{"gene":"SKI","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1999,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, overexpression in TGF-β-responsive cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, promoter binding assays, functional growth-arrest phenotype, replicated across multiple subsequent studies","pmids":["10485843"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Co-immunoprecipitation, reporter assays, Xenopus overexpression, mammalian cell differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP binding data, in vivo Xenopus rescue by BMP4, mammalian cell phenotype, independently reviewed/replicated","pmids":["11121043"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation, immunostaining, dominant-negative overexpression, antibody microinjection","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional dominant-negative assay in a single lab with two orthogonal methods","pmids":["11441023"],"is_preprint":false},{"year":1990,"finding":"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.","method":"DNA-cellulose binding assay, deletion mutagenesis, in vitro translation, specific antibody characterization","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro biochemical assay with deletion mutants, single lab","pmids":["2183181"],"is_preprint":false},{"year":1997,"finding":"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.","method":"SELEX, electrophoretic mobility shift assay (EMSA), co-immunoprecipitation, transcriptional reporter assays, dimerization mutant analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA + Co-IP + reporter assay + mutagenesis, single lab","pmids":["9380514"],"is_preprint":false},{"year":1998,"finding":"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.","method":"DNA binding site selection, EMSA, UV cross-linking, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA, cross-linking, and reporter assay in a single lab with multiple orthogonal methods","pmids":["9452486"],"is_preprint":false},{"year":1999,"finding":"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.","method":"In vitro translation/co-immunoprecipitation, in vivo co-immunoprecipitation, EMSA, transformation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo Co-IP plus EMSA and functional transformation assay in a single lab","pmids":["9927733"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation, reporter assays, genetic epistasis (double mutant mice), Ski-deficient fibroblasts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, reporter assay, genetic epistasis in vivo, and KO cell phenotype in a single rigorous study","pmids":["12435627"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation, reporter assays, GST pull-down","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pulldown with reporter assay, single lab","pmids":["12034730"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, reporter assays, overexpression in ski-/- melanocytes","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional reporter assay, single lab","pmids":["14583455"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Co-immunoprecipitation, reporter assays, dominant-negative mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, dominant-negative functional assay, single lab","pmids":["12874272"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Reporter assays, chromatin immunoprecipitation (ChIP), RNAi knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP on endogenous promoter, reporter assay, RNAi phenotype, multiple orthogonal methods in one rigorous study","pmids":["15128733"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro ubiquitination assay, in vivo overexpression/dominant-negative, immunoprecipitation, cell cycle synchronization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination assay plus in vivo dominant-negative functional data, single lab","pmids":["15122324"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Immunofluorescence microscopy, biochemical fractionation, in vitro kinase assay, cell cycle synchronization","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus immunofluorescence and biochemical fractionation, single lab","pmids":["15806149"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence, reporter assays, differentiation assays, mutant analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional differentiation assay, domain mutant, single lab","pmids":["16424870"],"is_preprint":false},{"year":2006,"finding":"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.","method":"NLS mutant analysis, subcellular fractionation, reporter assays, immunofluorescence, proteasome inhibitor treatment","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis-based NLS mapping, reporter assay, fractionation, single lab with multiple methods","pmids":["17054724"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Size-exclusion chromatography, isothermal titration calorimetry, mutational analysis of purified recombinant proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins using ITC and SEC plus mutagenesis, single lab","pmids":["17283070"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, tumor xenograft assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and functional RNAi data in a single lab","pmids":["19049980"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, cell proliferation assays, in vivo sciatic nerve analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD phenotype, in vivo localization, single lab","pmids":["18695043"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro