD2/3 binding, stabilizing SKI and counterintuitively attenuating rather than enhancing TGF-β responses—directly linking SKI to a Mendelian disorder.

    Evidence SKI-phospho-SMAD2 crystal structure, genome-edited knock-in cells, and patient fibroblast transcriptional assays

    PMID:33416497

    Open questions at the time
    • How a stabilized, Smad-binding-deficient SKI dampens TGF-β output mechanistically not fully reconciled
  15. 2021 Medium

    Placed SKI downstream of the E3 ligase Arkadia/RNF111 in the TGF-β-driven iTreg program, integrating SKI degradation into a defined regulatory immune differentiation pathway.

    Evidence Conditional CD4-Cre knockouts, in vitro differentiation, and intestinal inflammation model

    PMID:34473197

    Open questions at the time
    • Direct Arkadia-SKI ubiquitination not biochemically reconstituted here
  16. 2022 High

    Defined a distinct, non-transcriptional role for the human SKI complex in cytoplasmic RNA surveillance, gating RNA channeling from the 80S ribosome to the exosome via ATP-dependent helicase conformational switching.

    Evidence Cryo-EM of hSKI-80S ribosome-RNA complexes in multiple conformational states

    PMID:35120588

    Open questions at the time
    • Relationship between this complex's components and nuclear c-Ski co-repressor not addressed
    • Physiological consequence in human cells not tested here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SKI's distinct activities—Smad/Gli/RUNX1/Hippo transcriptional repression versus the SKI-complex role in cytoplasmic RNA surveillance—are functionally and structurally partitioned, and how the multiple degradation inputs (Cdc34, Akt, Arkadia) are coordinated in vivo, remain unresolved.
  • No unified model integrating SKI's transcriptional and RNA-surveillance functions
  • Coordination of overlapping degradation pathways unknown
  • Tissue-specific selection among SKI's many partners not explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3 R-HSA-168256 Immune System 2 R-HSA-8953854 Metabolism of RNA 1
Partners
GLI3LIMD1RUNX1SATB2SMAD2SMAD3SMAD4SNON
Complex memberships
N-CoR/HDAC co-repressor complexNuRD complexhuman SKI complex (hSKI)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 SKI (c-Ski) directly interacts with Smad2, Smad3, and Smad4 on a TGF-β-responsive promoter element and represses their transcriptional activation by recruiting the nuclear co-repressor N-CoR and its associated histone deacetylase complex, thereby blocking TGF-β-induced growth inhibition. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, overexpression in TGF-β-responsive cells Genes & development High 10485843
2000 Ski represses BMP signaling by directly interacting with BMP-specific Smad complexes (Smad1/Smad4) and blocking their transcriptional activity, resulting in neural specification in Xenopus embryos and inhibition of osteoblast differentiation in mammalian cells. Co-immunoprecipitation, reporter assays, Xenopus overexpression, mammalian cell differentiation assays Proceedings of the National Academy of Sciences of the United States of America High 11121043
2001 c-Ski directly binds MeCP2 (via the transcriptional repression domain of MeCP2 and two regions of c-Ski including the C-terminal coiled-coil) and is required for MeCP2-mediated transcriptional repression; co-localization of c-Ski and MeCP2 occurs in nuclear heterochromatin. Co-immunoprecipitation, immunostaining, dominant-negative overexpression, antibody microinjection The Journal of biological chemistry Medium 11441023
1990 The c-Ski protein (p100c-ski) is a nuclear protein that requires association with other nuclear protein(s) to bind DNA; the N-proximal cysteine/histidine-rich domain and C-terminal basic region of Ski are both necessary for DNA-binding activity of the Ski complex. DNA-cellulose binding assay, deletion mutagenesis, in vitro translation, specific antibody characterization Nucleic acids research Medium 2183181
1997 Ski binds NFI (nuclear factor I) family transcription factors and activates transcription of NFI-dependent reporters; Ski homodimerization (via C-terminal domain) is essential for co-activation with NFI, and Ski is a component of NFI-DNA complexes. SELEX, electrophoretic mobility shift assay (EMSA), co-immunoprecipitation, transcriptional reporter assays, dimerization mutant analysis Nucleic acids research Medium 9380514
