Affinage

Showing SKIL — SNON is a alias.

SKIL

Ski-like protein · UniProt P12757

Length
684 aa
Mass
77.0 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SKIL (SnoN) is a transcriptional coregulator that functions as a central negative-feedback node of the TGF-β/Smad pathway, directly binding Smad2, Smad3, and Smad4 to repress TGF-β-responsive genes in the absence of ligand through recruitment of the N-CoR corepressor and histone deacetylases (PMID:10531062, PMID:10535941, PMID:12764135). Repression requires intact Smad-binding regions, and this same activity underlies its oncogenic transforming potential, linking Smad antagonism directly to transformation (PMID:12764135). Structural work shows the SnoN SAND domain engages the SMAD4 MH2 domain in a manner compatible with simultaneous coordination of R-Smads, forming a stable Smad3–Smad4–SnoN complex (PMID:28397834). SnoN itself is subject to tightly controlled signal-induced destruction: TGF-β triggers its rapid ubiquitin-proteasomal degradation through at least three distinct E3 ligase routes — a Smad3-recruited APC/CDH1 complex acting on a destruction box, a Smad2–Smurf2 complex, and Arkadia/RNF111, which ubiquitylates SnoN specifically at K343 in the SAND domain only when complexed with phosphorylated Smad2/3 (PMID:11691834, PMID:11741538, PMID:11389444, PMID:17591695, PMID:17510063, PMID:34740826). This degradation, augmented by TAK1-mediated phosphorylation, transiently relieves repression before SnoN re-expression re-establishes feedback control (PMID:11691834, PMID:11741538, PMID:17591695, PMID:17510063). SnoN is also SUMOylated at K50/K383 via PIAS1/TIF1γ, a modification that promotes promoter-specific repression and suppresses EMT through HDAC1/p300 recruitment without altering protein stability (PMID:16966324, PMID:17202138, PMID:32770107, PMID:37414747). Beyond canonical TGF-β control, SnoN integrates additional signaling axes: it inhibits Lats2-mediated TAZ phosphorylation to stabilize TAZ in the Hippo pathway (PMID:27237790), binds ALK1 to promote Smad1/5 angiogenic signaling (PMID:24019535), and engages PML to stabilize p53 and induce senescence as a Smad-independent tumor-suppressive program (PMID:19745809). In vivo it controls cerebellar granule neuron precursor proliferation and axonal morphogenesis via a Smad2–SnoN–Ccd1–JNK pathway and interactions with N-myc and Pax6 (PMID:16675394, PMID:18287512, PMID:19339625, PMID:30425119), and governs developmental and tissue-specific fates including endoderm specification, mammary alveologenesis through Stat5, and adipocyte differentiation (PMID:23154981, PMID:22833129, PMID:30030373).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 High

    Established SnoN as a direct negative regulator of TGF-β signaling, answering how Smad transcriptional output is held off in the basal state and reset after stimulation.

    Evidence Co-IP, reporter assays, and proteasome inhibition showing SnoN-Smad2/3/4 binding, N-CoR recruitment, and TGF-β-induced degradation with delayed re-expression

    PMID:10531062 PMID:10535941

    Open questions at the time
    • Mechanism coupling Smad nuclear accumulation to SnoN turnover not yet defined
    • Promoter-level chromatin events not resolved
  2. 2001 High

    Defined the E3 ligase machinery for signal-induced SnoN destruction, explaining how TGF-β rapidly clears the repressor to permit gene activation.

    Evidence In vitro ubiquitination reconstitution, Co-IP, and mutagenesis identifying Smad3-recruited APC/CDH1 (D-box dependent) and Smad2–Smurf2 complexes

    PMID:11389444 PMID:11691834 PMID:11741538

    Open questions at the time
    • Relative contribution of each ligase in different cell types unresolved
    • Did not yet identify all ubiquitin acceptor lysines
  3. 2002 Medium

    Mapped the molecular interface for Smad recognition, explaining preferential binding to Smad2/3 over Smad1 and positioning of the degradation machinery.

    Evidence Mutagenesis and binding assays defining the SE/QPSMT sequences in the Smad3 MH2 domain and Smurf2 docking on the Smad2 linker

    PMID:12426322

    Open questions at the time
    • Structural detail of the interface not yet available at this stage
    • Single lab
  4. 2003 High

    Linked SnoN's Smad-repression function causally to its transforming activity, distinguishing the two binding regions required for antagonism.

    Evidence Systematic mutagenesis with reporter, cell-cycle, and transformation assays showing both Smad-binding regions are needed for repression and transformation

    PMID:12764135

    Open questions at the time
    • Downstream transforming target genes not defined here
    • Single lab
  5. 2005 High

    Revealed that SnoN can act in the cytoplasm by Smad sequestration, distinguishing nuclear repression from cytoplasmic antagonism and tying localization to cell state.

    Evidence Subcellular fractionation, immunofluorescence, and functional TGF-β assays across cell types

    PMID:16109768

    Open questions at the time
    • Signals controlling nuclear-cytoplasmic shuttling not defined
    • Determinants of cytoplasmic degradation resistance unclear
  6. 2006 High

    Identified Arkadia/RNF111 and uncovered SnoN's distinct neuronal role, broadening both its degradation control and its biological functions.