kinase assay, site-directed mutagenesis, immunoprecipitation, cycloheximide chase, reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with specific mutation, in vivo phosphorylation confirmed, single lab","pmids":["19875456"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Reciprocal co-immunoprecipitation, truncation mutant analysis, protein stability assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutants, single lab","pmids":["20691163"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence, protein stability assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus stability assay, single lab","pmids":["19341714"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Adenoviral overexpression, immunoprecipitation, gel contraction assay, immunofluorescence, subcellular fractionation","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional phenotypic assay, localization data, single lab","pmids":["20943957"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, genetic knockout analysis, in utero electroporation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP at endogenous locus, and KO phenotype with axon-tracing in a single rigorous study","pmids":["22334647"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, siRNA/overexpression, gene expression assays, HDAC inhibitor rescue","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, gain/loss of function, pharmacological rescue, single lab","pmids":["22461172"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, reporter assays, siRNA/overexpression, xenograft tumor assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple Co-IPs, functional reporter assays, in vivo xenograft phenotype, multiple mechanisms tested in one study","pmids":["25670202"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Proteomic analysis, co-immunoprecipitation, ChIP, genetic deletion (SMAD4-/- and SKI overexpression), chromatin histone modification assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics, Co-IP, ChIP, and genetic rescue experiments with multiple orthogonal methods in a high-rigor study","pmids":["29072299"],"is_preprint":false},{"year":2018,"finding":"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.","method":"ChIP-seq, RNA-seq, CRISPR/shRNA deletion, reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus RNA-seq plus KO with multiple orthogonal methods in one study","pmids":["29471413"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Genetic KO (conditional CD4-Cre), in vitro differentiation assays, in vivo intestinal inflammation model","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with conditional KO models in vivo and in vitro, single lab","pmids":["34473197"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Structural biology (crystal structure of SKI-phospho-SMAD2 complex), genome-edited knock-in cell lines, biochemical binding assays, transcriptional response assays in patient fibroblasts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus genome-edited cells plus patient-derived fibroblast validation with multiple orthogonal methods","pmids":["33416497"],"is_preprint":false},{"year":2021,"finding":"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.","method":"BioID2 proximity labeling/mass spectrometry, siRNA knockdown, adenoviral overexpression, luciferase assays, in vivo post-MI rat model","journal":"Basic research in cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID2 interactomics plus functional siRNA/OE assays and in vivo model, single lab","pmids":["33847835"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Cryo-EM structural analysis of hSKI-80S ribosome-RNA complexes in multiple conformational states","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of multiple functional states with mechanistic interpretation, high-rigor single study","pmids":["35120588"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Pharmacological inhibition, genetic loss/gain of function, co-immunoprecipitation, ChIP, chromatin accessibility assay, orthotopic xenograft","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and in vivo xenograft data, single lab","pmids":["37598220"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Ski knockout mouse analysis, overexpression in myelin-competent cultures, gene expression profiling, co-immunoprecipitation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO animal phenotype plus OE rescue plus Co-IP partner identification in a single rigorous study","pmids":["15312649"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Competitive HSC transplantation, blastocyst complementation, single-cell splicing analysis, gene expression profiling","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo genetic models with phenotype readouts, single lab","pmids":["30249787"],"is_preprint":false}],"current_model":"SKI (c-Ski) is a nuclear transcriptional co-repressor that inhibits TGF-β/BMP/Smad signaling by directly binding phosphorylated R-Smads (Smad2/3) and Smad4, recruiting HDAC complexes and N-CoR to Smad-regulated promoters, competing with coactivators such as CBP, and repressing target genes including Smad7; it also suppresses Hippo/TAZ signaling via LATS2 activation, inhibits RARα and Gli3 signaling, cooperates with Satb2 and RUNX1 in chromatin-level gene repression, undergoes cell cycle-dependent degradation mediated by Cdc34 and Akt-driven phosphorylation at T458, and its structure bound to phospho-SMADs has been solved, revealing that SGS disease mutations abolish this interaction and stabilize SKI to attenuate TGF-β responses."