Affinage

VCAN

Versican core protein · UniProt P13611

Length
3396 aa
Mass
372.8 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Versican (VCAN) is a large modular chondroitin sulfate proteoglycan of the extracellular matrix that organizes hyaluronan (HA)-rich pericellular matrices and transduces signals through cell-surface receptors to regulate cell adhesion, migration, proliferation, and senescence. Its N-terminal G1 domain assembles ternary aggregates with HA and link protein via the B-B' subdomain, and the A subdomain enhances HA binding and is essential for organizing a functional HA matrix that suppresses CD44-mediated ERK1/2 signaling toward premature senescence (PMID:12888576, PMID:19164294). The C-terminal G3 domain functions as a multivalent signaling hub: its C-type lectin domain mediates calcium-dependent sugar binding and heparin binding, while its EGF-like repeats promote integrin–EGFR complex formation and FAK activation, and it directly engages β1-integrin (non-RGD), fibronectin–VEGF complexes, and PSGL-1 to regulate cell adhesion, angiogenesis, and leukocyte aggregation (PMID:7961677, PMID:11805102, PMID:14766798, PMID:15126624, PMID:15522894). Alternative splicing generates isoforms V0–V3 differing in chondroitin sulfate attachment domains; CS chains on V0/V1 bind midkine and are required for mesenchymal condensation and chondrogenesis, versican is indispensable for cardiac cushion and ventricular septal formation in vivo, and intronic splice-site mutations that skew isoform ratios cause Wagner vitreoretinopathy (PMID:16257955, PMID:9758703, PMID:22692047, PMID:16877430).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1986 High

    Versican was identified as a large CS proteoglycan that mediates hyaluronate binding in the pericellular matrix and directly binds fibronectin and type I collagen, establishing it as a key ECM organizer linking HA matrices to fibrillar components.

    Evidence Immunoprecipitation, affinity chromatography, CsCl centrifugation, and direct binding assays on fibroblast-derived proteoglycan

    PMID:3759975 PMID:3759976

    Open questions at the time
    • Binding domains not yet mapped
    • In vivo function not established
    • Relationship to other hyalectans not defined
  2. 1993 High

    Full cDNA cloning revealed versican's modular architecture — N-terminal G1 HA-binding domain, central CS-attachment regions, and C-terminal G3 domain with EGF-like, lectin, and CRP-like modules — and demonstrated that alternative splicing of CS domains generates multiple isoforms (V0–V3), providing the structural framework for all subsequent functional studies.

    Evidence cDNA cloning, sequencing, domain homology analysis, PCR/Northern/Southern blot isoform characterization

    PMID:7730339 PMID:7876137 PMID:8314802

    Open questions at the time
    • Functional differences among isoforms not yet tested
    • G3 domain ligands unknown
  3. 1994 High

    The G3 domain was shown to have calcium-dependent C-type lectin activity and heparin-binding activity requiring the CRP-like subdomain, and versican was identified as an anti-adhesive molecule excluded from podosomes, establishing distinct functional roles for the G3 domain and the proteoglycan in cell adhesion regulation.

    Evidence Recombinant GST-fusion domain expression, sugar/heparin affinity chromatography, domain deletion mutagenesis; antisense inhibition in osteosarcoma cells

    PMID:7531202 PMID:7961677

    Open questions at the time
    • Cell-surface receptor for G3 not identified
    • Anti-adhesive mechanism molecularly undefined
  4. 1998 High

    Genetic loss-of-function in mice (hdf insertional mutant) demonstrated that versican is essential for cardiac cushion formation and right ventricular development, establishing an indispensable in vivo role in heart morphogenesis.

    Evidence Transgene insertional mutagenesis disrupting Cspg2, histology, immunohistochemistry, mRNA analysis in mouse embryos

    PMID:9758703

    Open questions at the time
    • Downstream cellular mechanisms (proliferation vs. migration vs. ECM assembly) not dissected
    • Isoform-specific requirements not tested
  5. 2000 High

    Versican V0/V1 were shown to guide neural crest cell migration in a haptotactic manner and to bind midkine with nanomolar affinity through chondroitin sulfate chains, revealing that both core protein and GAG chains serve as functional ligand-binding and cell-guidance modules.

    Evidence Orthotopic membrane implantation, 3D collagen gel migration assays, radioligand binding with Kd determination, chondroitinase digestion

    PMID:10851128 PMID:10866805

    Open questions at the time
    • Cell-surface receptor mediating neural crest migration not identified
    • In vivo confirmation of midkine–versican interaction lacking
  6. 2002 High

    β1-integrin was identified as a G3 domain receptor acting through a non-RGD, calcium-dependent mechanism to activate FAK and promote cell survival, while versican CS chains (particularly dermatan sulfate) were shown to mediate platelet adhesion under flow, expanding the repertoire of versican's cell-surface interactions.

    Evidence Pull-down, co-IP, native gel co-migration, FAK phosphorylation assay; real-time platelet perfusion under controlled shear, GAG lyase digestion

    PMID:11805102 PMID:12468455

    Open questions at the time
    • Specific integrin heterodimer engaged not determined
    • Platelet receptor identity (120–140 kDa complex) not confirmed by sequencing
  7. 2003 High

    SPR-based mapping showed the G1 B-B' subdomain is sufficient for HA and link protein binding while the A subdomain enhances HA interaction, defining the minimal structural requirements for ternary aggregate formation with HA and link protein.

