{"gene":"SVIL","run_date":"2026-04-28T21:42:57","timeline":{"discoveries":[{"year":1998,"finding":"Human supervillin (SVIL) is a 205-kDa F-actin binding protein that is tightly associated with both actin filaments and plasma membranes, forming a high-affinity link between the actin cytoskeleton and the membrane. The protein has a bipartite structure: the NH2-terminus contains three potential nuclear localization signals, while the COOH-terminus contains three potential actin-binding sequences and shares extensive homology with segments 2–6 plus the headpiece of villin. The gene maps to a single chromosomal locus at 10p11.2.","method":"cDNA cloning and sequence analysis, chromosomal localization, expression profiling across human tissues","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1–2 — original cloning with full sequence characterization, domain mapping, and chromosomal localization; strong foundational study","pmids":["9867483"],"is_preprint":false},{"year":2001,"finding":"Supervillin was identified as a component of the P2X7 receptor signalling complex in human embryonic kidney cells, co-purifying with the P2X7 receptor by affinity purification followed by mass spectrometry and immunoblotting, suggesting a role in cytoskeletal rearrangements (membrane blebbing) downstream of P2X7 receptor activation.","method":"Affinity purification followed by mass spectrometry and immunoblotting","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — identified by AP-MS and confirmed by immunoblot; single study, interaction context well-defined","pmids":["11707406"],"is_preprint":false},{"year":2002,"finding":"Supervillin co-isolates with cholesterol-rich, detergent-resistant membrane fragments (DRM-H) from the bovine neutrophil plasma membrane skeleton, resists extraction by sodium carbonate (which removes all actin), and localizes with F-actin in cell extensions and discrete basal puncta that partially overlap with Gαi staining. Co-immunoaffinity purification confirmed supervillin binding to DRM-H fragments, indicating supervillin is proximal to the lipid bilayer in leukocyte signalling domains.","method":"Sucrose density gradient fractionation, MALDI-TOF and tandem MS, sodium carbonate extraction, co-immunoaffinity purification, immunofluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (fractionation, MS, co-IP, imaging) in a single rigorous study","pmids":["12202484"],"is_preprint":false},{"year":2004,"finding":"Supervillin was identified as a 14-3-3 binding partner in HEK293 cells, placing it within a large group of cytoskeletal regulators whose interactions with 14-3-3 proteins are phosphorylation-dependent and important for controlling cellular morphology and membrane dynamics.","method":"Mass spectrometry-based proteomic analysis of 14-3-3 immunoprecipitates from HEK293 cells","journal":"Current biology : CB","confidence":"Low","confidence_rationale":"Tier 3 — single large-scale AP-MS screen; supervillin interaction not individually validated","pmids":["15324660"],"is_preprint":false},{"year":2011,"finding":"Supervillin was identified in the myosin-II-responsive focal adhesion proteome; its abundance in focal adhesions was enhanced by myosin II contractility, linking supervillin to tension-dependent focal adhesion maturation.","method":"Quantitative proteomic analysis of isolated focal adhesions with and without myosin II inhibition (blebbistatin treatment)","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative proteomics with pharmacological perturbation; supervillin not individually validated but part of a rigorous dataset","pmids":["21423176"],"is_preprint":false},{"year":2013,"finding":"SVIL is a substrate of PLK1 (polo-like kinase 1); PLK1 phosphorylates Ser238 of SVIL during mitosis, which promotes SVIL localization to the central spindle and its association with PRC1. Phosphorylated SVIL acts as a molecular link between the central spindle and the contractile ring. Expression of the phosphorylation-deficient S238A-SVIL mutant inhibits myosin II activation at the equatorial cortex and causes aberrant furrowing. The N-terminal myosin-II-binding region (but not the actin-binding region) of SVIL is required for myosin II activation and normal cytokinetic furrowing.","method":"In vitro kinase assay, phosphorylation-site mutagenesis, co-immunoprecipitation, live-cell imaging, expression of deletion mutants with phenotypic analysis of cytokinesis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay plus mutagenesis plus cellular phenotypic rescue in a single study with multiple orthogonal methods","pmids":["23750008"],"is_preprint":false},{"year":2015,"finding":"SVIL interacts with LSD1+8a (an alternatively spliced isoform of LSD1/KDM1A) and functions as a cofactor enabling LSD1+8a to demethylate H3K9me2 (but not H3K4me2) at target promoters. SVIL co-localizes to LSD1+8a-bound promoters in neuronal cells, and SVIL knockdown mimics the effect of LSD1+8a loss—increasing H3K9me2 at target promoters and compromising neuronal differentiation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi knockdown with histone modification analysis, neuronal differentiation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and functional KD with orthogonal readouts in a single study; replicated by multiple methods","pmids":["25684206"],"is_preprint":false},{"year":2022,"finding":"Somatic variants in SVIL are found in ~17% of saccular cerebral aneurysm tissues and are associated with reduced SVIL expression. CRISPR/Cas9-mediated knockdown of SVIL in vascular smooth muscle cells (vSMCs) induces phenotypic modulation to a synthetic phenotype via KLF4 and PDGF signalling, and impairs cell migration via the RhoA/ROCK pathway.","method":"Whole-exome sequencing of matched aneurysm/blood tissue, RNA sequencing, CRISPR/Cas9 knockdown in vSMCs, gene expression profiling, protein kinase phosphorylation analysis","journal":"Neurology. Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with pathway-level readouts (RhoA/ROCK, KLF4/PDGF), but pathway placement based on expression changes without full epistasis","pmids":["36475054"],"is_preprint":false},{"year":2024,"finding":"SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition (EMT) under hypoxic conditions by activating the TGFβ1/Smad2/3 signalling pathway; SVIL knockdown inhibits TGFβ1/Smad2/3 pathway activation, attenuates EMT and cancer progression, and increases cisplatin-induced apoptosis in cellular and in vivo mouse models.","method":"siRNA knockdown, CCK8 proliferation assay, wound-healing and Transwell migration assays, Western blot for Smad2/3 phosphorylation, apoptosis assay, nude mouse in situ tumor model","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with defined pathway readout (Smad2/3 phosphorylation) and in vivo validation, but no direct biochemical interaction demonstrated","pmids":["39197416"],"is_preprint":false}],"current_model":"Supervillin (SVIL) is a large (205 kDa) F-actin- and myosin-II-binding membrane-skeletal protein that links the actin cytoskeleton to the plasma membrane; during mitosis it is phosphorylated on Ser238 by PLK1, which localizes it to the central spindle where it bridges the spindle and contractile ring to activate myosin II for cytokinetic furrowing; in interphase it resides in cholesterol-rich membrane raft fractions and myosin-II-responsive focal adhesions; in neurons it acts as a cofactor for the LSD1+8a isoform to mediate H3K9me2 demethylation at target promoters, supporting neuronal differentiation; and in vascular smooth muscle cells its loss activates RhoA/ROCK-dependent phenotypic switching and impaired migration, while in cancer contexts it promotes TGFβ1/Smad2/3-dependent EMT."},"narrative":{"teleology":[{"year":1998,"claim":"Molecular cloning of SVIL established its identity as a novel 205-kDa protein that simultaneously binds F-actin and the plasma membrane, resolving how the cortical cytoskeleton could be anchored directly to the bilayer through a single polypeptide.","evidence":"cDNA cloning, sequence/domain analysis, and chromosomal mapping in human tissues","pmids":["9867483"],"confidence":"High","gaps":["No binding-site mapping for the membrane association","Functional consequence of nuclear localization signals untested"]},{"year":2002,"claim":"Biochemical fractionation demonstrated that supervillin is an intrinsic component of cholesterol-rich, detergent-resistant membrane raft domains rather than simply a peripheral actin-associated protein, establishing a membrane-proximal signalling role.","evidence":"Sucrose gradient fractionation, sodium carbonate extraction, co-immunoaffinity purification, and immunofluorescence in bovine neutrophils","pmids":["12202484"],"confidence":"High","gaps":["Lipid-binding determinant within supervillin not identified","Functional consequence of raft association not tested"]},{"year":2011,"claim":"Quantitative focal adhesion proteomics revealed that supervillin accumulation at focal adhesions is myosin-II-dependent, linking the protein to mechanotransduction at cell–matrix contacts.","evidence":"Quantitative proteomics of isolated focal adhesions ± blebbistatin in fibroblasts","pmids":["21423176"],"confidence":"Medium","gaps":["Supervillin not individually validated in focal adhesions by imaging","Mechanism of myosin-II-dependent recruitment unknown"]},{"year":2013,"claim":"Identification of SVIL as a PLK1 substrate phosphorylated at Ser238 during mitosis resolved how the contractile ring communicates with the central spindle: phospho-SVIL bridges PRC1 on spindle midzone microtubules and myosin II at the cortex, and a phospho-dead mutant causes aberrant furrowing.","evidence":"In vitro kinase assay, S238A mutagenesis, co-immunoprecipitation with PRC1, live-cell imaging of cytokinesis defects","pmids":["23750008"],"confidence":"High","gaps":["Structural basis of SVIL–PRC1 interaction not determined","Whether SVIL is required for all cell types' cytokinesis unknown","Additional PLK1-dependent phosphosites not explored"]},{"year":2015,"claim":"Discovery that SVIL serves as a chromatin-associated cofactor for the neuron-specific LSD1+8a demethylase expanded its functions beyond the cytoskeleton, showing it directs H3K9me2 demethylation at specific promoters required for neuronal differentiation.","evidence":"Reciprocal co-immunoprecipitation, ChIP for H3K9me2 at target promoters, RNAi knockdown with differentiation assays in neuronal cells","pmids":["25684206"],"confidence":"High","gaps":["Domain within SVIL that contacts LSD1+8a not mapped","Whether SVIL nuclear entry uses its predicted NLS sequences not tested","Genome-wide promoter targets not catalogued"]},{"year":2022,"claim":"CRISPR knockout of SVIL in vascular smooth muscle cells showed that SVIL loss drives phenotypic switching to a synthetic state via KLF4/PDGF and impairs migration through RhoA/ROCK, providing