    Evidence siRNA screen, Co-IP, ubiquitination assays for Arkadia; reciprocal Co-IP, RNAi, and in vivo cerebellar electroporation for axonal growth; ChIP for smad7 promoter feedback

    PMID:16442497 PMID:16675394 PMID:17510063 PMID:17591695

    Open questions at the time
    • How Arkadia substrate selectivity is achieved not yet resolved
    • Neuronal transcriptional targets not yet identified
  7. 2006 High

    Established SUMOylation as a regulatory layer controlling promoter-specific repression independent of stability.

    Evidence In vivo SUMOylation assays, K50R/K383R mutagenesis, Ubc9/PIAS1 dependence, and myogenin/muscle gene readouts

    PMID:16966324 PMID:17202138

    Open questions at the time
    • Mechanism by which SUMO alters promoter selectivity unresolved
    • Genome-wide SUMO-dependent target set undefined
  8. 2008 High

    Ordered the neuronal pathway, placing Smad2 upstream of SnoN in Cdh1-APC-controlled axonal morphogenesis.

    Evidence Endogenous Co-IP, RNAi, and genetic epistasis with axon-length measurement

    PMID:18287512

    Open questions at the time
    • Downstream effectors not yet identified at this step
  9. 2009 High

    Defined effector arms of SnoN function: a Ccd1-JNK axon-growth program and a Smad-independent PML/p53 senescence and tumor-suppressor program.

    Evidence Co-IP, gene profiling, in vivo electroporation for p300/Ccd1; Co-IP, PML body IF, p53 stability, and in vivo carcinogenesis for senescence

    PMID:19339625 PMID:19745809

    Open questions at the time
    • Switch between oncogenic and tumor-suppressive outputs not mechanistically defined
    • Threshold of SnoN level dictating senescence unclear
  10. 2010 Medium

    Provided the first structural view of a SnoN interaction domain, revealing conformational flexibility consistent with multipartner recognition.

    Evidence X-ray crystallography of the Dachshund homology domain

    PMID:20957027

    Open questions at the time
    • Crystal structure lacks biochemical/mutagenesis validation of the groove
    • Specific partners engaging the groove not tested
  11. 2012 High

    Demonstrated direct promoter occupancy and a self-regulating feedback loop, and expanded SnoN's targets to developmental and tissue-specific programs.

    Evidence ChIP/sequential ChIP on SKIL and developmental promoters, reporter assays, gain/loss of function in hESCs, KO mouse rescue with Stat5, and BMP cross-inhibition assays

    PMID:20457602 PMID:22674574 PMID:22767605 PMID:22833129 PMID:23154981

    Open questions at the time
    • Genome-wide direct binding map incomplete
    • Coregulator switching at distinct promoters not fully defined
  12. 2011 Medium

    Extended SnoN's corepressor function to ERα-enhanced and GnRH-regulated transcription, showing context-dependent coactivator and corepressor roles.

    Evidence Co-IP, LxxLL mutagenesis, ChIP and reporter assays for ERα; ChIP, reporter and knockdown for FSHβ promoter

    PMID:21659477 PMID:22227247

    Open questions at the time
    • Mechanistic basis for coactivator versus corepressor switching unresolved
    • Single lab for each context
  13. 2013 Medium

    Defined oncogenic outputs of SnoN amplification, linking it to invasion via SLUG and to tumor growth.

    Evidence Gain-of-function screen, invasion assays, expression analysis, and xenograft tumor assay

    PMID:23764425

    Open questions at the time
    • Direct versus indirect regulation of SLUG not resolved
    • Single lab
  14. 2016 High

    Connected SnoN to the Hippo pathway, showing it stabilizes TAZ by blocking Lats2 and is reciprocally regulated by Lats2/Scribble.

    Evidence Reciprocal Co-IP, kinase assays, and knockdown/overexpression with TAZ phosphorylation readout

    PMID:27237790

    Open questions at the time
    • Structural basis of Lats2-TAZ disruption undefined
    • Integration with TGF-β SnoN pool unclear
  15. 2017 High

    Provided structural and biochemical definition of the SnoN-SMAD4 complex, distinguishing SnoN's stable-complex mode from Ski's heteromer-disrupting mode.

    Evidence X-ray crystallography of the SAND domain–SMAD4 MH2 complex with co-purification and stability assays

    PMID:28397834

    Open questions at the time
    • Structure of full Smad3-Smad4-SnoN assembly not determined
    • Single lab
  16. 2018 High

    Established pathway-selective in vivo functions, separating activin-A/Smad2 from TGF-β/Smad3 outputs in adipogenesis and defining granule neuron precursor proliferation control.

    Evidence Conditional KO and Smad-binding mutant mice with metabolic phenotype; conditional KO with RNA-Seq and Co-IP identifying N-myc/Pax6

    PMID:30030373 PMID:30425119

    Open questions at the time
    • Basis for Smad2 versus Smad3 selectivity not mechanistically resolved
    • Direct N-myc/Pax6 target genes undefined
  17. 2020 High

    Defined the SUMO E3 machinery and its consequence, showing PIAS1/TIF1γ cooperate to SUMOylate SnoN and suppress EMT.

    Evidence Co-IP, in vivo SUMOylation assays, and loss-of-function in 3D organoids

    PMID:32770107

    Open questions at the time
    • Interdependence mechanism of PIAS1/TIF1γ not fully resolved
  18. 2021 High

    Resolved Arkadia's substrate specificity at proteome scale and demonstrated its physiological role in iTreg differentiation through SKI/SnoN degradation.