    Evidence Recombinant subdomain expression, BIAcore SPR, overlay sensorgrams, molecular modeling

    PMID:12888576

    Open questions at the time
    • Crystal structure of G1-HA-LP complex not solved
    • Stoichiometry of the aggregate not determined
  8. 2004 High

    The G3 domain was found to form a ternary complex with fibronectin and VEGF to promote angiogenesis, to bind PSGL-1 inducing leukocyte aggregation, and to activate EGFR signaling through its EGF-like repeats in concert with integrins, establishing G3 as a multivalent signaling hub linking ECM to growth factor and inflammatory pathways.

    Evidence Direct binding assays, endothelial cell functional assays, nude mouse tumor growth, PSGL-1 transfection and aggregation assays, EGFR/FAK co-IP with EGF-domain deletions

    PMID:14766798 PMID:15126624 PMID:15522894

    Open questions at the time
    • Whether G3-EGFR interaction is direct or integrin-mediated not resolved
    • PSGL-1 binding site on G3 not mapped
  9. 2005 High

    CS chains on versican were shown to be required for mesenchymal condensation and chondrogenesis: chondroitinase, β-xyloside, or forced V3 (CS-lacking) expression all blocked chondrogenesis, demonstrating that GAG-dependent functions are not redundant with core protein activities.

    Evidence Antisense knockdown, chondroitinase ABC, β-xyloside treatment, V3 overexpression in N1511 chondrocytic cells

    PMID:16257955

    Open questions at the time
    • CS chain-binding partner driving condensation not identified
    • In vivo genetic confirmation not provided
  10. 2006 High

    Intronic splice-site mutations in VCAN causing imbalanced isoform ratios (loss of exon 8-containing V0, upregulation of V2/V3) were identified as the cause of Wagner vitreoretinopathy/erosive vitreoretinopathy, linking versican isoform balance to vitreous structural integrity.

    Evidence RT-PCR, quantitative RT-PCR, Sanger sequencing, haplotype analysis across multiple families

    PMID:16043844 PMID:16877430 PMID:22739342

    Open questions at the time
    • Mechanism by which isoform imbalance disrupts vitreous architecture not defined at molecular level
    • No animal model recapitulating the vitreoretinal phenotype
  11. 2009 High

    A knock-in mouse model lacking the G1 A subdomain showed that versican organizes HA into a functional matrix network, and in its absence unincorporated HA fragments activate CD44–ERK1/2 signaling to drive premature senescence, revealing versican as a negative regulator of HA-CD44 signaling.

    Evidence Cspg2Δ3/Δ3 knock-in mice, confocal matrix imaging, ERK1/2 phosphorylation assay, hyaluronidase treatment, anti-CD44 blocking antibody, senescence markers

    PMID:19164294

    Open questions at the time
    • Whether this senescence mechanism operates in all tissues or is context-specific
    • Identity of the HA fragment size triggering CD44 signaling not determined
  12. 2012 High

    The G1 A-subdomain knock-in mice also exhibited ventricular septal defects, smaller AV cushions, and impaired mesenchymal cell migration, demonstrating that versican-dependent HA matrix organization is essential for cardiac septation — complementing the earlier hdf null phenotype with a hypomorphic allele.

    Evidence VcanΔ3/Δ3 knock-in mice, histology, immunostaining, ex vivo collagen gel explant migration assay

    PMID:22692047

    Open questions at the time
    • Whether impaired migration is cell-autonomous or matrix-dependent not resolved
    • Downstream signaling pathways in cardiac mesenchyme not identified
  13. 2014 High

    Exon 7 deletion mice (unable to express V0/V2) developed ventricular septal defects and valve abnormalities with compensatory cytoskeletal protein changes, confirming that specific isoform balance — not just total versican — is critical for cardiac morphogenesis.

    Evidence Exon deletion mouse model, histomorphometry, unbiased proteomics at E13.5

    PMID:24586547

    Open questions at the time
    • Relative contribution of V0 vs. V2 loss not dissected
    • Whether proteomics changes are cause or consequence unclear
  14. 2019 High

    A Wagner disease splice-site mutation was shown to remove an MMP proteolytic cleavage site at the GAGβ domain boundary, directly validated by FRET-based proteolysis assay, linking impaired versican turnover to vitreous pathology.

    Evidence FRET-based in vitro proteolysis assay, protein structural modeling, Sanger sequencing

    PMID:30657523

    Open questions at the time
    • Which specific MMP(s) cleave this site in vivo not determined
    • Whether cleavage fragment has signaling activity unknown
  15. 2024 Medium

    ADAMTS1-generated versican cleavage fragments were found to transactivate EGFR, creating a positive feedback loop (ADAMTS1–VCAN–EGFR) that promotes anoikis resistance and invasion in renal cell carcinoma, and versican was shown to interact with Twist1 to promote endothelial-to-mesenchymal transition in pulmonary hypertension, expanding the repertoire of versican's signaling roles via proteolytic fragments and transcription factor interactions.

    Evidence RTK arrays, IP, knockdown, anoikis/invasion assays, zebrafish xenotransplantation; co-IP for versican–Twist1, endothelium-specific knockdown in mouse hypoxia model

    PMID:39333870 PMID:39578365

    Open questions at the time
    • Identity of the specific versican fragment activating EGFR not characterized
    • Versican–Twist1 interaction not confirmed by reciprocal methods
    • Single-lab findings await independent replication
  16. 2025 High

    STAT5 was identified as a direct transcriptional activator of VCAN in fibroblasts during pulmonary fibrosis, and fibroblast-specific Vcan knockout significantly attenuated fibrosis through reduced PI3K pathway activation; separately, VCAN was shown to mediate CAF–TAM communication via CD44 and AhR-dependent trophoblast invasion, broadening versican's roles to fibrotic and tumor microenvironment contexts.