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1990,"claim":"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","pmids":["2183181"],"confidence":"Medium","gaps":["Identity of the required partner proteins not determined","No physiological target promoter defined"]},{"year":1998,"claim":"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","pmids":["9452486"],"confidence":"Medium","gaps":["Cellular co-factors mediating sequence recognition not all identified","Element relevance to endogenous genes unclear"]},{"year":1999,"claim":"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","pmids":["10485843"],"confidence":"High","gaps":["Structural basis of Smad binding not resolved","Which target genes drive the growth phenotype not enumerated"]},{"year":2000,"claim":"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","pmids":["11121043"],"confidence":"High","gaps":["Whether BMP-Smad and TGF-β-Smad repression use identical co-repressor surfaces unresolved"]},{"year":2002,"claim":"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","pmids":["12435627"],"confidence":"High","gaps":["Direct contribution of HDAC recruitment to Gli3 repression in vivo not isolated"]},{"year":2004,"claim":"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)","pmids":["15128733","15312649"],"confidence":"High","gaps":["How basal vs signal-induced Smad7 repression is partitioned not fully resolved","Direct Oct6 mechanism in myelin gene control incomplete"]},{"year":2004,"claim":"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","pmids":["15122324"],"confidence":"Medium","gaps":["E3 ligase partnering Cdc34 not identified here","Degron sequence not mapped"]},{"year":2007,"claim":"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","pmids":["17283070"],"confidence":"High","gaps":["Full-length SKI-Smad complex structure not determined here","Cellular stoichiometry not validated"]},{"year":2009,"claim":"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","pmids":["19875456"],"confidence":"Medium","gaps":["Link between phosphorylation and a specific degradation machinery not established"]},{"year":2012,"claim":"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","pmids":["22334647"],"confidence":"High","gaps":["Generality of Satb2-NuRD recruitment to other loci not tested"]},{"year":2015,"claim":"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)","pmids":["25670202","33847835"],"confidence":"High","gaps":["Why TAZ but not YAP is selectively degraded not fully resolved","LATS2-independent degradation pathway mechanism undefined"]},{"year":2017,"claim":"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","pmids":["29072299"],"confidence":"High","gaps":["Identity of the degradation machinery not specified in this study"]},{"year":2018,"claim":"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","pmids":["29471413"],"confidence":"High","gaps":["Direct RUNX1-SKI contact surface not mapped","Whether HDAC recruitment underlies all silenced loci unclear"]},{"year":2021,"claim":"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","pmids":["33416497"],"confidence":"High","gaps":["How a stabilized, Smad-binding-deficient SKI dampens TGF-β output mechanistically not fully reconciled"]},{"year":2021,"claim":"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","pmids":["34473197"],"confidence":"Medium","gaps":["Direct Arkadia-SKI ubiquitination not biochemically reconstituted here"]},{"year":2022,"claim":"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","pmids":["35120588"],"confidence":"High","gaps":["Relationship between this complex's components and nuclear c-Ski co-repressor not addressed","Physiological consequence in human cells not tested here"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,11,25,27]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,22,31]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,11,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,11,23,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[23,27,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,28]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[31]}],"complexes":["N-CoR/HDAC co-repressor complex","NuRD complex","human SKI complex (hSKI)"],"partners":["SMAD2","SMAD3","SMAD4","SATB2","RUNX1","GLI3","SNON","LIMD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P12755","full_name":"Ski oncogene","aliases":["Proto-oncogene c-Ski"],"length_aa":728,"mass_kda":80.0,"function":"May play a role in terminal differentiation of skeletal muscle cells but not in the determination of cells to the myogenic lineage. Functions as a repressor of TGF-beta signaling","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P12755/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SKI","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SKI","total_profiled":1310},"omim":[{"mim_id":"621386","title":"VALENCE-FARAZI CEREBELLAR ATAXIA SYNDROME; VAFCAS","url":"https://www.omim.org/entry/621386"},{"mim_id":"619991","title":"LIVER DISEASE, SEVERE CONGENITAL; SCOLIV","url":"https://www.omim.org/entry/619991"},{"mim_id":"617138","title":"SKI FAMILY TRANSCRIPTIONAL COREPRESSOR 2; SKOR2","url":"https://www.omim.org/entry/617138"},{"mim_id":"616592","title":"KOSAKI OVERGROWTH SYNDROME; KOGS","url":"https://www.omim.org/entry/616592"},{"mim_id":"614606","title":"FOCADHESIN; FOCAD","url":"https://www.omim.org/entry/614606"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":103.1}],"url":"https://www.proteinatlas.org/search/SKI"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P12755","domains":[{"cath_id":"3.10.260.20","chopping":"93-192","consensus_level":"medium","plddt":89.1211,"start":93,"end":192},{"cath_id":"3.10.390.10","chopping":"193-198_208-311","consensus_level":"medium","plddt":84.4805,"start":193,"end":311},{"cath_id":"1.20.5","chopping":"571-646","consensus_level":"medium","plddt":94.8614,"start":571,"end":646}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12755","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12755-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12755-F1-predicted_aligned_error_v6.png","plddt_mean":65.