a functional link to vascular pathology observed in cerebral aneurysm tissues carrying somatic SVIL variants.","evidence":"Whole-exome sequencing of aneurysm tissues, CRISPR/Cas9 KO in vSMCs, RNA-seq, phospho-kinase profiling","pmids":["36475054"],"confidence":"Medium","gaps":["Epistasis experiments for RhoA/ROCK pathway not performed","Whether SVIL loss is causal for aneurysm formation in vivo not established","Mechanism by which SVIL constrains RhoA activity unknown"]},{"year":2024,"claim":"SVIL was shown to promote ovarian cancer EMT under hypoxia by activating TGFβ1/Smad2/3 signalling, with knockdown sensitizing tumors to cisplatin, revealing a pro-tumorigenic role through a defined signalling axis.","evidence":"siRNA knockdown, Smad2/3 phosphorylation Western blot, Transwell migration, nude mouse xenograft model","pmids":["39197416"],"confidence":"Medium","gaps":["No direct biochemical interaction between SVIL and TGFβ pathway components demonstrated","Mechanism linking SVIL to Smad2/3 phosphorylation not resolved","Generalizability to other cancer types untested"]},{"year":null,"claim":"How SVIL's cytoskeletal scaffolding and nuclear/chromatin functions are coordinated — including the signals that govern its partitioning between membrane rafts, focal adhesions, the central spindle, and chromatin — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length supervillin exists","Regulation of nuclear vs. cytoplasmic localization not characterized","Whether the membrane-anchoring and LSD1-cofactor roles are cell-type-exclusive or concurrent is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]}],"complexes":[],"partners":["PLK1","PRC1","KDM1A","MYH9","P2RX7"],"other_free_text":[]},"mechanistic_narrative":"Supervillin (SVIL) is a large membrane-skeletal protein that bridges the actin cytoskeleton and the plasma membrane, functioning in cytokinesis, focal adhesion dynamics, chromatin regulation, and vascular smooth muscle cell homeostasis. Its N-terminus contains nuclear localization signals and a myosin-II-binding region, while the C-terminus harbors F-actin-binding sequences homologous to villin; the protein resides in cholesterol-rich detergent-resistant membrane domains and tension-responsive focal adhesions [PMID:9867483, PMID:12202484, PMID:21423176]. During mitosis, PLK1 phosphorylates SVIL at Ser238, directing it to the central spindle where it associates with PRC1 and activates myosin II at the equatorial cortex to drive cytokinetic furrowing [PMID:23750008]. In neurons, SVIL acts as a cofactor for the LSD1+8a histone demethylase, enabling H3K9me2 removal at target promoters to support neuronal differentiation [PMID:25684206]."},"prefetch_data":{"uniprot":{"accession":"O95425","full_name":"Supervillin","aliases":["Archvillin","p205/p250"],"length_aa":2214,"mass_kda":247.7,"function":"Forms a high-affinity link between the actin cytoskeleton and the membrane. Is among the first costameric proteins to assemble during myogenesis and it contributes to myogenic membrane structure and differentiation (PubMed:12711699). Appears to be involved in myosin II assembly. May modulate myosin II regulation through MLCK during cell spreading, an initial step in cell migration. May play a role in invadopodial function (PubMed:19109420). In addition to its cytoskeletal activities, acts as a cofactor or scaffold for KDM1A, facilitating H3K9me2 demethylation and promoting gene activation, especially in neuronal contexts (PubMed:25684206) May be involved in modulation of focal adhesions. Supervillin-mediated down-regulation of focal adhesions involves binding to TRIP6. Plays a role in cytokinesis through KIF14 interaction (By similarity)","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton; Cell projection, invadopodium; Cell projection, podosome; Midbody; Cleavage furrow","url":"https://www.uniprot.org/uniprotkb/O95425/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SVIL","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000197321","cell_line_id":"CID001935","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SPAST","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001935","total_profiled":1310},"omim":[{"mim_id":"619040","title":"MYOFIBRILLAR MYOPATHY 10; MFM10","url":"https://www.omim.org/entry/619040"},{"mim_id":"604126","title":"SUPERVILLIN; SVIL","url":"https://www.omim.org/entry/604126"},{"mim_id":"601419","title":"MYOPATHY, MYOFIBRILLAR, 1; MFM1","url":"https://www.omim.org/entry/601419"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":750.5},{"tissue":"tongue","ntpm":518.7}],"url":"https://www.proteinatlas.org/search/SVIL"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95425","domains":[{"cath_id":"3.40.20.10","chopping":"1436-1678","consensus_level":"medium","plddt":90.5858,"start":1436,"end":1678},{"cath_id":"3.40.20.10","chopping":"1861-1994","consensus_level":"medium","plddt":93.1962,"start":1861,"end":1994},{"cath_id":"3.40.20.10","chopping":"2000-2148","consensus_level":"medium","plddt":87.0789,"start":2000,"end":2148},{"cath_id":"1.10.950.10","chopping":"2155-2214","consensus_level":"medium","plddt":86.2138,"start":2155,"end":2214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95425","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95425-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95425-F1-predicted_aligned_error_v6.png","plddt_mean":53.