    Evidence ChIP for STAT5–VCAN promoter, conditional Vcan knockout mice, PI3K inhibitor; co-IP for VCAN–CD44, siRNA, RNA-seq, in vivo models

    PMID:39823128 PMID:40153926 PMID:40617369

    Open questions at the time
    • Whether STAT5 regulation of VCAN is tissue-specific not explored
    • Mechanism linking VCAN–CD44 to Hippo pathway activation requires structural detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the three-dimensional structure of the versican G1-HA-link protein aggregate, the identity and specificity of MMP/ADAMTS cleavage sites across all isoforms and their signaling-active fragments, whether isoform-specific functions can be dissected in vivo using isoform-selective knockouts, and the structural basis of G3 domain interactions with its multiple receptor partners (β1-integrin, PSGL-1, EGFR, fibronectin).
  • No crystal or cryo-EM structure of any versican domain–ligand complex
  • Comprehensive isoform-selective knockout panel not available
  • Systematic identification of versican cleavage fragments and their bioactivities not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0048018 receptor ligand activity 4 GO:0098631 cell adhesion mediator activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0031012 extracellular matrix 6 GO:0005576 extracellular region 5
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1643685 Disease 2
Partners
ADAMTS1CD44EGFRFN1HAPLN1HAS2ITGB1SELPLG
Complex memberships
Hyaluronan-versican-link protein aggregate