    Evidence Quantitative ubiquitylome MS with CRISPR controls identifying K343; conditional and double-KO epistasis in T cells with in vivo gut inflammation model

    PMID:34473197 PMID:34740826

    Open questions at the time
    • How RNF111 restricts itself to SKI/SnoN not structurally defined
    • Role of K343 ubiquitylation in non-immune contexts not tested
  19. 2023 Medium

    Showed SUMOylation directs SnoN's coregulator partner choice between HDAC1 and p300 to tune EMT-associated histone acetylation.

    Evidence Co-IP, gain/loss-of-function, and histone acetylation analysis in 3D mammary organoids

    PMID:37414747

    Open questions at the time
    • Promoter-level acetylation changes not mapped genome-wide
    • Single lab
  20. 2024 Medium

    Identified upstream RNA-level control of SKIL via m5C methylation, linking transcript stabilization to TAZ activation in cancer.

    Evidence m5C-meRIP, RNA stability assays, NSUN2 KO mouse, and Co-IP

    PMID:38468490

    Open questions at the time
    • Generality across tissues of m5C control unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SnoN switches between tumor-suppressive (PML/p53 senescence, Smad repression) and oncogenic (TAZ stabilization, SLUG-driven invasion) outputs in a given cellular context remains undefined.
  • No unifying model linking SnoN level, modification state, and context to functional output
  • Genome-wide direct binding and coregulator-switching map incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 1
Partners
ALK1PIAS1RNF111SMAD2SMAD3SMAD4SMURF2TAZ
Complex memberships
PIAS1-TIF1γ-SnoN SUMOylation complexSmad2-Smurf2 ubiquitin ligase complexSmad3-APC/CDH1 ubiquitin ligase complexSmad3-Smad4-SnoN repressor complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 SnoN directly interacts with Smad2 and Smad4, represses their transcriptional activity through recruitment of the transcriptional corepressor N-CoR, and maintains the repressed state of TGF-β-responsive genes in the absence of ligand. Upon TGF-β stimulation, Smad3 nuclear accumulation leads to rapid SnoN degradation, allowing target gene activation; by 2 hours, TGF-β induces SnoN re-expression to terminate Smad-mediated transactivation (negative feedback). Co-immunoprecipitation, transcriptional reporter assays, Western blotting Science High 10531062
1999 Smad3 associates with SnoN in the nucleus; overexpression of SnoN represses Smad3-mediated transcriptional activation. TGF-β stimulation leads to rapid, proteasome-mediated degradation of SnoN. Co-immunoprecipitation, transcriptional reporter assay, proteasome inhibitor treatment Proceedings of the National Academy of Sciences High 10535941
2001 TGF-β induces assembly of a Smad2–Smurf2 ubiquitin ligase complex that targets SnoN for ubiquitin-mediated proteasomal degradation. Smad2 interacts with Smurf2 via its PPXY motif and WW domains, and Smad2 mediates the interaction of Smurf2 with SnoN. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment Nature Cell Biology High 11389444
2001 Smad3 (and to a lesser extent Smad2) recruits the anaphase-promoting complex (APC) with UbcH5 ubiquitin-conjugating enzymes to SnoN, causing ubiquitination at a destruction box (D box) and proteasomal degradation of SnoN. Mutation of the Smad3-binding site or key lysine residues in SnoN stabilizes it and enhances antagonism of TGF-β signaling. In vitro ubiquitination assay, co-immunoprecipitation, mutagenesis, proteasome inhibitor treatment Genes & Development High 11691834 11741538
2001 The APC activator CDH1 forms a quaternary complex with SnoN, Smad3, and APC to mediate SnoN destruction in response to TGF-β. The destruction box of SnoN is required for its degradation. Co-immunoprecipitation, ubiquitination assay, mutagenesis Molecular Cell High 11741538
2003 Smad2 and Smad3 bind to distinct regions of SnoN; mutation of both Smad-binding regions (but not individually) impairs SnoN-mediated repression of TGF-β transcription and cell cycle arrest. Mutant SnoN defective in Smad binding fails to induce oncogenic transformation, demonstrating that transforming activity requires Smad repression. Mutagenesis, co-immunoprecipitation, transcriptional reporter assay, transformation assay Journal of Biological Chemistry High 12764135
2005 In normal tissues and non-tumorigenic epithelial cells, SnoN is predominantly cytoplasmic and antagonizes TGF-β signaling by sequestering Smad proteins in the cytoplasm rather than by nuclear transcriptional repression. Cytoplasmic SnoN is resistant to TGF-β-induced degradation. Upon differentiation or cell-cycle arrest, SnoN translocates to the nucleus. Subcellular fractionation, immunofluorescence, functional TGF-β signaling assays Proceedings of the National Academy of Sciences High 16109768