1998 Both v-Ski and c-Ski, as components of multi-protein complexes in nuclear extracts, bind a specific DNA sequence (consensus GTCTAGAC) cooperatively and repress transcription through this element or when tethered via a heterologous DNA-binding domain; Ski requires additional cellular proteins for sequence-specific DNA binding. DNA binding site selection, EMSA, UV cross-linking, transcriptional reporter assays The Journal of biological chemistry Medium 9452486
1999 c-Ski and SnoN preferentially form heterodimers over homodimers in vitro and in vivo; heterodimerization requires the TR/LZ domain and the heterodimers bind the GTCTAGAC element and are more potent in transcriptional repression and cellular transformation than homodimers. In vitro translation/co-immunoprecipitation, in vivo co-immunoprecipitation, EMSA, transformation assay Nucleic acids research Medium 9927733
2002 Ski binds Gli3 (both full-length and repressor forms) and recruits the histone deacetylase complex; genetic evidence shows that Ski mutation enhances digit abnormalities from Gli3 mutation (epistasis), and Ski-deficient fibroblasts show impaired Gli3-mediated repression of Shh-induced Gli1 transcription. Co-immunoprecipitation, reporter assays, genetic epistasis (double mutant mice), Ski-deficient fibroblasts Genes & development High 12435627
2002 c-Jun directly interacts with Ski and enhances the association of Ski with Smad2 in the basal state, maintaining repression of Smad2-responsive genes; TGF-β signaling induces dissociation of c-Jun from Ski, and activation of JNK suppresses this dissociation, thus providing negative feedback regulation of TGF-β signaling. Co-immunoprecipitation, reporter assays, GST pull-down The Journal of biological chemistry Medium 12034730
2003 SKI activates Wnt/β-catenin signaling by interacting with FHL2/DRAL (identified by yeast two-hybrid and co-immunoprecipitation); SKI-FHL2 complexes enhance activation of FHL2/β-catenin-regulated gene promoters (including MITF and Nr-CAM) in melanoma cells. Yeast two-hybrid screen, co-immunoprecipitation, reporter assays, overexpression in ski-/- melanocytes Cancer research Medium 14583455
2003 HIPK2 directly binds both c-Ski and Smad1; dominant-negative HIPK2 enhances Smad1/4-dependent transcription, and suppresses c-Ski-induced inhibition of Smad1/4-dependent transcription, indicating HIPK2 cooperates with Ski in negative regulation of BMP-induced transcriptional activation. Co-immunoprecipitation, reporter assays, dominant-negative mutants The Journal of biological chemistry Medium 12874272
2004 Ski represses the Smad7 promoter basal activity through the Smad-binding element (SBE) in a Smad4-dependent manner; chromatin immunoprecipitation shows Ski and Smad4 co-occupy the endogenous Smad7 promoter; RNAi knockdown of Ski increases endogenous Smad7 mRNA levels. Reporter assays, chromatin immunoprecipitation (ChIP), RNAi knockdown The Journal of biological chemistry High 15128733
2004 Cell cycle-dependent degradation of c-Ski during interphase is mediated by the ubiquitin-conjugating enzyme Cdc34 both in vitro and in vivo; Ski is stabilized during mitosis, and dominant-negative Cdc34 stabilizes Ski and enhances its antagonism of TGF-β signaling. In vitro ubiquitination assay, in vivo overexpression/dominant-negative, immunoprecipitation, cell cycle synchronization Oncogene Medium 15122324
2005 The Ski protein is upregulated, phosphorylated by Cdc2/CyclinB kinase, and redistributes from the nucleus to centrosomes and mitotic spindle during mitosis, suggesting a role for Ski outside of transcriptional regulation during cell division. Immunofluorescence microscopy, biochemical fractionation, in vitro kinase assay, cell cycle synchronization Oncogene Medium 15806149
2006 Ski associates with RARα and inhibits retinoic acid (RA)-induced differentiation of U937 leukemia cells; Ski mutant lacking the N-CoR binding domain fails to repress RARα signaling, and HDAC inhibitor valproic acid partially reverses Ski-mediated repression. Co-immunoprecipitation, immunofluorescence, reporter assays, differentiation assays, mutant analysis Leukemia Medium 16424870