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 PG-M/versican binds directly to fibronectin and type I collagen (but not laminin or type IV collagen), and mediates hyaluronate binding in the pericellular matrix of fibroblasts; most hyaluronate-binding activity in fibronectin preparations was shown by immunoprecipitation to be attributable to this proteoglycan. Immunoprecipitation, affinity chromatography, CsCl isopycnic centrifugation, direct binding assays The Journal of biological chemistry High 3759976
1986 PG-M/versican is a large chondroitin sulfate proteoglycan with a core protein of ~550 kDa, carrying large chondroitin sulfate chains; its progressive enrichment in condensing mesenchymal cells of developing chick limb buds parallels the condensation process, suggesting a role in cell condensation via interaction with fibronectin and type I collagen. Metabolic labeling with [35S]sulfate, CsCl centrifugation, SDS-PAGE, tryptic peptide mapping, immunofluorescence localization The Journal of biological chemistry High 3759975
1993 PG-M/versican core protein contains an N-terminal hyaluronic acid-binding domain and C-terminal EGF-like, C-type lectin-like, and complement regulatory protein-like domains, establishing its modular domain architecture; alternative splicing of the chondroitin sulfate attachment domain generates multiple isoforms, with versican being a short spliced form of PG-M. cDNA cloning, sequencing, domain homology analysis, alternative splicing characterization The Journal of biological chemistry High 8314802
1994 The C-terminal (G3) domain of PG-M/versican binds to D-mannose, D-galactose, L-fucose, and N-acetyl-D-glucosamine in a calcium-dependent manner, and also binds heparin/heparan sulfate; the complement regulatory protein-like (CRP-like) domain is required for both C-type lectin and heparin binding activities. Recombinant protein expression (GST fusion), affinity chromatography on immobilized sugars and heparin-Sepharose, domain deletion mutagenesis The Journal of biological chemistry High 7961677
1994 PG-M/versican acts as an anti-adhesive molecule: it is selectively excluded from podosomes of osteosarcoma cells, and antisense inhibition of its biosynthesis suppresses the malignant podosome-associated cell adhesion phenotype. Antisense oligonucleotide inhibition, immunolocalization, cell adhesion phenotyping Journal of cell science Medium 7531202
1995 Multiple isoforms of PG-M/versican (V0, V1, V2, V3) are generated by alternative splicing of two chondroitin sulfate attachment domains (CSα and CSβ encoded by exons VII and VIII respectively); V3 lacks both CS attachment domains and has no glycosaminoglycan chains, suggesting a unique function distinct from other isoforms. PCR, Northern blot, Southern blot, cDNA cloning and sequencing, genomic DNA analysis The Journal of biological chemistry High 7730339 7822336 7876137
1998 Versican/Cspg2 is required for right cardiac chamber and endocardial cushion formation in mice; homozygous Cspg2 disruption (hdf mouse insertional mutant) results in absence of endocardial cushions and failure of the future right ventricle to form, establishing versican as essential for early heart morphogenesis. Transgene insertional mutagenesis, chromosome mapping, immunohistochemistry, mRNA expression analysis, genomic cloning Developmental biology High 9758703
2000 PG-M/versican V0 and V1 isoforms are deposited in neural crest (NC) migratory pathways and promote directed NC cell movement in a haptotactic manner via engagement of HNK-1 antigen-bearing cell surface components, whereas aggrecan defines impenetrable areas; the effects are mediated by both core protein and glycosaminoglycan side chains. Immunohistochemistry, in situ hybridization, orthotopic membrane implantation, 3D collagen gel migration assays, TEM/rotary shadowing, proteoglycan purification Development (Cambridge, England) High 10851128
2000 PG-M/versican binds the heparin-binding growth factor midkine with Kd = 1.0 nM; binding is mediated by polysulfated chondroitin sulfate chains (chondroitinase ABC digestion abolishes binding), specifically involving 4-sulfated, 6-sulfated, 2,6-disulfated, and 4,6-disulfated unsaturated disaccharides. Proteoglycan purification, in-gel trypsin digestion and peptide sequencing for identification, radioligand binding assay, chondroitinase ABC/AC-I/B digestion, competition with heparin and CS species European journal of biochemistry High 10866805
2002 β1-integrin binds to the C-terminal G3 domain of PG-M/versican in a calcium- and manganese-dependent manner via a non-RGD mechanism; this interaction activates focal adhesion kinase, enhances integrin expression, promotes cell adhesion, and confers resistance to free radical-induced apoptosis. Pull-down assay, immunoprecipitation, cell-surface binding assay, native gel electrophoresis co-migration, FAK phosphorylation assay, apoptosis assay The Journal of biological chemistry High 11805102
2003 The G1 domain of versican binds to both hyaluronan (HA) and link protein (LP); the B-B' segment of the G1 domain is sufficient for HA and LP binding, while the A subdomain enhances HA binding; a molecular model of B-B' shows that a deletion and insertion in B and B' are critical for stable structure and HA binding. Versican forms a ternary complex with HA and LP. Recombinant subdomain expression, BIAcore (SPR) binding analysis, overlay sensorgrams, molecular modeling The Journal of biological chemistry High 12888576