2006 Cdh1-APC forms a physical complex with SnoN in neurons and stimulates ubiquitin-dependent proteasomal degradation of SnoN. SnoN promotes axonal growth downstream of Cdh1-APC; SnoN knockdown reduces axonal growth and suppresses Cdh1 RNAi-induced axonal enhancement. SnoN is required for cerebellar granule neuron parallel fiber development in vivo. Co-immunoprecipitation, RNAi knockdown, in vivo cerebellar electroporation, axon length quantification Neuron High 16675394
2006 SnoN is sumoylated primarily at lysine residues 50 and 383. The SUMO E2 enzyme Ubc9 is critical for this modification and SUMO E3 ligase PIAS1 selectively interacts with and enhances SnoN sumoylation. Sumoylation of SnoN augments its ability to repress gene expression in a promoter-specific manner, particularly suppressing myogenin transcription. In vivo sumoylation assay, mutagenesis (K50R, K383R), co-immunoprecipitation, transcriptional reporter assay Journal of Biological Chemistry High 16966324 17202138
2007 Arkadia (RNF111), an E3 ubiquitin ligase, interacts with SnoN, induces its ubiquitination, and is essential for TGF-β-induced SnoN degradation. SnoN is efficiently degraded only when it forms a complex with both Arkadia and phosphorylated Smad2 or Smad3. Arkadia is required for Smad3/Smad4-dependent transcription but not for Smad1/Smad4 or Smad2/Smad4/FoxH1-dependent responses. siRNA library screen, co-immunoprecipitation, ubiquitination assay, transcriptional reporter assay, dominant-negative mutant Molecular and Cellular Biology High 17510063 17591695
2007 TAK1 (MAP3K7) interacts with and phosphorylates SnoN; this phosphorylation destabilizes SnoN. Inactivation of TAK1 prevents TGF-β-induced SnoN degradation and impairs induction of TGF-β-responsive genes. Co-immunoprecipitation, in vitro kinase assay, TAK1 dominant-negative/knockdown, Western blotting Journal of Biological Chemistry Medium 17276978
2007 SnoN sumoylation at lysine 50 is regulated by PIAS1 and PIASx as SUMO E3 ligases. Loss of sumoylation (K50R mutation) potently activates muscle-specific gene expression and enhances myotube formation. Sumoylation does not alter SnoN stability or its ability to repress TGF-β signaling but specifically controls myogenic differentiation. In vivo sumoylation assay, mutagenesis, myotube formation assay, gene expression analysis Journal of Biological Chemistry High 17202138
2008 In neurons, TGFβ-regulated Smad2 is phosphorylated and localized in the nucleus where it forms a physical complex with endogenous SnoN. Smad2 knockdown stimulates axonal growth. Epistasis analyses show Smad2 acts upstream of SnoN in the Cdh1-APC pathway controlling axonal morphogenesis. Co-immunoprecipitation of endogenous proteins, RNAi knockdown, genetic epistasis, axon length measurement Journal of Neuroscience High 18287512
2009 SnoN interacts with the coactivator p300 in neurons, and p300 is required for SnoN-induced axon growth. SnoN transcriptionally activates the Ccd1 gene; Ccd1 localizes to the actin cytoskeleton at axon terminals, activates JNK, and is required for SnoN-dependent axonal growth in vivo. Co-immunoprecipitation, gene profiling, RNAi knockdown, in vivo cerebellar electroporation Journal of Neuroscience High 19339625
2009 High levels of SnoN induce premature senescence by a Smad-independent mechanism: SnoN interacts with PML protein, is recruited to PML nuclear bodies, and stabilizes p53. SnoN overexpression inhibits oncogenic transformation by Ras and Myc and blocks papilloma development in vivo. Co-immunoprecipitation, PML nuclear body immunofluorescence, p53 stability assay, in vivo carcinogenesis model EMBO Journal High 19745809
2010 SnoN acts as a master repressor of ADAM12 gene expression in response to TGF-β1 stimulation. SnoN overexpression reduces TGF-β1-induced ADAM12 induction; SnoN shRNA knockdown enhances it. This repression is Smad2/Smad3-dependent and occurs via derepression of the Adam12 gene. shRNA knockdown, overexpression, mRNA/protein analysis, Smad2/3 dependence assay Journal of Biological Chemistry Medium 20457602
2011 SnoN interacts with the estrogen-activated form of ERα in the nucleus via conserved LxxLL-like motifs. SnoN overexpression enhances ERα transcriptional activity at ERE-reporter and target genes; SnoN knockdown reduces it. SnoN supports p300 recruitment to the ERα target gene TTF1 promoter. Co-immunoprecipitation, LxxLL mutagenesis, chromatin immunoprecipitation, transcriptional reporter assay Cellular Signalling Medium 22227247
2012 The SNON-SMAD4 complex binds the SKIL gene promoter via a TGF-β response element (containing SMAD-binding elements) and negatively regulates basal SKIL gene expression by recruiting histone deacetylases, forming a negative feedback loop. Upon TGF-β signaling, SNON is removed from the promoter, allowing activated SMAD complexes to induce SKIL expression. ChIP, sequential ChIP, promoter cloning, luciferase reporter assay, HDAC recruitment assay Journal of Biological Chemistry High 22674574