2006 c-Ski contains a nuclear localization signal (NLS); cytoplasmic c-Ski suppresses TGF-β superfamily-induced Smad signaling by sequestering activated Smad complexes in the cytoplasm but fails to suppress basal Smad7 transcription (which requires nuclear Ski); c-Ski accumulates in the cytoplasm when proteasome activity is inhibited. NLS mutant analysis, subcellular fractionation, reporter assays, immunofluorescence, proteasome inhibitor treatment Genes to cells Medium 17054724
2007 Ski-(16-192) competes with CBP for binding to the same surface on Smad2/Smad3 (the SARA-binding surface); Ski forms hexamers with R-Smad homotrimers and pentamers with R-Smad/Smad4 heterotrimers; Ski and CBP compete for binding to Smad3 in vitro. Size-exclusion chromatography, isothermal titration calorimetry, mutational analysis of purified recombinant proteins The Journal of biological chemistry High 17283070
2008 SKI and MEL1 (both on amplified chr 1p36.32) cooperate in TGF-β signaling inhibition; MEL1 interacts with SKI and stabilizes the inactive Smad3-SKI complex on the promoter of TGF-β target genes; combined knockdown synergistically restores TGF-β responsiveness. Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, tumor xenograft assay The Journal of biological chemistry Medium 19049980
2008 In Schwann cells (but not epithelial cells), Ski and phospho-Rb co-localize in the cytoplasm in response to TGF-β; Ski overexpression induces Rb hyperphosphorylation and cell proliferation; Ski knockdown blocks TGF-β-induced proliferation and pRb cytoplasmic relocalization, revealing cell-type-specific TGF-β/Ski/Rb signaling. Immunofluorescence, co-immunoprecipitation, siRNA knockdown, cell proliferation assays, in vivo sciatic nerve analysis The Journal of cell biology Medium 18695043
2009 Akt/PKB phosphorylates Ski at a conserved Akt motif (threonine 458) both in vitro and in vivo; this phosphorylation destabilizes Ski and reduces Ski-mediated repression of Smad7 expression, thereby modulating TGF-β signaling. In vitro kinase assay, site-directed mutagenesis, immunoprecipitation, cycloheximide chase, reporter assay The Journal of biological chemistry Medium 19875456
2010 Ski interacts with Siah2 (E3 ubiquitin ligase) via co-immunoprecipitation and inhibits Siah2's auto-ubiquitination/self-degradation activity, thereby stabilizing HDAC3 and maintaining a transcriptional co-repressor complex for retinoic acid signaling. Reciprocal co-immunoprecipitation, truncation mutant analysis, protein stability assays Biochemical and biophysical research communications Medium 20691163
2009 Ski and RARα are in the same complex in both the absence and presence of RA; Ski stabilizes RARα and HDAC3 protein levels, providing a mechanism for Ski-mediated repression of RA signaling distinct from other co-repressors. Co-immunoprecipitation, immunofluorescence, protein stability assays Biochemical and biophysical research communications Medium 19341714
2010 c-Ski overexpression in cardiac myofibroblasts inhibits type I collagen secretion, reduces myofibroblast contractility, and induces loss of α-smooth muscle actin expression; overexpressed c-Ski binds phospho-Smad2 (by Co-IP) but does not prevent nuclear translocation of pSmad2; TGF-β stimulation induces nuclear shuttling of c-Ski. Adenoviral overexpression, immunoprecipitation, gel contraction assay, immunofluorescence, subcellular fractionation American journal of physiology. Cell physiology Medium 20943957
2012 Ski cooperates with the chromatin-remodeling factor Satb2 to repress Ctip2 transcription in callosal neurons; Satb2 recruits Ski to the Ctip2 locus, and Ski attracts HDACs to form a NuRD repressor complex; loss of Ski leads to failure of corpus callosum formation. Co-immunoprecipitation, chromatin immunoprecipitation, genetic knockout analysis, in utero electroporation Proceedings of the National Academy of Sciences of the United States of America High 22334647
2012 Ski inhibits TGF-β/Smad3 signaling in chondrocytes by associating with phospho-Smad2 and phospho-Smad3, and Ski's association with phospho-Smad3 is required for recruitment of HDAC4 and HDAC5, leading to accelerated chondrocyte hypertrophic differentiation. Co-immunoprecipitation, siRNA/overexpression, gene expression assays, HDAC inhibitor rescue Journal of cellular biochemistry Medium 22461172