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SKI","jax_strain_url":"https://www.jax.org/strain/search?query=SKI"},"sequence":{"accession":"P12755","fasta_url":"https://rest.uniprot.org/uniprotkb/P12755.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12755/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12755"}},"corpus_meta":[{"pmid":"10485843","id":"PMC_10485843","title":"The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling.","date":"1999","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10485843","citation_count":380,"is_preprint":false},{"pmid":"10852791","id":"PMC_10852791","title":"Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine.","date":"2000","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10852791","citation_count":243,"is_preprint":false},{"pmid":"19114989","id":"PMC_19114989","title":"Ski and SnoN, potent negative regulators of TGF-beta signaling.","date":"2009","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19114989","citation_count":227,"is_preprint":false},{"pmid":"11532933","id":"PMC_11532933","title":"Ski7p G protein interacts with the exosome and the Ski complex for 3'-to-5' mRNA decay in yeast.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11532933","citation_count":184,"is_preprint":false},{"pmid":"11312113","id":"PMC_11312113","title":"Ski/Sno and TGF-beta signaling.","date":"2001","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11312113","citation_count":178,"is_preprint":false},{"pmid":"2762147","id":"PMC_2762147","title":"Isolation of human cDNA clones of ski and the ski-related gene, sno.","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2762147","citation_count":166,"is_preprint":false},{"pmid":"11441023","id":"PMC_11441023","title":"The Ski protein family is required for MeCP2-mediated transcriptional repression.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11441023","citation_count":164,"is_preprint":false},{"pmid":"23953113","id":"PMC_23953113","title":"The yeast ski complex: crystal structure and RNA channeling to the exosome complex.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23953113","citation_count":151,"is_preprint":false},{"pmid":"18483306","id":"PMC_18483306","title":"SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells.","date":"2008","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18483306","citation_count":127,"is_preprint":false},{"pmid":"19339499","id":"PMC_19339499","title":"A homolog of human ski-interacting protein in rice positively regulates cell viability and stress tolerance.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19339499","citation_count":117,"is_preprint":false},{"pmid":"10816641","id":"PMC_10816641","title":"The subtilisin/kexin family of precursor convertases. 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PELO.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39910293","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47283,"output_tokens":7950,"usd":0.13055,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17582,"output_tokens":5231,"usd":0.109342,"stage2_stop_reason":"end_turn"},"total_usd":0.239892,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, overexpression in TGF-β-responsive cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, promoter binding assays, functional growth-arrest phenotype, replicated across multiple subsequent studies\",\n      \"pmids\": [\"10485843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, Xenopus overexpression, mammalian cell differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP binding data, in vivo Xenopus rescue by BMP4, mammalian cell phenotype, independently reviewed/replicated\",\n      \"pmids\": [\"11121043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunostaining, dominant-negative overexpression, antibody microinjection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional dominant-negative assay in a single lab with two orthogonal methods\",\n      \"pmids\": [\"11441023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"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.