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SVIL","jax_strain_url":"https://www.jax.org/strain/search?query=SVIL"},"sequence":{"accession":"O95425","fasta_url":"https://rest.uniprot.org/uniprotkb/O95425.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95425/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95425"}},"corpus_meta":[{"pmid":"9867483","id":"PMC_9867483","title":"Cloning, characterization, and chromosomal localization of human superillin (SVIL).","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9867483","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23750008","id":"PMC_23750008","title":"The role of PLK1-phosphorylated SVIL in myosin II activation and cytokinetic furrowing.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23750008","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35068325","id":"PMC_35068325","title":"N6-methyladenosine-induced SVIL antisense RNA 1 restrains lung adenocarcinoma cell proliferation by destabilizing E2F1.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35068325","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39197416","id":"PMC_39197416","title":"SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions through the TGF-β/Smad pathway.","date":"2024","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39197416","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40135844","id":"PMC_40135844","title":"AKT1E17K-Interacting lncRNA SVIL-AS1 Promotes AKT1 Oncogenic Functions by Preferentially Blocking AKT1E17K Dephosphorylation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40135844","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39113865","id":"PMC_39113865","title":"Engineered exosomes transporting the lncRNA, SVIL-AS1, inhibit the progression of lung cancer via targeting miR-21-5p.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39113865","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36475054","id":"PMC_36475054","title":"Somatic Variants in SVIL in Cerebral Aneurysms.","date":"2022","source":"Neurology. 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American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/19047128","citation_count":195,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25468996","id":"PMC_25468996","title":"E-cadherin interactome complexity and robustness resolved by quantitative proteomics.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25468996","citation_count":162,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36217030","id":"PMC_36217030","title":"A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.","date":"2022","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36217030","citation_count":140,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16385451","id":"PMC_16385451","title":"A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16385451","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30425250","id":"PMC_30425250","title":"Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30425250","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6986,"output_tokens":965,"usd":0.017716},"stage2":{"model":"claude-opus-4-6","input_tokens":4153,"output_tokens":1332,"usd":0.081098},"total_usd":0.280449,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":19465,"output_tokens":3707,"usd":0.057},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6093,"output_tokens":2105,"usd":0.124635}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human supervillin (SVIL) is a 205-kDa F-actin binding protein that is tightly associated with both actin filaments and plasma membranes, forming a high-affinity link between the actin cytoskeleton and the membrane. It has a bipartite structure with potential nuclear localization signals in the NH2-terminus and actin-binding sequences in the COOH-terminus, the latter sharing homology with villin segments 2-6 and headpiece.\",\n      \"method\": \"cDNA cloning, sequence analysis, biochemical fractionation showing co-isolation with actin filaments and membranes\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original biochemical characterization with sequence-domain mapping and fractionation, foundational paper with 43 citations\",\n      \"pmids\": [\"9867483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PLK1 phosphorylates SVIL at Ser238, which promotes SVIL localization to the central spindle and its association with PRC1. Phosphorylated SVIL acts as a molecular link between the central spindle and the contractile ring. SVIL's myosin-II-binding region (not its actin-binding region) is required for myosin II activation at the equatorial cortex and proper cleavage furrow ingression during cytokinesis.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis (S238A), deletion mutants (ΔMyo-SVIL, ΔAct-SVIL), co-immunoprecipitation with PRC1, live-cell imaging of furrowing defects\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase assay with mutagenesis, domain deletions, localization experiments, and functional cytokinesis readout; moderate citation count\",\n      \"pmids\": [\"23750008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of SVIL in vascular smooth muscle cells (vSMCs) via CRISPR/Cas9 induces phenotypic modulation to the synthetic phenotype via Krüppel-like factor 4 (KLF4) and platelet-derived growth factor (PDGF) signaling, and impairs vSMC migration via the RhoA/ROCK pathway.