2015 Ski suppresses TAZ and YAP (Hippo pathway effectors) in breast cancer cells by interacting with multiple Hippo pathway components to facilitate Lats2 activation, increasing TAZ phosphorylation and degradation; Ski also binds TEAD and recruits NCoR1 to repress TAZ-dependent transcription; a Lats2-independent degradation pathway for constitutively active TAZ also exists. Co-immunoprecipitation, reporter assays, siRNA/overexpression, xenograft tumor assays Science signaling High 25670202
2017 TGF-β enables Th17 cell differentiation by inducing proteasomal degradation of SKI; in the absence of TGF-β, SKI binds SMAD4 and the SKI-SMAD4 complex suppresses RORγt expression by controlling H3K9 deacetylation at the Rorc locus; TGF-β-induced SKI degradation reverses this repression to permit RORγt expression and Th17 differentiation. Proteomic analysis, co-immunoprecipitation, ChIP, genetic deletion (SMAD4-/- and SKI overexpression), chromatin histone modification assays Nature High 29072299
2018 SKI functions as a co-repressor for RUNX1 in AML cells; ChIP-seq shows SKI binding sites are enriched for RUNX1 consensus motifs; ~70% of RUNX1 binding sites overlap SKI peaks at enhancer regions; SKI and RUNX1 co-occupy the same genomic sites and cooperate in gene silencing related to myeloid differentiation. ChIP-seq, RNA-seq, CRISPR/shRNA deletion, reporter assays Nucleic acids research High 29471413
2021 Arkadia (RNF111 E3 ubiquitin ligase) targets SKI and SnoN for degradation; genetic ablation of SKI and SnoN rescues impaired iTreg differentiation in Arkadia-deficient T cells, placing SKI downstream of Arkadia in the TGF-β-driven iTreg differentiation pathway. Genetic KO (conditional CD4-Cre), in vitro differentiation assays, in vivo intestinal inflammation model The Journal of experimental medicine Medium 34473197
2021 SKI mutations found in Shprintzen-Goldberg syndrome (SGS) abolish binding of SKI to phosphorylated SMAD2 and SMAD3, resulting in SKI stabilization and attenuation (not enhancement) of TGF-β-induced transcriptional responses in both SGS patient fibroblasts and knock-in cells. Structural biology (crystal structure of SKI-phospho-SMAD2 complex), genome-edited knock-in cell lines, biochemical binding assays, transcriptional response assays in patient fibroblasts eLife High 33416497
2021 SKI activates the Hippo tumor-suppressor pathway in cardiac fibroblasts via interaction with LIMD1 (identified by BioID2 interactomics), leading to LATS2-mediated (not LATS1-mediated) phosphorylation and specific proteasomal degradation of TAZ but not YAP, inhibiting myofibroblast activation. BioID2 proximity labeling/mass spectrometry, siRNA knockdown, adenoviral overexpression, luciferase assays, in vivo post-MI rat model Basic research in cardiology Medium 33847835
2022 The human SKI complex (hSKI) exhibits a gatekeeping mechanism for RNA channeling to the exosome: in a pre-hydrolytic ATP state, hSKI adopts a closed conformation that traps 80S-bound RNA in the hSKI2 helicase; upon activation, an open conformation releases gating and allows 3′ RNA exit. Structural characterization was performed in the context of 80S ribosomes. Cryo-EM structural analysis of hSKI-80S ribosome-RNA complexes in multiple conformational states Molecular cell High 35120588
2023 HDAC2 forms a functional complex with SMAD3 and SKI in glioblastoma brain tumour stem cells (BTSCs); the HDAC2-SMAD3-SKI axis maintains BTSC self-renewal and tumorigenic potential, and disruption of this complex reduces BTSC growth in vitro and in orthotopic xenograft models. Pharmacological inhibition, genetic loss/gain of function, co-immunoprecipitation, ChIP, chromatin accessibility assay, orthotopic xenograft Nature communications Medium 37598220
2004 The protooncogene Ski controls Schwann cell proliferation and myelination: Ski overexpression inhibits TGF-β-mediated Schwann cell proliferation, and Ski-deficient animals show a myelination block and downregulation of myelin component genes; Ski interacts with the myelination regulator Oct6. Ski knockout mouse analysis, overexpression in myelin-competent cultures, gene expression profiling, co-immunoprecipitation Neuron High 15312649
2019 SKI loss in hematopoietic stem cells (HSCs) results in a profound competitive fitness defect and upregulation of TGF-β signaling and aberrant alternative splicing of spliceosome genes including Hnrnpk, as demonstrated in Ski-/- competitive HSC transplants and blastocyst complementation. Competitive HSC transplantation, blastocyst complementation, single-cell splicing analysis, gene expression profiling Blood Medium 30249787