\",\n      \"method\": \"DNA-cellulose binding assay, deletion mutagenesis, in vitro translation, specific antibody characterization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro biochemical assay with deletion mutants, single lab\",\n      \"pmids\": [\"2183181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"SELEX, electrophoretic mobility shift assay (EMSA), co-immunoprecipitation, transcriptional reporter assays, dimerization mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA + Co-IP + reporter assay + mutagenesis, single lab\",\n      \"pmids\": [\"9380514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"DNA binding site selection, EMSA, UV cross-linking, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA, cross-linking, and reporter assay in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9452486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro translation/co-immunoprecipitation, in vivo co-immunoprecipitation, EMSA, transformation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo Co-IP plus EMSA and functional transformation assay in a single lab\",\n      \"pmids\": [\"9927733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, genetic epistasis (double mutant mice), Ski-deficient fibroblasts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, reporter assay, genetic epistasis in vivo, and KO cell phenotype in a single rigorous study\",\n      \"pmids\": [\"12435627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, GST pull-down\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pulldown with reporter assay, single lab\",\n      \"pmids\": [\"12034730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, reporter assays, overexpression in ski-/- melanocytes\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by Co-IP, functional reporter assay, single lab\",\n      \"pmids\": [\"14583455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, dominant-negative mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, dominant-negative functional assay, single lab\",\n      \"pmids\": [\"12874272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter assays, chromatin immunoprecipitation (ChIP), RNAi knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP on endogenous promoter, reporter assay, RNAi phenotype, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"15128733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ubiquitination assay, in vivo overexpression/dominant-negative, immunoprecipitation, cell cycle synchronization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination assay plus in vivo dominant-negative functional data, single lab\",\n      \"pmids\": [\"15122324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence microscopy, biochemical fractionation, in vitro kinase assay, cell cycle synchronization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus immunofluorescence and biochemical fractionation, single lab\",\n      \"pmids\": [\"15806149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, reporter assays, differentiation assays, mutant analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional differentiation assay, domain mutant, single lab\",\n      \"pmids\": [\"16424870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"NLS mutant analysis, subcellular fractionation, reporter assays, immunofluorescence, proteasome inhibitor treatment\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-based NLS mapping, reporter assay, fractionation, single lab with multiple methods\",\n      \"pmids\": [\"17054724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Size-exclusion chromatography, isothermal titration calorimetry, mutational analysis of purified recombinant proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins using ITC and SEC plus mutagenesis, single lab\",\n      \"pmids\": [\"17283070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, tumor xenograft assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and functional RNAi data in a single lab\",\n      \"pmids\": [\"19049980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, cell proliferation assays, in vivo sciatic nerve analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD phenotype, in vivo localization, single lab\",\n      \"pmids\": [\"18695043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, immunoprecipitation, cycloheximide chase, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with specific mutation, in vivo phosphorylation confirmed, single lab\",\n      \"pmids\": [\"19875456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, truncation mutant analysis, protein stability assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutants, single lab\",\n      \"pmids\": [\"20691163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, protein stability assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus stability assay, single lab\",\n      \"pmids\": [\"19341714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Adenoviral overexpression, immunoprecipitation, gel contraction assay, immunofluorescence, subcellular fractionation\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional phenotypic assay, localization data, single lab\",\n      \"pmids\": [\"20943957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, genetic knockout analysis, in utero electroporation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP at endogenous locus, and KO phenotype with axon-tracing in a single rigorous study\",\n      \"pmids\": [\"22334647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/overexpression, gene expression assays, HDAC inhibitor rescue\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, gain/loss of function, pharmacological rescue, single lab\",\n      \"pmids\": [\"22461172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, siRNA/overexpression, xenograft tumor assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple Co-IPs, functional reporter assays, in vivo xenograft phenotype, multiple mechanisms tested in one study\",\n      \"pmids\": [\"25670202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, ChIP, genetic deletion (SMAD4-/- and SKI overexpression), chromatin histone modification assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics, Co-IP, ChIP, and genetic rescue experiments with multiple orthogonal methods in a