\",\n      \"method\": \"CRISPR/Cas9 knockdown in vSMCs, gene expression profiling, protein kinase phosphorylation analysis, functional migration assays\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with pathway-level readouts in a defined cell type, but single study with moderate citation count\",\n      \"pmids\": [\"36475054\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SVIL (supervillin) is a membrane-associated F-actin binding protein that links the actin cytoskeleton to the plasma membrane via its N-terminal membrane-binding and myosin-II-binding domains and C-terminal villin-like actin-binding domains; during cytokinesis, PLK1-mediated phosphorylation at Ser238 directs SVIL to the central spindle where it associates with PRC1 and activates myosin II at the equatorial cortex to drive cleavage furrow ingression, while in vascular smooth muscle cells SVIL regulates phenotypic identity and migration through KLF4/PDGF and RhoA/ROCK pathways.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:9867483 — KEEP (canonical SVIL protein cloning/characterization)\n2. PMID:23750008 — KEEP (canonical SVIL, PLK1 phosphorylation, cytokinesis)\n3. PMID:35068325 — EXCLUDE (case B: alt-locus product, SVIL-AS1 lncRNA)\n4. PMID:39197416 — KEEP (canonical SVIL protein in ovarian cancer, TGFβ pathway)\n5. PMID:40135844 — EXCLUDE (case B: alt-locus product, SVIL-AS1 lncRNA)\n6. PMID:39113865 — EXCLUDE (case B: alt-locus product, SVIL-AS1 lncRNA)\n7. PMID:36475054 — KEEP (canonical SVIL, vSMC phenotype, RhoA/ROCK pathway)\n8. PMID:32582973 — EXCLUDE (epigenetic/methylation association study, no mechanistic finding about SVIL protein)\n9. bio_10.1101_2025.08.10.669560 — EXCLUDE (expression correlation only)\n10. bio_10.1101_2025.05.05.652238 — EXCLUDE (expression/transcriptomics, no SVIL mechanism)\n11. bio_10.1101_2024.06.24.600323 — EXCLUDE (describes bird-specific SVIL+ Purkinje cell subtype, symbol collision context)\n\nAdditional curated papers — checking for SVIL-specific mechanistic content:\n- PMID:17081983 — EXCLUDE (large phosphoproteomics, no SVIL-specific mechanism)\n- PMID:16169070 — EXCLUDE (large Y2H screen, no SVIL-specific mechanism extracted)\n- PMID:12477932 — EXCLUDE (cDNA sequencing resource)\n- PMID:15302935 — EXCLUDE (large phosphoproteomics)\n- PMID:26186194 — EXCLUDE (large interactome, no SVIL-specific mechanism)\n- PMID:28514442 — EXCLUDE (large interactome)\n- PMID:26496610 — EXCLUDE (large interactome)\n- PMID:29507755 — EXCLUDE (m6A/VIRMA, no SVIL protein mechanism)\n- PMID:14702039 — EXCLUDE (cDNA sequencing resource)\n- PMID:22939629 — EXCLUDE (large proteomics)\n- PMID:21873635 — EXCLUDE (GO annotation methodology)\n- PMID:17110338 — EXCLUDE (CFTR/Hsp90, no SVIL)\n- PMID:21423176 — KEEP (identifies supervillin in focal adhesion proteome, myosin-II-responsive)\n- PMID:26638075 — EXCLUDE (centrosome/cilium BioID, no SVIL-specific mechanism)\n- PMID:35271311 — EXCLUDE (large proteome cartography)\n- PMID:20360068 — EXCLUDE (chromosome segregation complexes, no SVIL-specific mechanism)\n- PMID:15324660 — KEEP (14-3-3 interactome identifies supervillin)\n- PMID:19010793 — EXCLUDE (MS GWAS, no SVIL mechanism)\n- PMID:34079125 — EXCLUDE (BioID map, no SVIL-specific mechanism)\n- PMID:11707406 — KEEP (P2X7 receptor complex, supervillin identified as interactor)\n- PMID:12202484 — KEEP (supervillin in neutrophil DRM membrane skeleton, localization)\n- PMID:23752268 — EXCLUDE (HDAC interactome, no SVIL-specific mechanism)\n- PMID:25684206 — KEEP (SVIL interacts with LSD1+8a, H3K9 demethylation, neuronal differentiation)\n- PMID:29568061 — EXCLUDE (MAC-tag methodology)\n- PMID:19047128 — EXCLUDE (miRNA SNPs, no SVIL)\n- PMID:25468996 — EXCLUDE (E-cadherin interactome)\n- PMID:36217030 — EXCLUDE (SARS-CoV-2 interactome)\n- PMID:16385451 — EXCLUDE (Alzheimer GWAS)\n- PMID:30425250 — EXCLUDE (USP14/FASN)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human supervillin (SVIL) is a 205-kDa F-actin binding protein that is tightly associated with both actin filaments and plasma membranes, forming a high-affinity link between the actin cytoskeleton and the membrane. The protein has a bipartite structure: the NH2-terminus contains three potential nuclear localization signals, while the COOH-terminus contains three potential actin-binding sequences and shares extensive homology with segments 2–6 plus the headpiece of villin. The gene maps to a single chromosomal locus at 10p11.2.\",\n      \"method\": \"cDNA cloning and sequence analysis, chromosomal localization, expression profiling across human tissues\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — original cloning with full sequence characterization, domain mapping, and chromosomal localization; strong foundational study\",\n      \"pmids\": [\"9867483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Supervillin was identified as a component of the P2X7 receptor signalling complex in human embryonic kidney cells, co-purifying with the P2X7 receptor by affinity purification followed by mass spectrometry and immunoblotting, suggesting a role in cytoskeletal rearrangements (membrane blebbing) downstream of P2X7 receptor activation.