2012 In human embryonic stem cells, SNON predominantly associates with SMAD2 at the promoters of primitive streak and early definitive endoderm marker genes to repress them. SNON knockdown causes premature activation of PS and DE genes and loss of hESC morphology; enforced SNON expression inhibits DE formation and diverts hESCs toward extraembryonic fate. ChIP, RNAi knockdown, overexpression, gene expression analysis Genes & Development High 23154981
2012 SnoN promotes Stat5 stability and signaling in mammary epithelial cells. SnoN expression is induced at late pregnancy by coordinated TGF-β and prolactin actions. SnoN-/- mice show severe alveologenesis and lactogenesis defects rescued by active Stat5, placing SnoN upstream of Stat5 in a TGF-β/prolactin-coordinating pathway. Knockout mouse model, rescue experiment with active Stat5, co-immunoprecipitation, Stat5 stability assay Development High 22833129
2012 SnoN suppresses BMP signaling (ID1 expression) in chondrocytes in a TGF-β-induced manner downstream of Smad2 phosphorylation, but upstream of BMP-regulated Smad1/5/8 activation; this mediates TGF-β cross-inhibition of BMP-driven hypertrophic chondrocyte maturation (Col10a1 expression). siRNA knockdown, overexpression, luciferase reporter assay, pharmacological inhibitor (SB431542) Journal of Biological Chemistry Medium 22767605
2013 SnoN directly binds to ALK1 on the plasma membrane in endothelial cells and facilitates the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation and promoting angiogenesis. Disruption of the SnoN-Smad interaction impairs Smad1/5 activation, up-regulates Smad2/3 activity, causes arteriovenous malformations, and leads to embryonic lethality at E12.5. Co-immunoprecipitation, mutagenesis, conditional knockout mouse model, phospho-Smad assays Journal of Cell Biology High 24019535
2016 SnoN interacts with multiple components of the Hippo pathway and inhibits the binding of Lats2 to TAZ, preventing TAZ phosphorylation and promoting TAZ stabilization. SnoN enhances transcriptional and oncogenic activities of TAZ; reducing SnoN decreases TAZ expression. SnoN itself is downregulated by Lats2 activated by the Scribble polarity protein. Co-immunoprecipitation, kinase assay, knockdown/overexpression, TAZ phosphorylation assay Developmental Cell High 27237790
2017 Crystal structure of the SAND domain of SnoN in complex with the MH2 domain of SMAD4 was determined, showing a binding mode compatible with simultaneous coordination of R-SMADs. SnoN forms a stable complex with SMAD3 and SMAD4, and this complex formation is distinct from Ski, which disrupts R-SMAD/Co-SMAD heteromers. X-ray crystallography, biochemical co-purification, stability assay Scientific Reports High 28397834
2010 Crystal structure of the Dachshund homology domain of human SnoN was determined, revealing a conserved groove with properties of a protein-interaction surface showing conformational flexibility (open and tight conformations), suggesting SnoN can recognize multiple interaction partners. X-ray crystallography PLoS One Medium 20957027
2018 SnoN promotes mesenchymal stem cell differentiation into the adipocyte lineage by antagonizing activin A/Smad2 (but not TGF-β/Smad3) signaling. Mice lacking SnoN or expressing a SnoN mutant defective in Smad binding are protected from high-fat diet-induced obesity. SnoN represses activin A expression through an autocrine mechanism in adipocytes. Conditional knockout mouse, high-fat diet model, MSC differentiation assay, Smad-binding mutant Journal of Biological Chemistry High 30030373
2018 Conditional knockout of SnoN in cerebellar granule neuron precursors inhibits their proliferation and promotes cell cycle exit at later postnatal stages. SnoN promotes expression of cell proliferation genes and represses differentiation genes in vivo. SnoN physically interacts with N-myc and Pax6 transcription factors. Conditional KO, laser capture microdissection/RNA-Seq, Co-immunoprecipitation, behavioral analysis Journal of Neuroscience High 30425119
2021 Quantitative ubiquitylome proteomics established that RNF111/Arkadia E3 ubiquitin ligase specifically ubiquitylates SKI and SKIL/SnoN (and no other substrates) upon TGF-β activation. Lysine 343 within the SAND domain of SKIL is identified as the principal ubiquitylation site targeted by RNF111. Quantitative ubiquitylome mass spectrometry (diGly remnant immunoprecipitation, ubiquitin nanobody IP), CRISPR-engineered cell lines Molecular & Cellular Proteomics High 34740826