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes & development 380 10485843
2000 Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. American journal of respiratory and critical care medicine 243 10852791
2009 Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell research 227 19114989
2001 Ski7p G protein interacts with the exosome and the Ski complex for 3'-to-5' mRNA decay in yeast. The EMBO journal 184 11532933
2001 Ski/Sno and TGF-beta signaling. Cytokine & growth factor reviews 178 11312113
1989 Isolation of human cDNA clones of ski and the ski-related gene, sno. Nucleic acids research 166 2762147
2001 The Ski protein family is required for MeCP2-mediated transcriptional repression. The Journal of biological chemistry 164 11441023
2013 The yeast ski complex: crystal structure and RNA channeling to the exosome complex. Cell 151 23953113
2008 SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Molecular cancer therapeutics 127 18483306
2009 A homolog of human ski-interacting protein in rice positively regulates cell viability and stress tolerance. Proceedings of the National Academy of Sciences of the United States of America 117 19339499
1999 The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Annals of the New York Academy of Sciences 108 10816641
2018 Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease. Signal transduction and targeted therapy 102 29892481
2000 Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 100 11121043
2001 Biosynthesis and cellular trafficking of the convertase SKI-1/S1P: ectodomain shedding requires SKI-1 activity. The Journal of biological chemistry 99 11756446
2017 Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 96 29072299
2003 SKI activates Wnt/beta-catenin signaling in human melanoma. Cancer research 93 14583455
2000 Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment. The Journal of biological chemistry 79 10644685
2012 Protooncogene Ski cooperates with the chromatin-remodeling factor Satb2 in specifying callosal neurons. Proceedings of the National Academy of Sciences of the United States of America 75 22334647
2008 SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells. The Journal of biological chemistry 75 19049980
2003 Repression of TGF-beta signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis. Oncogene 74 12793438
2002 Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes & development 71 12435627
2011 MicroRNA-155 targets the SKI gene in human melanoma cell lines. Pigment cell & melanoma research 69 21466664
1990 Requirement of protein co-factor for the DNA-binding function of the human ski proto-oncogene product. Nucleic acids research 64 2183181
2006 Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia. Leukemia 59 16424870
2015 Ski regulates Hippo and TAZ signaling to suppress breast cancer progression. Science signaling 57 25670202
2003 Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation. The Journal of biological chemistry 55 12874272
2004 The protooncogene Ski controls Schwann cell proliferation and myelination. Neuron 54 15312649
2010 Antifibrotic properties of c-Ski and its regulation of cardiac myofibroblast phenotype and contractility. American journal of physiology. Cell physiology 53 20943957
2005 SKI pathways inducing progression of human melanoma. Cancer metastasis reviews 53 15986136
1998 Transcriptional repression by v-Ski and c-Ski mediated by a specific DNA binding site. The Journal of biological chemistry 53 9452486
2012 SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth. Developmental cell 52 22340500
2009 Dual role of Ski in pancreatic cancer cells: tumor-promoting versus metastasis-suppressive function. Carcinogenesis 50 19546161
2011 c-Ski in health and disease. Cell and tissue research 48 21647564
2005 Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p. RNA (New York, N.Y.) 48 16043509
1991 Expression of yeast L-A double-stranded RNA virus proteins produces derepressed replication: a ski- phenocopy. Journal of virology 48 1985195
2020 Extraction of mRNA from Stalled Ribosomes by the Ski Complex. Molecular cell 46 32006463
2015 SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo. Biochemical and biophysical research communications 45 25824043