\",\n      \"method\": \"Affinity purification followed by mass spectrometry and immunoblotting\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — identified by AP-MS and confirmed by immunoblot; single study, interaction context well-defined\",\n      \"pmids\": [\"11707406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Supervillin co-isolates with cholesterol-rich, detergent-resistant membrane fragments (DRM-H) from the bovine neutrophil plasma membrane skeleton, resists extraction by sodium carbonate (which removes all actin), and localizes with F-actin in cell extensions and discrete basal puncta that partially overlap with Gαi staining. Co-immunoaffinity purification confirmed supervillin binding to DRM-H fragments, indicating supervillin is proximal to the lipid bilayer in leukocyte signalling domains.\",\n      \"method\": \"Sucrose density gradient fractionation, MALDI-TOF and tandem MS, sodium carbonate extraction, co-immunoaffinity purification, immunofluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (fractionation, MS, co-IP, imaging) in a single rigorous study\",\n      \"pmids\": [\"12202484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Supervillin was identified as a 14-3-3 binding partner in HEK293 cells, placing it within a large group of cytoskeletal regulators whose interactions with 14-3-3 proteins are phosphorylation-dependent and important for controlling cellular morphology and membrane dynamics.\",\n      \"method\": \"Mass spectrometry-based proteomic analysis of 14-3-3 immunoprecipitates from HEK293 cells\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single large-scale AP-MS screen; supervillin interaction not individually validated\",\n      \"pmids\": [\"15324660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Supervillin was identified in the myosin-II-responsive focal adhesion proteome; its abundance in focal adhesions was enhanced by myosin II contractility, linking supervillin to tension-dependent focal adhesion maturation.\",\n      \"method\": \"Quantitative proteomic analysis of isolated focal adhesions with and without myosin II inhibition (blebbistatin treatment)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative proteomics with pharmacological perturbation; supervillin not individually validated but part of a rigorous dataset\",\n      \"pmids\": [\"21423176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SVIL is a substrate of PLK1 (polo-like kinase 1); PLK1 phosphorylates Ser238 of SVIL during mitosis, which promotes SVIL localization to the central spindle and its association with PRC1. Phosphorylated SVIL acts as a molecular link between the central spindle and the contractile ring. Expression of the phosphorylation-deficient S238A-SVIL mutant inhibits myosin II activation at the equatorial cortex and causes aberrant furrowing. The N-terminal myosin-II-binding region (but not the actin-binding region) of SVIL is required for myosin II activation and normal cytokinetic furrowing.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-site mutagenesis, co-immunoprecipitation, live-cell imaging, expression of deletion mutants with phenotypic analysis of cytokinesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay plus mutagenesis plus cellular phenotypic rescue in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"23750008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SVIL interacts with LSD1+8a (an alternatively spliced isoform of LSD1/KDM1A) and functions as a cofactor enabling LSD1+8a to demethylate H3K9me2 (but not H3K4me2) at target promoters. SVIL co-localizes to LSD1+8a-bound promoters in neuronal cells, and SVIL knockdown mimics the effect of LSD1+8a loss—increasing H3K9me2 at target promoters and compromising neuronal differentiation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi knockdown with histone modification analysis, neuronal differentiation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and functional KD with orthogonal readouts in a single study; replicated by multiple methods\",\n      \"pmids\": [\"25684206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Somatic variants in SVIL are found in ~17% of saccular cerebral aneurysm tissues and are associated with reduced SVIL expression. CRISPR/Cas9-mediated knockdown of SVIL in vascular smooth muscle cells (vSMCs) induces phenotypic modulation to a synthetic phenotype via KLF4 and PDGF signalling, and impairs cell migration via the RhoA/ROCK pathway.\",\n      \"method\": \"Whole-exome sequencing of matched aneurysm/blood tissue, RNA sequencing, CRISPR/Cas9 knockdown in vSMCs, gene expression profiling, protein kinase phosphorylation analysis\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with pathway-level readouts (RhoA/ROCK, KLF4/PDGF), but pathway placement based on expression changes without full epistasis\",\n      \"pmids\": [\"36475054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition (EMT) under hypoxic conditions by activating the TGFβ1/Smad2/3 signalling pathway; SVIL knockdown inhibits TGFβ1/Smad2/3 pathway activation, attenuates EMT and cancer progression, and increases cisplatin-induced apoptosis in cellular and in vivo mouse models.