2003 The G3 domains of aggrecan and PG-M/versican form intermolecular disulfide bonds involving all subdomains and potentially all 10 cysteine residues; disruption of these disulfide bonds with reducing agents (β-mercaptoethanol, DTT) disrupts chondrocyte-matrix interaction and reduces versican G3-mediated cell adhesion. In vitro disulfide bond formation assay, reducing agent treatment, cell adhesion assay, matrix structure analysis Biochemistry Medium 12846582
2004 The versican G3 domain directly binds fibronectin and forms a complex together with VEGF; this G3-fibronectin-VEGF complex enhances endothelial cell adhesion, proliferation, and migration, and G3-expressing tumor cells show increased fibronectin and VEGF levels, promoting tumor growth and angiogenesis. G3 construct transfection in U87 astrocytoma cells, direct binding assay (G3 to fibronectin), colony growth in soft agarose, tumor growth in nude mice, endothelial cell adhesion/proliferation/migration assays, removal of complex FASEB journal High 14766798
2004 The versican G3 domain lacking EGF-like motifs (G3ΔEGF) impairs EGFR phosphorylation and disrupts integrin/EGFR complex association in astrocytoma cells, preventing anchorage-independent growth; the full G3 domain modulates tumorigenesis by promoting integrin-EGFR signaling. Stable transfection of G3ΔEGF, serum withdrawal assays, FAK phosphorylation, integrin/EGFR co-immunoprecipitation, EGFR phosphorylation assay, anchorage-independent growth, nude mouse tumor assay Journal of cell science High 15126624
2004 The versican G3 domain binds to PSGL-1 (P-selectin glycoprotein ligand-1) on leukocyte surfaces; G3 multimers cross-link PSGL-1 to induce leukocyte aggregation, and endogenous G3-containing versican fragments in human plasma contribute to this aggregation. Transfection of PSGL-1, cell aggregation assay, binding assay, plasma G3 fragment removal, mouse model Journal of cell science High 15522894
2004 The G1 domain of versican, upon binding cell surface CD44, inhibits proliferation of G1-overexpressing sarcoma cells in a dose-dependent manner when exogenous hyaluronan is added; G1 overexpression also reduces apoptotic rate via mitochondrial apoptotic genes, shifting the proliferation-apoptosis equilibrium. Stable transfection of G1 or G3 domains, serum-free growth assays, hyaluronan treatment, cell invasion assay, apoptosis measurement, nude mouse subcutaneous tumor assay FASEB journal Medium 14977887
2005 Versican/PG-M positively regulates mesenchymal condensation and chondrogenesis: chondrogenic stimuli increase versican transcription and protein synthesis; antisense suppression reduces aggrecan deposition; chondroitinase ABC treatment or β-xyloside (CS chain synthesis inhibitor) suppresses chondrogenesis; forced V3 expression (no CS chains) disrupts versican V0/V1 deposition and inhibits chondrogenesis, demonstrating that CS chains on versican are required. Stable antisense clones, chondroitinase ABC treatment, β-xyloside treatment, V3 forced expression, RT-PCR, protein deposition assay in N1511 chondrocytic cell line The Journal of biological chemistry High 16257955
2006 Versican is present as a proteoglycan aggregate with link protein and hyaluronan in articular cartilage (distinct from the aggrecan aggregate); chondroitin sulfate chains of versican are primarily non-sulfated (71%) and 4-sulfated (28%), contrasting with aggrecan's predominantly 4-sulfated chains; link protein overexpression enhances versican matrix deposition and prevents subsequent aggrecan deposition. Immunostaining, biochemical analysis of normal and aggrecan-null (cmd/cmd) cartilage, chondroitinase ABC digestion, disaccharide analysis, link protein overexpression in N1511 cells The Journal of biological chemistry High 16648631
2006 Wagner disease and erosive vitreoretinopathy are caused by intronic splice site mutations in CSPG2/versican that result in an imbalanced ratio of splice variants: mutations at the splice acceptor site of intron 7 cause activation of a cryptic splice site, leading to 39-nt exon 8 deletion in V0, and a highly significant upregulation of V2 (>38-fold) and V3 (>12-fold) isoforms. RT-PCR, quantitative RT-PCR (QPCR), Sanger sequencing, haplotype analysis Investigative ophthalmology & visual science High 16043844 16877430 22739342
2007 Hyaluronan-versican aggregates (but not native hyaluronan alone) promote stromal cell and endothelial cell recruitment in vivo (Matrigel plug assay), demonstrating that the versican-HA complex is the active form for promoting angiogenesis. MMTV-Neu/Has2 bigenic mouse model, Matrigel plug angiogenesis assay, comparison of HA oligosaccharides vs. HA-versican aggregates The American journal of pathology Medium 17322391
2009 Versican assembles hyaluronan into extracellular matrix and inhibits CD44-mediated ERK1/2 signaling toward premature senescence; knock-in mice lacking the A subdomain of versican G1 (Cspg2Δ3/Δ3) show ~35% versican deposition and ~85% HA deposition without matrix network structure, increased ERK1/2 phosphorylation, and elevated senescence markers (p53, p21, p16); free HA fragments interact with CD44 to drive ERK1/2 phosphorylation and senescence. Knock-in mouse model, cell fractionation, confocal microscopy of matrix structure, ERK1/2 phosphorylation assay, hyaluronidase treatment, exogenous HA addition, anti-CD44 antibody blocking, senescence marker Western blot The Journal of biological chemistry High 19164294