high-rigor study\",\n      \"pmids\": [\"29072299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, RNA-seq, CRISPR/shRNA deletion, reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus RNA-seq plus KO with multiple orthogonal methods in one study\",\n      \"pmids\": [\"29471413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic KO (conditional CD4-Cre), in vitro differentiation assays, in vivo intestinal inflammation model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with conditional KO models in vivo and in vitro, single lab\",\n      \"pmids\": [\"34473197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Structural biology (crystal structure of SKI-phospho-SMAD2 complex), genome-edited knock-in cell lines, biochemical binding assays, transcriptional response assays in patient fibroblasts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus genome-edited cells plus patient-derived fibroblast validation with multiple orthogonal methods\",\n      \"pmids\": [\"33416497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"BioID2 proximity labeling/mass spectrometry, siRNA knockdown, adenoviral overexpression, luciferase assays, in vivo post-MI rat model\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID2 interactomics plus functional siRNA/OE assays and in vivo model, single lab\",\n      \"pmids\": [\"33847835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structural analysis of hSKI-80S ribosome-RNA complexes in multiple conformational states\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of multiple functional states with mechanistic interpretation, high-rigor single study\",\n      \"pmids\": [\"35120588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition, genetic loss/gain of function, co-immunoprecipitation, ChIP, chromatin accessibility assay, orthotopic xenograft\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and in vivo xenograft data, single lab\",\n      \"pmids\": [\"37598220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Ski knockout mouse analysis, overexpression in myelin-competent cultures, gene expression profiling, co-immunoprecipitation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO animal phenotype plus OE rescue plus Co-IP partner identification in a single rigorous study\",\n      \"pmids\": [\"15312649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Competitive HSC transplantation, blastocyst complementation, single-cell splicing analysis, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo genetic models with phenotype readouts, single lab\",\n      \"pmids\": [\"30249787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SKI (c-Ski) is a nuclear transcriptional co-repressor that inhibits TGF-β/BMP/Smad signaling by directly binding phosphorylated R-Smads (Smad2/3) and Smad4, recruiting HDAC complexes and N-CoR to Smad-regulated promoters, competing with coactivators such as CBP, and repressing target genes including Smad7; it also suppresses Hippo/TAZ signaling via LATS2 activation, inhibits RARα and Gli3 signaling, cooperates with Satb2 and RUNX1 in chromatin-level gene repression, undergoes cell cycle-dependent degradation mediated by Cdc34 and Akt-driven phosphorylation at T458, and its structure bound to phospho-SMADs has been solved, revealing that SGS disease mutations abolish this interaction and stabilize SKI to attenuate TGF-β responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #11]. 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 [#0]; it similarly represses BMP-specific Smad1/Smad4 complexes to influence neural specification and osteoblast differentiation [#1]. 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 [#16]. 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 [#11]. SKI extends this co-repressor logic beyond canonical Smad signaling, binding Gli3 to support Shh/Gli repression [#7], cooperating with Satb2 to recruit NuRD/HDAC complexes and silence Ctip2 during corpus callosum formation [#23], and acting as a genome-wide co-repressor for RUNX1 at myeloid enhancers [#27]. SKI also restrains Hippo signaling, promoting LATS2-mediated phosphorylation and degradation of TAZ and recruiting NCoR1 to repress TEAD-dependent transcription [#25, #30]. 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 [#12, #19, #28]. In immune differentiation, TGF-β-induced SKI degradation relieves SKI-SMAD4-mediated repression of the Rorc locus to permit Th17 differentiation [#26]. SKI mutations cause Shprintzen-Goldberg syndrome: disease mutations abolish SKI binding to phospho-SMAD2/3, stabilizing SKI and attenuating TGF-β transcriptional responses [#29]. 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 [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"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.\",\n      \"evidence\": \"DNA-cellulose binding and deletion mutagenesis of in vitro-translated Ski\",\n      \"pmids\": [\"2183181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the required partner proteins not determined\", \"No physiological target promoter defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"DNA binding-site selection, EMSA, UV cross-linking, and reporter assays\",\n      \"pmids\": [\"9452486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular co-factors mediating sequence recognition not all identified\", \"Element relevance to endogenous genes unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, and reporter assays in TGF-β-responsive cells\",\n      \"pmids\": [\"10485843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Smad binding not resolved\", \"Which target genes drive the growth phenotype not enumerated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Extended SKI repression to BMP-specific Smad1/4 complexes, establishing it as a pan-TGF-β-superfamily antagonist with developmental consequences.