\",\n      \"method\": \"siRNA knockdown, CCK8 proliferation assay, wound-healing and Transwell migration assays, Western blot for Smad2/3 phosphorylation, apoptosis assay, nude mouse in situ tumor model\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with defined pathway readout (Smad2/3 phosphorylation) and in vivo validation, but no direct biochemical interaction demonstrated\",\n      \"pmids\": [\"39197416\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Supervillin (SVIL) is a large (205 kDa) F-actin- and myosin-II-binding membrane-skeletal protein that links the actin cytoskeleton to the plasma membrane; during mitosis it is phosphorylated on Ser238 by PLK1, which localizes it to the central spindle where it bridges the spindle and contractile ring to activate myosin II for cytokinetic furrowing; in interphase it resides in cholesterol-rich membrane raft fractions and myosin-II-responsive focal adhesions; in neurons it acts as a cofactor for the LSD1+8a isoform to mediate H3K9me2 demethylation at target promoters, supporting neuronal differentiation; and in vascular smooth muscle cells its loss activates RhoA/ROCK-dependent phenotypic switching and impaired migration, while in cancer contexts it promotes TGFβ1/Smad2/3-dependent EMT.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SVIL (supervillin) is a 205-kDa membrane-associated F-actin binding protein with an N-terminal membrane- and myosin-II-binding region and a C-terminal villin-homologous actin-binding region, forming a high-affinity structural link between the actin cytoskeleton and the plasma membrane [PMID:9867483]. During cytokinesis, PLK1 phosphorylates SVIL at Ser238, directing it to the central spindle where it associates with PRC1 and activates myosin II at the equatorial cortex through its myosin-II-binding domain to drive cleavage furrow ingression [PMID:23750008]. In vascular smooth muscle cells, SVIL loss induces phenotypic modulation to the synthetic state via KLF4/PDGF signaling and impairs migration through the RhoA/ROCK pathway [PMID:36475054].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of SVIL as a novel protein that physically bridges F-actin filaments and the plasma membrane established it as a cytoskeletal–membrane linker with a bipartite domain architecture — villin-homologous actin-binding segments at the C-terminus and membrane-association/nuclear-localization motifs at the N-terminus.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and biochemical fractionation showing co-isolation with actin filaments and membranes in human cells\",\n      \"pmids\": [\"9867483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional assay demonstrating a cellular phenotype upon SVIL loss\",\n        \"Mechanism of membrane association not resolved at the molecular level\",\n        \"In vivo relevance of putative nuclear localization signals untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that PLK1 phosphorylates SVIL at Ser238 to direct it to the central spindle where it binds PRC1 and activates myosin II resolved how the actin–membrane linker is repurposed during cytokinesis to couple the central spindle with the contractile ring.\",\n      \"evidence\": \"In vitro kinase assay, phospho-site mutagenesis (S238A), domain deletion constructs, co-immunoprecipitation with PRC1, and live-cell imaging of cleavage furrow ingression defects\",\n      \"pmids\": [\"23750008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of SVIL–PRC1 interaction not determined\",\n        \"Whether additional PLK1-independent mechanisms regulate SVIL localization during mitosis is unknown\",\n        \"The downstream mechanism by which SVIL's myosin-II-binding domain activates myosin II (direct vs. indirect) is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR-mediated SVIL depletion in vascular smooth muscle cells revealed a role beyond cytokinesis: SVIL maintains the contractile phenotype and migration capacity of vSMCs through KLF4/PDGF and RhoA/ROCK signaling, broadening SVIL function to cell-identity regulation.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in vSMCs with gene expression profiling, protein kinase phosphorylation analysis, and functional migration assays\",\n      \"pmids\": [\"36475054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-study finding not yet independently replicated in other vSMC models or in vivo\",\n        \"Direct versus indirect regulation of KLF4 and RhoA by SVIL not distinguished\",\n        \"Relevance to vascular disease phenotypes in animal models untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how SVIL's membrane-association mechanism works at the structural level, whether SVIL has non-cytokinetic roles in other dividing cell types, and whether its smooth muscle phenotypic regulation is generalizable to other tissue contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of SVIL or its domain interactions exists\",\n        \"No animal knockout phenotype reported\",\n        \"Post-translational regulation beyond Ser238 phosphorylation is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLK1\",\n      \"PRC1\",\n      \"MYH9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Supervillin (SVIL) is a large membrane-skeletal protein that bridges the actin cytoskeleton and the plasma membrane, functioning in cytokinesis, focal adhesion dynamics, chromatin regulation, and vascular smooth muscle cell homeostasis. Its N-terminus contains nuclear localization signals and a myosin-II-binding region, while the C-terminus harbors F-actin-binding sequences homologous to villin; the protein resides in cholesterol-rich detergent-resistant membrane domains and tension-responsive focal adhesions [PMID:9867483, PMID:12202484, PMID:21423176]. During mitosis, PLK1 phosphorylates SVIL at Ser238, directing it to the central spindle where it associates with PRC1 and activates myosin II at the equatorial cortex to drive cytokinetic furrowing [PMID:23750008]. In neurons, SVIL acts as a cofactor for the LSD1+8a histone demethylase, enabling H3K9me2 removal at target promoters to support neuronal differentiation [PMID:25684206].