Affinage

SVIL

Supervillin · UniProt O95425

Round 2 corrected
Length
2214 aa
Mass
247.7 kDa
Annotated
2026-04-28
38 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1998 High

    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

    PMID:9867483

    Open questions at the time
    • No binding-site mapping for the membrane association
    • Functional consequence of nuclear localization signals untested
  2. 2002 High

    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

    PMID:12202484

    Open questions at the time
    • Lipid-binding determinant within supervillin not identified
    • Functional consequence of raft association not tested
  3. 2011 Medium

    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

    PMID:21423176

    Open questions at the time
    • Supervillin not individually validated in focal adhesions by imaging
    • Mechanism of myosin-II-dependent recruitment unknown
  4. 2013 High

    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

    PMID:23750008

    Open questions at the time
    • Structural basis of SVIL–PRC1 interaction not determined
    • Whether SVIL is required for all cell types' cytokinesis unknown
    • Additional PLK1-dependent phosphosites not explored
  5. 2015 High

    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

    PMID:25684206

    Open questions at the time
    • 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
  6. 2022 Medium

    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

    PMID:36475054

    Open questions at the time
    • 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
  7. 2024 Medium

    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

    PMID:39197416

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1
Partners
KDM1AMYH9P2RX7PLK1PRC1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. cDNA cloning and sequence analysis, chromosomal localization, expression profiling across human tissues Genomics High 9867483
2001 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. Affinity purification followed by mass spectrometry and immunoblotting The EMBO journal Medium 11707406
2002 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. Sucrose density gradient fractionation, MALDI-TOF and tandem MS, sodium carbonate extraction, co-immunoaffinity purification, immunofluorescence microscopy The Journal of biological chemistry High 12202484
2004 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. Mass spectrometry-based proteomic analysis of 14-3-3 immunoprecipitates from HEK293 cells Current biology : CB Low 15324660
2011 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. Quantitative proteomic analysis of isolated focal adhesions with and without myosin II inhibition (blebbistatin treatment) Nature cell biology Medium 21423176
2013 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. In vitro kinase assay, phosphorylation-site mutagenesis, co-immunoprecipitation, live-cell imaging, expression of deletion mutants with phenotypic analysis of cytokinesis Journal of cell science High 23750008
2015 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. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi knockdown with histone modification analysis, neuronal differentiation assays Molecular cell High 25684206
2022 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. Whole-exome sequencing of matched aneurysm/blood tissue, RNA sequencing, CRISPR/Cas9 knockdown in vSMCs, gene expression profiling, protein kinase phosphorylation analysis Neurology. Genetics Medium 36475054
2024 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. 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 Gynecologic oncology Medium 39197416

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2011 Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation. Nature cell biology 490 21423176
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2004 Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Current biology : CB 386 15324660
2008 Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Human molecular genetics 366 19010793
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2001 Proteomic and functional evidence for a P2X7 receptor signalling complex. The EMBO journal 319 11707406
2002 Proteomic analysis of a detergent-resistant membrane skeleton from neutrophil plasma membranes. The Journal of biological chemistry 249 12202484
2013 The functional interactome landscape of the human histone deacetylase family. Molecular systems biology 235 23752268
2015 A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Molecular cell 224 25684206
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2008 Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 195 19047128
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2005 A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease. American journal of human genetics 137 16385451
2018 Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN. Nature communications 123 30425250
1998 Cloning, characterization, and chromosomal localization of human superillin (SVIL). Genomics 43 9867483
2013 The role of PLK1-phosphorylated SVIL in myosin II activation and cytokinetic furrowing. Journal of cell science 28 23750008
2022 N6-methyladenosine-induced SVIL antisense RNA 1 restrains lung adenocarcinoma cell proliferation by destabilizing E2F1. Bioengineered 15 35068325
2024 SVIL promotes ovarian cancer progression and epithelial-mesenchymal transition under hypoxic conditions through the TGF-β/Smad pathway. Gynecologic oncology 7 39197416
2025 AKT1E17K-Interacting lncRNA SVIL-AS1 Promotes AKT1 Oncogenic Functions by Preferentially Blocking AKT1E17K Dephosphorylation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40135844
2024 Engineered exosomes transporting the lncRNA, SVIL-AS1, inhibit the progression of lung cancer via targeting miR-21-5p. American journal of cancer research 4 39113865
2022 Somatic Variants in SVIL in Cerebral Aneurysms. Neurology. Genetics 3 36475054
2020 A twin‑pair analysis indicates congenital scoliosis is associated with allele‑specific methylation in the SVIL gene. Molecular medicine reports 3 32582973