2021 Arkadia inactivation in CD4+ T cells impairs iTreg differentiation in vitro and in vivo. Genetic ablation of both SKI and SnoN rescues Arkadia-deficient iTreg cell differentiation, establishing that Arkadia promotes iTreg differentiation by targeting SKI/SnoN for degradation. Arkadia is dispensable for Th17 cell responses. Conditional KO, double KO rescue/epistasis, flow cytometry, in vivo gut inflammation model Journal of Experimental Medicine High 34473197
2020 PIAS1 and TIF1γ form a trimeric complex with SnoN and collaborate in an interdependent manner to promote SnoN SUMOylation, leading to suppression of EMT in mammary epithelial organoids. Loss of PIAS1 and TIF1γ shows cooperative requirement for EMT suppression. Co-immunoprecipitation, in vivo SUMOylation assay, loss-of-function in 3D organoids Cell Death and Differentiation High 32770107
2023 Sumoylation promotes the interaction of SnoN with HDAC1 and p300. HDAC1 suppresses, whereas p300 promotes, TGF-β-induced EMT-associated changes in 3D mammary organoids. Sumoylated SnoN modulates EMT via regulation of histone acetylation. Co-immunoprecipitation, gain/loss-of-function, 3D mammary organoid assay, histone acetylation analysis Cell Death & Disease Medium 37414747
2011 GnRH pulse frequency differentially regulates SKIL (SnoN) expression in gonadotrope cells, where SnoN functions as a corepressor of the FSHβ promoter. Overexpression of Smad-binding or phosphorylation-defective SKIL mutants fails to repress FSHβ promoter activity; SKIL knockdown increases FSHβ promoter activity. ChIP shows FOS and SKIL occupy the FSHβ promoter cyclically after GnRH stimulation. ChIP, transfection reporter assay, siRNA knockdown, dominant-negative mutant analysis Molecular Endocrinology Medium 21659477
2006 SnoN binds the smad7 gene promoter at basal conditions and represses it. After short TGF-β treatment, SnoN is downregulated and leaves the promoter; after prolonged TGF-β treatment, upregulated SnoN returns to the smad7 promoter, functioning as a negative feedback control. Chromatin immunoprecipitation, transcriptional reporter assay Biochemical and Biophysical Research Communications Medium 16442497
1994 The C-terminal third of c-Ski mediates stable homodimerization with itself and heterodimerization with SnoN. Two structural motifs constitute the dimerization domain: a domain of five tandem 25-amino-acid repeats required for dimerization, and a predicted leucine zipper that enhances dimerization. c-Ski forms heterodimers with SnoN that are detectable by cross-linking of native protein. In vitro translated protein cross-linking, bacterial fusion protein pulldown, deletion analysis Journal of Biological Chemistry Medium 7929440
1998 SnoN binds a specific DNA sequence (GTCTAGAC) and represses transcription through a tripartite repression domain. One subdomain of SnoN interacts with TAF(II)110 as part of a quenching mechanism of transcriptional repression. Two of the three repression subdomains are required for both DNA binding and cellular transformation. Transcriptional reporter assay, Gal4 fusion assay, deletion mutagenesis, transformation assay Oncogene Medium 9824161
1999 c-Ski and SnoN preferentially form heterodimers over homodimers when co-expressed. Tethered Ski:Sno heterodimers lacking TR/LZ domains are more active than monomeric counterparts or tethered homodimers in transcriptional repression and cellular transformation. In vitro transcription/translation co-expression, DNA binding assay, transformation assay, tethered dimer constructs Nucleic Acids Research Medium 9927733
2002 c-Ski and SnoN bind to the 'SE' sequence in the C-terminal MH2 domain of Smad3, with 'QPSMT' sequence nearby supporting the interaction. Similar sequences exist in Smad2 but not Smad1, explaining preferential binding. Smurf2 is located close to SnoN via binding to the linker region of Smad2, enabling ubiquitin-dependent degradation of SnoN. Mutagenesis, binding assays, structural analysis of Smad3 MH2 domain Journal of Biological Chemistry Medium 12426322
2024 NSUN2 RNA methyltransferase induces m5C modification of SKIL mRNA, stabilizing it via Y-box binding protein 1 (YBX1)-mediated recognition. Elevated SKIL levels in turn increase TAZ transcriptional coactivator activation, promoting colorectal cancer progression. m5C-methylated RNA immunoprecipitation, RNA stability assay, NSUN2 knockout mouse, siRNA knockdown, Co-immunoprecipitation Clinical and Translational Medicine Medium 38468490
2013 SKIL (SnoN) overexpression induces cell invasion in immortalized human mammary epithelial cells, and SKIL induces invasion through upregulation of SLUG (SNAI2) expression. Co-expression of TLOC1 and SKIL induces subcutaneous tumor growth in vivo. Gain-of-function genetic screen, invasion assay, gene expression analysis, xenograft tumor assay Cancer Discovery Medium 23764425