2005 CHES1/FOXN3 interacts with Ski-interacting protein and acts as a transcriptional repressor. Gene 45 16102918
2013 c-Ski activates cancer-associated fibroblasts to regulate breast cancer cell invasion. Molecular oncology 44 24011664
2004 Ski-interacting protein, a bifunctional nuclear receptor coregulator that interacts with N-CoR/SMRT and p300. Biochemical and biophysical research communications 44 14985122
2015 Ski prevents TGF-β-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer. Oncology reports 42 25955797
2007 Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Molecular and cellular neurosciences 42 17292623
1997 DNA binding and transcriptional activation by the Ski oncoprotein mediated by interaction with NFI. Nucleic acids research 42 9380514
2014 The c-Ski family member and transcriptional regulator Corl2/Skor2 promotes early differentiation of cerebellar Purkinje cells. Developmental biology 41 24491816
2013 The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype. Journal of cell science 41 24155330
2022 The human SKI complex regulates channeling of ribosome-bound RNA to the exosome via an intrinsic gatekeeping mechanism. Molecular cell 39 35120588
2019 AAV1.SERCA2a Gene Therapy Reverses Pulmonary Fibrosis by Blocking the STAT3/FOXM1 Pathway and Promoting the SNON/SKI Axis. Molecular therapy : the journal of the American Society of Gene Therapy 39 31879190
2002 c-Jun associates with the oncoprotein Ski and suppresses Smad2 transcriptional activity. The Journal of biological chemistry 38 12034730
2004 Repression of endogenous Smad7 by Ski. The Journal of biological chemistry 37 15128733
2021 Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. The Journal of experimental medicine 36 34473197
2007 Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells. The Prostate 35 17879964
2021 SKI activates the Hippo pathway via LIMD1 to inhibit cardiac fibroblast activation. Basic research in cardiology 34 33847835
2006 Nuclear and cytoplasmic c-Ski differently modulate cellular functions. Genes to cells : devoted to molecular & cellular mechanisms 34 17054724
2005 Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues. Laboratory investigation; a journal of technical methods and pathology 34 16200078
1999 Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents. Nucleic acids research 34 9927733
1995 Enhanced expression of mouse c-ski accompanies terminal skeletal muscle differentiation in vivo and in vitro. Developmental dynamics : an official publication of the American Association of Anatomists 34 8573720
2012 Ski inhibits TGF-β/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes. Journal of cellular biochemistry 33 22461172
2022 Targeting sphingosine kinase 1/2 by a novel dual inhibitor SKI-349 suppresses non-small cell lung cancer cell growth. Cell death & disease 32 35831279
2020 Apigenin attenuates TGF-β1-stimulated cardiac fibroblast differentiation and extracellular matrix production by targeting miR-155-5p/c-Ski/Smad pathway. Journal of ethnopharmacology 32 32800930
2007 Competition between Ski and CREB-binding protein for binding to Smad proteins in transforming growth factor-beta signaling. The Journal of biological chemistry 32 17283070
2018 SKI controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness. Blood 30 30249787
2017 SKI-178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models. Cancer translational medicine 30 28890935
2009 Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. Journal of biochemistry 30 19959502
2008 Identification of STRA6 and SKI sequence variants in patients with anophthalmia/microphthalmia. Molecular vision 30 19112531
2010 The Ski protein negatively regulates Siah2-mediated HDAC3 degradation. Biochemical and biophysical research communications 29 20691163
2007 The proprotein convertase SKI-1/S1P: alternate translation and subcellular localization. The Journal of biological chemistry 29 17623657
2005 The Ski oncoprotein is upregulated and localized at the centrosomes and mitotic spindle during mitosis. Oncogene 29 15806149
2017 Dual sphingosine kinase inhibitor SKI-II enhances sensitivity to 5-fluorouracil in hepatocellular carcinoma cells via suppression of osteopontin and FAK/IGF-1R signalling. Biochemical and biophysical research communications 28 28433634
2011 MicroRNA29a regulates the expression of the nuclear oncogene Ski. Blood 27 21685371