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Molecular cloning of SVIL established its identity as a novel 205-kDa protein that simultaneously binds F-actin and the plasma membrane, resolving how the cortical cytoskeleton could be anchored directly to the bilayer through a single polypeptide.\",\n      \"evidence\": \"cDNA cloning, sequence/domain analysis, and chromosomal mapping in human tissues\",\n      \"pmids\": [\"9867483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding-site mapping for the membrane association\", \"Functional consequence of nuclear localization signals untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Biochemical fractionation demonstrated that supervillin is an intrinsic component of cholesterol-rich, detergent-resistant membrane raft domains rather than simply a peripheral actin-associated protein, establishing a membrane-proximal signalling role.\",\n      \"evidence\": \"Sucrose gradient fractionation, sodium carbonate extraction, co-immunoaffinity purification, and immunofluorescence in bovine neutrophils\",\n      \"pmids\": [\"12202484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-binding determinant within supervillin not identified\", \"Functional consequence of raft association not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Quantitative focal adhesion proteomics revealed that supervillin accumulation at focal adhesions is myosin-II-dependent, linking the protein to mechanotransduction at cell–matrix contacts.\",\n      \"evidence\": \"Quantitative proteomics of isolated focal adhesions ± blebbistatin in fibroblasts\",\n      \"pmids\": [\"21423176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Supervillin not individually validated in focal adhesions by imaging\", \"Mechanism of myosin-II-dependent recruitment unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of SVIL as a PLK1 substrate phosphorylated at Ser238 during mitosis resolved how the contractile ring communicates with the central spindle: phospho-SVIL bridges PRC1 on spindle midzone microtubules and myosin II at the cortex, and a phospho-dead mutant causes aberrant furrowing.\",\n      \"evidence\": \"In vitro kinase assay, S238A mutagenesis, co-immunoprecipitation with PRC1, live-cell imaging of cytokinesis defects\",\n      \"pmids\": [\"23750008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SVIL–PRC1 interaction not determined\", \"Whether SVIL is required for all cell types' cytokinesis unknown\", \"Additional PLK1-dependent phosphosites not explored\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that SVIL serves as a chromatin-associated cofactor for the neuron-specific LSD1+8a demethylase expanded its functions beyond the cytoskeleton, showing it directs H3K9me2 demethylation at specific promoters required for neuronal differentiation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ChIP for H3K9me2 at target promoters, RNAi knockdown with differentiation assays in neuronal cells\",\n      \"pmids\": [\"25684206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain within SVIL that contacts LSD1+8a not mapped\", \"Whether SVIL nuclear entry uses its predicted NLS sequences not tested\", \"Genome-wide promoter targets not catalogued\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR knockout of SVIL in vascular smooth muscle cells showed that SVIL loss drives phenotypic switching to a synthetic state via KLF4/PDGF and impairs migration through RhoA/ROCK, providing a functional link to vascular pathology observed in cerebral aneurysm tissues carrying somatic SVIL variants.\",\n      \"evidence\": \"Whole-exome sequencing of aneurysm tissues, CRISPR/Cas9 KO in vSMCs, RNA-seq, phospho-kinase profiling\",\n      \"pmids\": [\"36475054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epistasis experiments for RhoA/ROCK pathway not performed\", \"Whether SVIL loss is causal for aneurysm formation in vivo not established\", \"Mechanism by which SVIL constrains RhoA activity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SVIL was shown to promote ovarian cancer EMT under hypoxia by activating TGFβ1/Smad2/3 signalling, with knockdown sensitizing tumors to cisplatin, revealing a pro-tumorigenic role through a defined signalling axis.\",\n      \"evidence\": \"siRNA knockdown, Smad2/3 phosphorylation Western blot, Transwell migration, nude mouse xenograft model\",\n      \"pmids\": [\"39197416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction between SVIL and TGFβ pathway components demonstrated\", \"Mechanism linking SVIL to Smad2/3 phosphorylation not resolved\", \"Generalizability to other cancer types untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SVIL's cytoskeletal scaffolding and nuclear/chromatin functions are coordinated — including the signals that govern its partitioning between membrane rafts, focal adhesions, the central spindle, and chromatin — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length supervillin exists\", \"Regulation of nuclear vs. cytoplasmic localization not characterized\", \"Whether the membrane-anchoring and LSD1-cofactor roles are cell-type-exclusive or concurrent is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLK1\",\n      \"PRC1\",\n      \"KDM1A\",\n      \"MYH9\",\n      \"P2RX7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}