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Science (New York, N.Y.) 433 10531062
2001 TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nature cell biology 269 11389444
2009 Ski and SnoN, potent negative regulators of TGF-beta signaling. Cell research 227 19114989
1999 SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proceedings of the National Academy of Sciences of the United States of America 221 10535941
2001 Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoN. Genes & development 186 11691834
2001 The anaphase-promoting complex mediates TGF-beta signaling by targeting SnoN for destruction. Molecular cell 153 11741538
2007 Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Molecular and cellular biology 148 17591695
2007 Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling. The Journal of biological chemistry 144 17510063
2006 Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron 143 16675394
2010 Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells. Cell death and differentiation 117 20508647
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
2006 Dual role of SnoN in mammalian tumorigenesis. Molecular and cellular biology 88 17074815
2003 The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. The Journal of biological chemistry 88 12764135
1993 Sequence and biological activity of chicken snoN cDNA clones. Oncogene 83 8426750
2008 TGFbeta-Smad2 signaling regulates the Cdh1-APC/SnoN pathway of axonal morphogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 18287512
2002 Up-regulated transcriptional repressors SnoN and Ski bind Smad proteins to antagonize transforming growth factor-beta signals during liver regeneration. The Journal of biological chemistry 76 12023281
2013 Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers. Cancer discovery 72 23764425
2003 Downregulation of Smad transcriptional corepressors SnoN and Ski in the fibrotic kidney: an amplification mechanism for TGF-beta1 signaling. Journal of the American Society of Nephrology : JASN 72 14638915
2005 Cytoplasmic SnoN in normal tissues and nonmalignant cells antagonizes TGF-beta signaling by sequestration of the Smad proteins. Proceedings of the National Academy of Sciences of the United States of America 66 16109768
2012 Transforming growth factor β1 inhibits bone morphogenic protein (BMP)-2 and BMP-7 signaling via upregulation of Ski-related novel protein N (SnoN): possible mechanism for the failure of BMP therapy? BMC medicine 64 22958403
2006 Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney international 63 16625151
2024 NSUN2 promotes colorectal cancer progression by enhancing SKIL mRNA stabilization. Clinical and translational medicine 62 38468490
2005 SnoN is a cell type-specific mediator of transforming growth factor-beta responses. The Journal of biological chemistry 60 15677458
2006 Downregulation of SnoN expression in obstructive nephropathy is mediated by an enhanced ubiquitin-dependent degradation. Journal of the American Society of Nephrology : JASN 59 16959829
2009 A SnoN-Ccd1 pathway promotes axonal morphogenesis in the mammalian brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 52 19339625
2010 Bone morphogenetic protein-7 inhibits proximal tubular epithelial cell Smad3 signaling via increased SnoN expression. The American journal of pathology 48 20093492
2012 Transforming growth factor-β/SMAD Target gene SKIL is negatively regulated by the transcriptional cofactor complex SNON-SMAD4. The Journal of biological chemistry 46 22674574
2012 SnoN suppresses maturation of chondrocytes by mediating signal cross-talk between transforming growth factor-β and bone morphogenetic protein pathways. The Journal of biological chemistry 44 22767605
2006 Sumoylated SnoN represses transcription in a promoter-specific manner. The Journal of biological chemistry 43 16966324
2002 Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN. The Journal of biological chemistry 43 12426322
1994 A carboxyl-terminal region of the ski oncoprotein mediates homodimerization as well as heterodimerization with the related protein SnoN. The Journal of biological chemistry 43 7929440
2016 Oxymatrine Inhibits Renal Tubular EMT Induced by High Glucose via Upregulation of SnoN and Inhibition of TGF-β1/Smad Signaling Pathway. PloS one 42 27010330
2020 SKIL facilitates tumorigenesis and immune escape of NSCLC via upregulating TAZ/autophagy axis. Cell death & disease 41 33268765
2005 Requirement for the SnoN oncoprotein in transforming growth factor beta-induced oncogenic transformation of fibroblast cells. Molecular and cellular biology 41 16314499
2011 Efficient TGF-β/SMAD signaling in human melanoma cells associated with high c-SKI/SnoN expression. Molecular cancer 40 21211030
2005 Inability of transforming growth factor-beta to cause SnoN degradation leads to resistance to transforming growth factor-beta-induced growth arrest in esophageal cancer cells. Cancer research 40 15930298
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
2021 Arkadia-SKI/SnoN signaling differentially regulates TGF-β-induced iTreg and Th17 cell differentiation. The Journal of experimental medicine 36 34473197
2020 miR‑574‑5p attenuates proliferation, migration and EMT in triple‑negative breast cancer cells by targeting BCL11A and SOX2 to inhibit the SKIL/TAZ/CTGF axis. International journal of oncology 35 32319565
2010 SnoN in mammalian development, function and diseases. Current opinion in pharmacology 35 20822955
2007 TAK1 MAPK kinase kinase mediates transforming growth factor-beta signaling by targeting SnoN oncoprotein for degradation. The Journal of biological chemistry 35 17276978
2017 Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN. Human cell 34 28707079
1999 Heterodimers of the SnoN and Ski oncoproteins form preferentially over homodimers and are more potent transforming agents. Nucleic acids research 34 9927733
2014 SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis. American journal of physiology. Heart and circulatory physiology 33 25380815
2011 Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone-beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1. Molecular endocrinology (Baltimore, Md.) 32 21659477
2009 SnoN functions as a tumour suppressor by inducing premature senescence. The EMBO journal 31 19745809
2016 SnoN Antagonizes the Hippo Kinase Complex to Promote TAZ Signaling during Breast Carcinogenesis. Developmental cell 30 27237790
2010 The role of SnoN in transforming growth factor beta1-induced expression of metalloprotease-disintegrin ADAM12. The Journal of biological chemistry 30 20457602
2022 BMP-7 ameliorates partial epithelial-mesenchymal transition by restoring SnoN protein level via Smad1/5 pathway in diabetic kidney disease. Cell death & disease 29 35314669
2014 Potential therapeutic targets for oral cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70. PloS one 29 25029526
2008 SnoN in TGF-beta signaling and cancer biology. Current molecular medicine 29 18537639