2012 Versican/PG-M is essential for ventricular septal formation; knock-in mice (VcanΔ3/Δ3) lacking the A subdomain of the G1 domain show smaller AV cushions, ventricular septal defects, condensed HA deposition without versican matrix network, increased Ki67-positive cell proliferation, and impaired mesenchymal cell migration ex vivo on collagen gel. Knock-in mouse generation, histology, immunostaining (Vcan, HA, Ki67), ex vivo collagen gel explant culture Glycobiology High 22692047
2002 Vascular versican variants (V1 and V2) promote platelet adhesion at low shear rates in a dose- and shear rate-dependent manner, primarily mediated by dermatan sulfate chains; incorporation into fibrillar collagen augments adhesive activity and promotes platelet aggregation; a 120–140 kDa platelet surface polypeptide complex was identified as the versican binding ligand. Versican purification, real-time platelet perfusion assays under diverse shear forces, glycosaminoglycan lyase digestion, competition with purified GAGs, affinity chromatography of platelet surface proteins FASEB journal High 12468455
2014 Imbalanced expression of Vcan splice forms alters heart morphology; mice homozygous for exon 7 deletion (Vcan(tm1Zim)) cannot express V2 or V0 isoforms and develop ventricular septal defects, smaller valve leaflets with diminished myocardialization, and altered outflow tracts; large-scale protein profiling reveals compensatory alterations in cytoskeletal and muscle contraction proteins. Exon deletion mouse model, histology, valve/cushion morphometry, proteomics (differential protein expression profiling) at E13.5 PloS one High 24586547
2019 The VCAN splice site mutation (c.4004-2A>G) removes an MMP proteolytic cleavage site at the beginning of the GAGβ chain (residues 1335–1347), as validated by FRET-based in vitro proteolysis assay; loss of this site alters versican structure and results in abnormal vitreous modeling. Sanger DNA sequencing, protein structural modeling, FRET-based proteolysis assay, histopathology Investigative ophthalmology & visual science High 30657523
2018 Snail induces expression of PAPSS2 (rate-limiting sulfation enzyme) and VCAN in breast cancer cells; depletion of VCAN dampens cell migration induced by Snail or PAPSS2, establishing VCAN as a downstream effector in the Snail-driven sulfation program that promotes breast cancer cell migration and metastasis. shRNA knockdown and overexpression of PAPSS2/VCAN, cell migration assay, lung metastasis assay in nude mice, PAPSS2 inhibitor (sodium chlorate) treatment Cell death and differentiation High 29955124
2024 ADAMTS1 cleaves versican V1 (VCAN V1), and the resulting proteolytic fragment leads to EGFR transactivation in renal cell carcinoma; this creates a positive feedback cyclic axis (ADAMTS1-VCAN-EGFR) promoting anoikis resistance and invasion; ADAMTS1 also forms a complex with p53 to influence EGFR signaling. RTK array screening, luciferase reporter assays, immunoprecipitation, western blotting, RT-qPCR, anoikis resistance assays, invasion assays, zebrafish xenotransplantation model, VCAN/EGFR knockdown Cellular & molecular biology letters Medium 39333870
2025 STAT5 acts as a transcription factor that promotes VCAN expression in fibroblasts under bleomycin-induced pulmonary fibrosis; elevated VCAN promotes fibroblast activation through the PI3K signaling pathway; VCAN-specific knockout in fibroblasts significantly reduces lung fibroblast activation and fibrosis in mouse models. Bleomycin mouse model, fibroblast-specific Vcan knockout mice, chromatin immunoprecipitation (ChIP), luciferase reporter gene assay, western blotting, immunofluorescence, Transwell/scratch assay, PI3K inhibitor treatment, adeno-associated virus knockdown Cellular signalling High 40617369
2024 Versican promotes EndMT in hypoxia-induced pulmonary hypertension by interacting with (targeting) the transcription factor Twist1; promoter hypomethylation under hypoxia (mediated by reduced DNA methyltransferase activity) drives versican upregulation; endothelium-specific knockdown of versican reverses HPH progression and prevents EndMT. Co-immunoprecipitation (versican-Twist1 interaction), methylation-specific PCR, immunohistochemistry, immunofluorescence, Western blot, mouse model with endothelium-specific versican knockdown, hemodynamic measurements Journal of the American Heart Association Medium 39578365
2025 VCAN promotes trophoblast migration and invasion via the AhR/VCAN pathway: ILA activates AhR signaling in trophoblasts, which upregulates VCAN expression; VCAN knockdown abolishes ILA-promoted migration/invasion; VCAN upregulation promotes spiral artery remodeling in preeclampsia mouse models. Transwell migration/invasion assay, qRT-PCR, western blotting, siRNA transfection, RNA-seq, AhR pathway analysis, in vivo ILA supplementation in PE-like mice, immunohistochemistry Placenta Medium 40153926
2025 VCAN secreted by cancer-associated fibroblasts (CAFs) interacts with CD44 receptors on tumor-associated macrophages (TAMs) via paracrine secretion, promoting M2 macrophage polarization and VEGF-C secretion to enhance lymphangiogenesis; VCAN also binds CD44 on gastric cancer cells via autocrine secretion, activating the Hippo pathway and upregulating SP1 to promote MIR181A2HG transcription in a feedback loop. Immunofluorescence, immunohistochemistry, ELISA, ChIP, RNA pull-down, luciferase reporter assay, co-immunoprecipitation, qRT-PCR, in vitro and in vivo functional studies Cancer medicine Medium 39823128