\",\n      \"evidence\": \"Co-IP, reporter assays, Xenopus overexpression and mammalian differentiation assays\",\n      \"pmids\": [\"11121043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BMP-Smad and TGF-β-Smad repression use identical co-repressor surfaces unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, reporter assays, Gli3/Ski double-mutant mice, and Ski-deficient fibroblasts\",\n      \"pmids\": [\"12435627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of HDAC recruitment to Gli3 repression in vivo not isolated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP, reporter, and RNAi for Smad7 (15128733); Ski knockout mice, overexpression, and Oct6 Co-IP for myelination (15312649)\",\n      \"pmids\": [\"15128733\", \"15312649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How basal vs signal-induced Smad7 repression is partitioned not fully resolved\", \"Direct Oct6 mechanism in myelin gene control incomplete\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealed that SKI levels are regulated by cell cycle-dependent ubiquitin-mediated degradation, coupling its co-repressor output to proliferative state.\",\n      \"evidence\": \"In vitro ubiquitination, dominant-negative Cdc34, and cell-cycle synchronization\",\n      \"pmids\": [\"15122324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase partnering Cdc34 not identified here\", \"Degron sequence not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"SEC, ITC, and mutational analysis of purified recombinant proteins\",\n      \"pmids\": [\"17283070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length SKI-Smad complex structure not determined here\", \"Cellular stoichiometry not validated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro kinase assay, T458 mutagenesis, cycloheximide chase, and reporter assays\",\n      \"pmids\": [\"19875456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between phosphorylation and a specific degradation machinery not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ChIP, Ski knockout, and in utero electroporation\",\n      \"pmids\": [\"22334647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of Satb2-NuRD recruitment to other loci not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SKI as a suppressor of Hippo effectors TAZ/YAP, broadening its tumor-suppressive repressor activity to LATS2 activation and TEAD-NCoR1 transcriptional repression.\",\n      \"evidence\": \"Co-IP, reporter assays, siRNA/overexpression, and xenografts (25670202); BioID2, LIMD1 interaction, and post-MI model (33847835)\",\n      \"pmids\": [\"25670202\", \"33847835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why TAZ but not YAP is selectively degraded not fully resolved\", \"LATS2-independent degradation pathway mechanism undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomics, Co-IP, ChIP, and SMAD4/SKI genetic perturbation with histone-modification assays\",\n      \"pmids\": [\"29072299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the degradation machinery not specified in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genome-wide mapping established SKI as a co-repressor co-occupying RUNX1 enhancers in AML, defining a chromatin-scale role in myeloid differentiation control.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, CRISPR/shRNA deletion, and reporter assays\",\n      \"pmids\": [\"29471413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RUNX1-SKI contact surface not mapped\", \"Whether HDAC recruitment underlies all silenced loci unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"SKI-phospho-SMAD2 crystal structure, genome-edited knock-in cells, and patient fibroblast transcriptional assays\",\n      \"pmids\": [\"33416497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a stabilized, Smad-binding-deficient SKI dampens TGF-β output mechanistically not fully reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional CD4-Cre knockouts, in vitro differentiation, and intestinal inflammation model\",\n      \"pmids\": [\"34473197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Arkadia-SKI ubiquitination not biochemically reconstituted here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM of hSKI-80S ribosome-RNA complexes in multiple conformational states\",\n      \"pmids\": [\"35120588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between this complex's components and nuclear c-Ski co-repressor not addressed\", \"Physiological consequence in human cells not tested here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 11, 25, 27]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 22, 31]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 11, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 11, 23, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [23, 27, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 28]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [31]}\n    ],\n    \"complexes\": [\"N-CoR/HDAC co-repressor complex\", \"NuRD complex\", \"human SKI complex (hSKI)\"],\n    \"partners\": [\"SMAD2\", \"SMAD3\", \"SMAD4\", \"SATB2\", \"RUNX1\", \"GLI3\", \"SNON\", \"LIMD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":10,"faith_pct":90.0}}