2019 miR-130a-3p inhibition protects against renal fibrosis in vitro via the TGF-β1/Smad pathway by targeting SnoN. Experimental and molecular pathology 28 31836508
2014 The proteasome inhibitor, MG132, attenuates diabetic nephropathy by inhibiting SnoN degradation in vivo and in vitro. BioMed research international 28 25003128
2013 Cooperative involvement of NFAT and SnoN mediates transforming growth factor-β (TGF-β) induced EMT in metastatic breast cancer (MDA-MB 231) cells. Clinical & experimental metastasis 27 23832742
2009 TGF-beta repressors SnoN and Ski are implicated in human colorectal carcinogenesis. Cellular oncology : the official journal of the International Society for Cellular Oncology 27 19096149
2007 Molecular basis for the cell type specific induction of SnoN expression by hepatocyte growth factor. Journal of the American Society of Nephrology : JASN 27 17625116
2012 The SMAD2/3 corepressor SNON maintains pluripotency through selective repression of mesendodermal genes in human ES cells. Genes & development 26 23154981
2010 Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis. Cancer research 26 20460516
2019 SNHG14 promotes the tumorigenesis and metastasis of colorectal cancer through miR-32-5p/SKIL axis. In vitro cellular & developmental biology. Animal 25 31471872
2008 Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus. Human pathology 25 18261624
2013 Docosahexaenoic acid (DHA) ameliorates paraquat-induced pulmonary fibrosis in rats possibly through up-regulation of Smad 7 and SnoN. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 24 23590892
2012 SnoN regulates mammary gland alveologenesis and onset of lactation by promoting prolactin/Stat5 signaling. Development (Cambridge, England) 24 22833129
2012 SnoN/SKIL modulates proliferation through control of hsa-miR-720 transcription in esophageal cancer cells. Biochemical and biophysical research communications 23 23154181
2015 Recurrent SKIL-activating rearrangements in ETS-negative prostate cancer. Oncotarget 22 25749039
2013 Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells. Molecular cancer 22 23621864
2008 Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: a role in ovarian pathogenesis. Molecular oncology 22 19383336
1998 A domain necessary for the transforming activity of SnoN is required for specific DNA binding, transcriptional repression and interaction with TAF(II)110. Oncogene 22 9824161
2020 Smad2 and Smad3 play antagonistic roles in high glucose-induced renal tubular fibrosis via the regulation of SnoN. Experimental and molecular pathology 20 31917288
2018 Interplay between FMRP and lncRNA TUG1 regulates axonal development through mediating SnoN-Ccd1 pathway. Human molecular genetics 20 29211876
2017 Repression of Smad3 by Stat3 and c-Ski/SnoN induces gefitinib resistance in lung adenocarcinoma. Biochemical and biophysical research communications 20 28115165
2015 The downregulation of SnoN expression in human renal proximal tubule epithelial cells under high-glucose conditions is mediated by an increase in Smurf2 expression through TGF-β1 signaling. International journal of molecular medicine 20 26743567
2012 SnoN signaling in proliferating cells and postmitotic neurons. FEBS letters 20 22710173
2008 Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. Journal of dermatological science 20 18782659
2007 Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation. The Journal of biological chemistry 19 17202138
2013 SnoN facilitates ALK1-Smad1/5 signaling during embryonic angiogenesis. The Journal of cell biology 18 24019535
2017 SnoN upregulation ameliorates renal fibrosis in diabetic nephropathy. PloS one 17 28350874
2012 SnoN as a key regulator of the high glucose-induced epithelial-mesenchymal transition in cells of the proximal tubule. Kidney & blood pressure research 17 22813962
2012 SnoN/SkiL expression is modulated via arsenic trioxide-induced activation of the PI3K/AKT pathway in ovarian cancer cells. FEBS letters 17 23178716
2009 Oncogene and tumour suppressor: the two faces of SnoN. The EMBO journal 17 19920850
2006 SnoN co-repressor binds and represses smad7 gene promoter. Biochemical and biophysical research communications 16 16442497
2017 SnoN Stabilizes the SMAD3/SMAD4 Protein Complex. Scientific reports 15 28397834
2016 SnoN suppresses TGF-β-induced epithelial-mesenchymal transition and invasion of bladder cancer in a TIF1γ-dependent manner. Oncology reports 15 27430247
2021 Quantitative Ubiquitylome Analysis Reveals the Specificity of RNF111/Arkadia E3 Ubiquitin Ligase for its Degradative Substrates SKI and SKIL/SnoN in TGF-β Signaling Pathway. Molecular & cellular proteomics : MCP 14 34740826
2017 Molecular mechanism of smurf2 in regulating the expression of SnoN in diabetic nephropathy. Molecular medicine reports 14 28447757
2010 SnoN/SkiL, a TGFβ signaling mediator: a participant in autophagy induced by arsenic trioxide. Autophagy 14 20699661
2020 PIAS1 and TIF1γ collaborate to promote SnoN SUMOylation and suppression of epithelial-mesenchymal transition. Cell death and differentiation 13 32770107
2017 BMP-7 enhances SnoN mRNA expression in renal tubular epithelial cells under high-glucose conditions. Molecular medicine reports 13 28765970
2011 SnoN oncoprotein enhances estrogen receptor-α transcriptional activity. Cellular signalling 13 22227247
2006 Drosophila SnoN modulates growth and patterning by antagonizing TGF-beta signalling. Mechanisms of development 13 17289352
1996 A transient increase of snoN transcript by growth arrest upon serum deprivation and cell-to-cell contact. FEBS letters 13 8955358
2018 The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 30425119
2012 SnoN in regulation of embryonic development and tissue morphogenesis. FEBS letters 12 22710172
2006 SnoN expression is differently regulated in microsatellite unstable compared with microsatellite stable colorectal cancers. BMC cancer 12 17062133
2018 The regulatory protein SnoN antagonizes activin/Smad2 protein signaling and thereby promotes adipocyte differentiation and obesity in mice. The Journal of biological chemistry 11 30030373
2016 MAD2B-mediated SnoN downregulation is implicated in fibroblast activation and tubulointerstitial fibrosis. American journal of physiology. Renal physiology 11 27122545
2015 Actin-cytoskeleton polymerization differentially controls the stability of Ski and SnoN co-repressors in normal but not in transformed hepatocytes. Biochimica et biophysica acta 11 26002202
2010 The crystal structure of the Dachshund domain of human SnoN reveals flexibility in the putative protein interaction surface. PloS one 11 20957027
2023 Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT-associated phenotypes in mammary organoids. Cell death & disease 10 37414747
2009 The expression of SnoN in normal human skin and cutaneous keratinous neoplasms. International journal of dermatology 10 19538364
2007 Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor beta signaling in scleroderma fibroblasts. Arthritis and rheumatism 10 17469184

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