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The Cspg2 gene, disrupted in the hdf mutant, is required for right cardiac chamber and endocardial cushion formation. Developmental biology 270 9758703
1986 A large chondroitin sulfate proteoglycan (PG-M) synthesized before chondrogenesis in the limb bud of chick embryo. The Journal of biological chemistry 175 3759975
1995 Multiple forms of mouse PG-M, a large chondroitin sulfate proteoglycan generated by alternative splicing. The Journal of biological chemistry 157 7822336
1993 cDNA cloning of PG-M, a large chondroitin sulfate proteoglycan expressed during chondrogenesis in chick limb buds. Alternative spliced multiforms of PG-M and their relationships to versican. The Journal of biological chemistry 156 8314802
2004 Versican/PG-M G3 domain promotes tumor growth and angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 151 14766798
1986 Chondroitin sulfate proteoglycan (PG-M-like proteoglycan) is involved in the binding of hyaluronic acid to cellular fibronectin. The Journal of biological chemistry 143 3759976
2007 Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. The American journal of pathology 134 17322391
2000 Avian neural crest cell migration is diversely regulated by the two major hyaluronan-binding proteoglycans PG-M/versican and aggrecan. Development (Cambridge, England) 121 10851128
2003 Distinct interaction of versican/PG-M with hyaluronan and link protein. The Journal of biological chemistry 120 12888576
1995 Expression of PG-M(V3), an alternatively spliced form of PG-M without a chondroitin sulfate attachment in region in mouse and human tissues. The Journal of biological chemistry 113 7876137
2002 beta 1-Integrin-mediated glioma cell adhesion and free radical-induced apoptosis are regulated by binding to a C-terminal domain of PG-M/versican. The Journal of biological chemistry 112 11805102
2002 Distribution of PG-M/versican variants in human tissues and de novo expression of isoform V3 upon endothelial cell activation, migration, and neoangiogenesis in vitro. The Journal of biological chemistry 103 12221092
2018 Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis. Cell death and differentiation 97 29955124
1996 2B1 antigen characteristically expressed on extracellular matrices of human malignant tumors is a large chondroitin sulfate proteoglycan, PG-M/versican. Cancer research 91 8752156
1994 Repression of a malignant cell-substratum adhesion phenotype by inhibiting the production of the anti-adhesive proteoglycan, PG-M/versican. Journal of cell science 91 7531202
1993 Tissue variation of two large chondroitin sulfate proteoglycans (PG-M/versican and PG-H/aggrecan) in chick embryos. Anatomy and embryology 83 8342790
1997 Immunohistochemical localization of extracellular matrix components in human breast tumours with special reference to PG-M/versican. The Histochemical journal 81 9088942
1996 Inhibitory effects of PG-H/aggrecan and PG-M/versican on avian neural crest cell migration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 78 8641562
1999 Versican/PG-M isoforms in vascular smooth muscle cells. Arteriosclerosis, thrombosis, and vascular biology 74 10397680
2012 Versican/PG-M is essential for ventricular septal formation subsequent to cardiac atrioventricular cushion development. Glycobiology 69 22692047
2000 A heparin-binding growth factor, midkine, binds to a chondroitin sulfate proteoglycan, PG-M/versican. European journal of biochemistry 67 10866805
2006 Erosive vitreoretinopathy and wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants. Investigative ophthalmology & visual science 66 16877430
2004 PG-M/versican binds to P-selectin glycoprotein ligand-1 and mediates leukocyte aggregation. Journal of cell science 63 15522894
2005 Identification of a novel splice site mutation of the CSPG2 gene in a Japanese family with Wagner syndrome. Investigative ophthalmology & visual science 62 16043844
1992 Mapping of the versican proteoglycan gene (CSPG2) to the long arm of human chromosome 5 (5q12-5q14). Genomics 59 1478664
2004 The globular domains of PG-M/versican modulate the proliferation-apoptosis equilibrium and invasive capabilities of tumor cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 56 14977887
2005 Versican/PG-M regulates chondrogenesis as an extracellular matrix molecule crucial for mesenchymal condensation. The Journal of biological chemistry 55 16257955
1995 The gene structure and organization of mouse PG-M, a large chondroitin sulfate proteoglycan. Genomic background for the generation of multiple PG-M transcripts. The Journal of biological chemistry 51 7730339
2004 Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and beta1-integrin. Journal of cell science 48 15126624
1996 Distinct rat aortic smooth muscle cells differ in versican/PG-M expression. Arteriosclerosis, thrombosis, and vascular biology 48 8640411
2006 Identification and characterization of versican/PG-M aggregates in cartilage. The Journal of biological chemistry 47 16648631
2023 TGF-β1 dominates stromal fibroblast-mediated EMT via the FAP/VCAN axis in bladder cancer cells. Journal of translational medicine 43 37461061
1994 Expression and binding activity of the carboxyl-terminal portion of the core protein of PG-M, a large chondroitin sulfate proteoglycan. The Journal of biological chemistry 43 7961677
2009 Versican/PG-M Assembles Hyaluronan into Extracellular Matrix and Inhibits CD44-mediated Signaling toward Premature Senescence in Embryonic Fibroblasts. The Journal of biological chemistry 42 19164294
2019 Long noncoding RNA VCAN-AS1 contributes to the progression of gastric cancer via regulating p53 expression. Journal of cellular physiology 39 31637706
2012 Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome. European journal of human genetics : EJHG 35 22739342
2017 MiR-135a-5p modulates biological functions of thyroid carcinoma cells via targeting VCAN 3'-UTR. Cancer biomarkers : section A of Disease markers 34 28869452
1996 Deposition of PG-M/versican is a major cause of human coronary restenosis after percutaneous transluminal coronary angioplasty. The Journal of pathology 34 8958811
1999 Refined genetic and physical localization of the Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of chromosome 5q14.3. Genomics 33 10198161
2002 Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 12468455
1997 Transient expression of PG-M/versican, a large chondroitin sulfate proteoglycan in developing chicken retina. Journal of neurochemistry 31 9349562
1995 Expression pattern and mapping of the murine versican gene (Cspg2) to chromosome 13. Genomics 31 8530092
2021 INHBA promotes the proliferation, migration and invasion of colon cancer cells through the upregulation of VCAN. The Journal of international medical research 29 34130530
2008 Complex t(5;8) involving the CSPG2 and PTK2B genes in a case of dermatofibrosarcoma protuberans without the COL1A1-PDGFB fusion. Virchows Archiv : an international journal of pathology 28 18253748
2019 Up-regulation of EMT-related gene VCAN by NPM1 mutant-driven TGF-β/cPML signalling promotes leukemia cell invasion. Journal of Cancer 27 31777586
2020 VUp-Regulation of VCAN Promotes the Proliferation, Invasion and Migration and Serves as a Biomarker in Gastric Cancer. OncoTargets and therapy 26 32922041
2011 A new VCAN/versican splice acceptor site mutation in a French Wagner family associated with vascular and inflammatory ocular features. Molecular vision 26 21738396
2014 Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm. Meta gene 24 25606449
2009 Mutational hot spot potential of a novel base pair mutation of the CSPG2 gene in a family with Wagner syndrome. Archives of ophthalmology (Chicago, Ill. : 1960) 24 19901218
2020 The circ_VCAN with radioresistance contributes to the carcinogenesis of glioma by regulating microRNA-1183. Medicine 20 32080097
2019 VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site. Investigative ophthalmology & visual science 20 30657523
2014 Imbalanced expression of Vcan mRNA splice form proteins alters heart morphology and cellular protein profiles. PloS one 20 24586547