2003 Negative regulation of BMP signaling by the ski oncoprotein. The Journal of bone and joint surgery. American volume 27 12925608
2020 The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses. Proceedings of the National Academy of Sciences of the United States of America 26 33184176
2010 Control of mammary tumor differentiation by SKI-606 (bosutinib). Oncogene 26 20818417
2008 Expression and localization of Ski determine cell type-specific TGFbeta signaling effects on the cell cycle. The Journal of cell biology 26 18695043
2021 Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-β responses through SKI stabilization. eLife 25 33416497
2008 Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus. Human pathology 25 18261624
2009 The phosphatidylinositol 3-kinase/Akt pathway regulates transforming growth factor-{beta} signaling by destabilizing ski and inducing Smad7. The Journal of biological chemistry 24 19875456
2023 Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics. Nature communications 23 37598220
2022 Loss of FOCAD, operating via the SKI messenger RNA surveillance pathway, causes a pediatric syndrome with liver cirrhosis. Nature genetics 23 35864190
2019 A specialised SKI complex assists the cytoplasmic RNA exosome in the absence of direct association with ribosomes. The EMBO journal 23 31304628
2004 Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34. Oncogene 23 15122324
2006 Expression and possible mechanism of c-ski, a novel tissue repair-related gene during normal and radiation-impaired wound healing. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 22 16630105
2005 Muscle hypertrophy induced by the Ski protein: cyto-architecture and ultrastructure. Acta physiologica Scandinavica 22 16168008
1993 C-ski transcripts with and without exon 2 are expressed in skeletal muscle and throughout chick embryogenesis. Oncogene 22 8378095
2019 Ski-related novel protein suppresses the development of diabetic nephropathy by modulating transforming growth factor-β signaling and microRNA-21 expression. Journal of cellular physiology 21 30847937
2017 Expression of Ski and its role in astrocyte proliferation and migration. Neuroscience 21 28844002
2014 A sphingosine kinase-1 inhibitor, SKI-II, induces growth inhibition and apoptosis in human gastric cancer cells. Asian Pacific journal of cancer prevention : APJCP 21 25556479
2019 Knockdown of Ski decreases osteosarcoma cell proliferation and migration by suppressing the PI3K/Akt signaling pathway. International journal of oncology 20 31746363
2017 Spatiotemporal expression of Ski after rat spinal cord injury. Neuroreport 20 28059863
2017 Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma. Biochemical and biophysical research communications 20 28115165
2011 A two-gene signature, SKI and SLAMF1, predicts time-to-treatment in previously untreated patients with chronic lymphocytic leukemia. PloS one 20 22194822
2000 Ectopic expression of c-ski disrupts gastrulation and neural patterning in zebrafish. Mechanisms of development 20 10906458
2019 SKI and SMAD4 are essential for IL-21-induced Th17 differentiation. Molecular immunology 19 31398665
2009 The Ski protein can inhibit ligand induced RARalpha and HDAC3 degradation in the retinoic acid signaling pathway. Biochemical and biophysical research communications 19 19341714
2018 Combined cistrome and transcriptome analysis of SKI in AML cells identifies SKI as a co-repressor for RUNX1. Nucleic acids research 18 29471413
2016 Chronic expression of Ski induces apoptosis and represses autophagy in cardiac myofibroblasts. Biochimica et biophysica acta 18 27039037
2023 Targeting SphK1/2 by SKI-178 inhibits prostate cancer cell growth. Cell death & disease 17 37604912
1990 Structure and activities of the ski oncogene. Seminars in cancer biology 17 2103510
2017 Ski regulates Smads and TAZ signaling to suppress lung cancer progression. Molecular carcinogenesis 16 28398634
2010 Cell damage, antioxidant status, and cortisol levels related to nutrition in ski mountaineering during a two-day race. Journal of sports science & medicine 16 24149705
2025 SKI complex loss renders 9p21.3-deleted or MSI-H cancers dependent on PELO. Nature 15 39910293

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