2021 miR-543 impairs cell proliferation, migration, and invasion in breast cancer by suppressing VCAN. Biochemical and biophysical research communications 19 34293593
2021 Long non-coding RNA VCAN-AS1 promotes the malignant behaviors of breast cancer by regulating the miR-106a-5p-mediated STAT3/HIF-1α pathway. Bioengineered 19 34365889
2024 Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression. Cell death & disease 18 38267463
1994 Abnormal occurrence of a large chondroitin sulfate proteoglycan, PG-M/versican in osteoarthritic cartilage. Osteoarthritis and cartilage 18 11548223
2005 Expression of a chondroitin sulfate proteoglycan, versican (PG-M), during development of rat cornea. Current eye research 16 16020278
1999 Genetic analysis of steel and the PG-M/versican-encoding gene AxPG as candidates for the white (d) pigmentation mutant in the salamander Ambystoma mexicanum. Development genes and evolution 16 10370116
2003 G3 domains of aggrecan and PG-M/versican form intermolecular disulfide bonds that stabilize cell-matrix interaction. Biochemistry 15 12846582
2006 Involvement of tenascin-C and PG-M/versican in flexor tenosynovial pathology of idiopathic carpal tunnel syndrome. Histology and histopathology 14 16493581
2021 Circular RNA Circ-0002570 Accelerates Cancer Progression by Regulating VCAN via MiR-587 in Gastric Cancer. Frontiers in oncology 13 34692507
2015 The Bacterial Component Flagellin Induces Anti-Sepsis Protection Through TLR-5, IL-1RN and VCAN During Polymicrobial Sepsis in Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 25968570
2018 Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome. American journal of medical genetics. Part A 12 30055036
1997 PG-M/versican-like proteoglycans are components of large disulfide-stabilized complexes in the axolotl embryo. The Journal of biological chemistry 12 9013561
2022 JAM-A facilitates hair follicle regeneration in alopecia areata through functioning as ceRNA to protect VCAN expression in dermal papilla cells. Precision clinical medicine 11 36132055
2022 VCAN, expressed highly in hepatitis B virus-induced hepatocellular carcinoma, is a potential biomarker for immune checkpoint inhibitors. World journal of gastrointestinal oncology 9 36310697
2010 The intracranial aneurysm susceptibility genes HSPG2 and CSPG2 are not associated with abdominal aortic aneurysm. Angiology 9 20053631
2001 Age differences in immunohistochemical localizations of large proteoglycan, PG-M/versican, and small proteoglycan, decorin, in the dermis of rats. Experimental animals 9 11381620
1997 Reduced epidermal expression of a PG-M/versican-like proteoglycan in embryos of the white mutant axolotl. Experimental cell research 9 9344585
2023 VCAN Hypomethylation and Expression as Predictive Biomarkers of Drug Sensitivity in Upper Urinary Tract Urothelial Carcinoma. International journal of molecular sciences 8 37108649
2022 Comprehensive bioinformatics and machine learning analysis identify VCAN as a novel biomarker of hepatitis B virus-related liver fibrosis. Frontiers in molecular biosciences 8 36275632
2020 Semen Modulates the Expression of NGF, ABHD2, VCAN, and CTEN in the Reproductive Tract of Female Rabbits. Genes 8 32645906
2007 Chondroitin sulfate proteoglycan 2 (CSPG2) gene polymorphisms rs173686 and rs251124 are not associated with intracranial aneurysms in Chinese Han nationality. Upsala journal of medical sciences 8 18484070
2024 The oncogenic ADAMTS1-VCAN-EGFR cyclic axis drives anoikis resistance and invasion in renal cell carcinoma. Cellular & molecular biology letters 7 39333870
2020 Identification of Novel Copy Number Variations of VCAN Gene in Three Chinese Families with Wagner Disease. Genes 6 32854301
2023 MiRNA-30a-5p/VCAN Arrests Tumor Metastasis via Modulating the Adhesion of Lung Adenocarcinoma Cells. Applied biochemistry and biotechnology 5 37032373
1998 Differentiation of EL4 lymphoma cells by tumoral environment is associated with inappropriate expression of the large chondroitin sulfate proteoglycan PG-M and the tumor-associated antigen HTgp-175. International journal of cancer 5 9797141
2025 The MIR181A2HG/miR-5680/VCAN-CD44 Axis Regulates Gastric Cancer Lymph Node Metastasis by Promoting M2 Macrophage Polarization. Cancer medicine 4 39823128
2024 Promotor Hypomethylation Mediated Upregulation of VCAN Targets Twist1 to Promote EndMT in Hypoxia-Induced Pulmonary Hypertension. Journal of the American Heart Association 4 39578365
2023 DSE inhibits melanoma progression by regulating tumor immune cell infiltration and VCAN. Cell death discovery 4 37833287
2025 Revealing VCAN as a Potential Common Diagnostic Biomarker of Renal Tubules and Glomerulus in Diabetic Kidney Disease Based on Machine Learning, Single-Cell Transcriptome Analysis and Mendelian Randomization. Diabetes & metabolism journal 3 39849979
2025 Resveratrol suppresses growth and VCAN expression in a Cancer-associated fibroblast-breast Cancer hybrid organoid. International immunopharmacology 3 40101422
2025 STAT5/VCAN/PI3K signaling pathway promotes fibroblast activation and lung fibrosis. Cellular signalling 3 40617369
2023 COL3A1, CXCL8, VCAN, THBS2, and COL1A2 are correlated with the onset of biliary atresia. Medicine 3 36930067
2023 Pan-cancer analysis of the oncogenic role of the core osteosarcoma gene VCAN in human tumors. American journal of translational research 3 37854213
2022 Downregulation of miR-23a-3p improves cognitive function in rats after subarachnoid hemorrhage by targeting VCAN. Medical molecular morphology 3 35137264
2021 Expression of VCAN and its receptors in canine mammary carcinomas with or without myoepithelial proliferation. Research in veterinary science 3 34399281
2013 [Association of single nucleotide polymorphisms of CSPG2 and HSPG2 genes with intracranial aneurysm in ethnic Han Chinese population]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 23568740
2025 Indole-3-lactic acid derived from tryptophan metabolism promotes trophoblast migration and invasion by activating the AhR/VCAN pathway. Placenta 2 40153926
2024 VCAN in the extracellular matrix drives glioma recurrence by enhancing cell proliferation and migration. Frontiers in neuroscience 2 39554845
2024 Long non-coding RNA VCAN-AS1 promotes gastric cancer progression via the HuR/F11R pathway. American journal of translational research 2 39678543
2023 Sevoflurane Exposure of Clinical Doses in Pregnant Rats Induces Vcan Changes without Significant Neural Apoptosis in the Offspring. Medicina (Kaunas, Lithuania) 2 36837392
2022 A novel splicing variant of VCAN identified in a Chinese family initially diagnosed with familial exudative vitreoretinopathy. Molecular genetics & genomic medicine 2 36333947
2022 Multimodal Retinal Imaging Findings in Two Cousins With VCAN-Related Vitreoretinopathy or Wagner Disease. Ophthalmic surgery, lasers & imaging retina 2 36378611
2019 The Association between Genes Polymorphisms of Heparan Sulfate Proteoglycan 2 (HSPG2) and Chondroitin Sulfate Proteoglycan 2 (CSPG2) and Intracranial Aneurysm Susceptibility: A Meta-Analysis. Iranian journal of public health 2 31970092
2026 Bulk Sequencing Combined With Single-Cell Sequencing Identifies High Expression of VCAN in Fibroblasts Promoting the Progression of High-Stemness Gastric Adenocarcinoma Cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41555841
2026 Trichosanthes kirilowii extract alleviated liver fibrosis and acute myocardial infarction by inhibiting VCAN to restrain monocyte senescence: Insights from bioinformatic analyses and experimental validation. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41720002
2026 LncRNA VCAN-AS1 Sponges miR-374c-3p to Promote Proliferation, Invasion, Migration, and EMT in Thyroid Cancer. International journal of endocrinology 0 41800331
2025 Visfatin facilitates esophageal cancer migration by suppressing miR‑3613‑5p expression and promoting VEZF1/VCAN production. Oncology reports 0 40747711
2024 Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study. BMC pulmonary medicine 0 38685004