Affinage

TNC

Tenascin · UniProt P24821

Round 2 corrected
Length
2201 aa
Mass
240.9 kDa
Annotated
2026-04-28
130 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Tenascin-C (TNC) is a hexabrachion-forming extracellular matrix glycoprotein that orchestrates cell adhesion, inflammation, fibrosis, and tissue remodeling by engaging multiple receptor systems and signaling pathways. Its modular architecture—comprising EGF-like repeats, alternatively spliced fibronectin type III (FNIII) domains, and a fibrinogen-like globe—enables distinct receptor interactions: EGF-like repeats directly activate EGFR to stimulate mitogenesis and RhoA inactivation favoring invasion (PMID:11470832, PMID:15059978); FNIII domains engage integrins α2β1, αvβ3, α8β1, and α9β1 through RGD-dependent and -independent mechanisms (PMID:7694284, PMID:7693733, PMID:7523411, PMID:7559467); the alternatively spliced FNIII segment binds annexin II with nanomolar affinity (PMID:7518469); and the fibrinogen-like domain activates TLR4 to drive NF-κB–dependent cytokine production, sustaining chronic inflammation in arthritis and organ fibrosis (PMID:19561617, PMID:27256716). TNC expression is transcriptionally controlled by HIF1α (downstream of IDH1 status and tissue stiffness), Twist1→Prrx1, and CREB5, and post-transcriptionally repressed by miR-218 and miR-9-5p (PMID:27820599, PMID:39181396, PMID:39915455, PMID:34558654, PMID:31169312). Missense mutations in the fibrinogen-like domain co-segregate with autosomal dominant nonsyndromic hearing loss (DFNA56) (PMID:23936043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    Establishing the complete modular architecture of human TNC—including 14.5 EGF-like repeats, 15 FNIII repeats, and alternatively spliced isoforms—provided the domain framework necessary for all subsequent receptor-mapping and signaling studies.

    Evidence cDNA sequencing with PCR-based splice variant identification and monoclonal antibody epitope mapping

    PMID:1707164

    Open questions at the time
    • No functional assays for individual domains at this stage
    • Stoichiometry of isoform expression across tissues not determined
  2. 1992 High

    Solving the FNIII domain crystal structure at 1.8 Å revealed the immunoglobulin-superfamily fold and exposed RGD loop, explaining how TNC presents cell-adhesion motifs and providing the first atomic-level understanding of an ECM repeat module.

    Evidence X-ray crystallography with MAD phasing of selenomethionyl protein

    PMID:1279805

    Open questions at the time
    • Only one of 15 FNIII repeats was structurally resolved
    • No structures of EGF-like repeats or the fibrinogen-like globe
  3. 1993 High

    Identification of multiple integrin receptors (αvβ3 via RGD, α2β1 via a non-RGD site) revealed that TNC engages the cell surface through mechanistically distinct, partially redundant adhesion pathways rather than a single integrin.

    Evidence Recombinant FNIII fragment adhesion assays, RGD mutagenesis, anti-integrin blocking antibodies, and affinity purification of integrins on TNC columns in endothelial cells

    PMID:7693733 PMID:7694284

    Open questions at the time
    • Structural basis of α2β1 binding to TNC not defined
    • Relative contribution of each integrin in vivo not determined
  4. 1994 High

    Discovery that α9β1 binds TNC's third FNIII repeat at a non-RGD site, and that annexin II serves as a high-affinity receptor for the alternatively spliced FNIII segment, expanded the receptor repertoire beyond classical integrins and demonstrated isoform-specific signaling potential.

    Evidence α9 cDNA transfection with RGD mutagenesis (α9β1); radioligand Scatchard analysis, affinity chromatography, and anti-annexin II blocking (annexin II)

    PMID:7518469 PMID:7523411

    Open questions at the time
    • Downstream signaling from α9β1–TNC interaction not characterized
    • In vivo relevance of annexin II–TNC interaction not tested
  5. 1995 High

    Identification of α8β1 as an additional TNC integrin receptor reinforced the emerging picture of TNC as a multi-integrin ligand and showed that among RGD-containing ECM proteins, TNC has an unusually broad integrin-binding repertoire.

    Evidence α8 cDNA transfection in 293 cells, adhesion assays on recombinant TNC fragments, GRGDSP peptide elution from affinity columns

    PMID:7559467

    Open questions at the time
    • Functional consequences of α8β1–TNC binding in tissue contexts undefined
  6. 1997 High

    Demonstrating that TNC–αvβ3 interaction redistributes actin and clusters EGFR, increasing its tyrosine phosphorylation, established the first mechanistic link between TNC-mediated adhesion and growth factor receptor transactivation.

    Evidence Exogenous TNC on SMCs, β3-integrin cross-linking, EGFR phosphorylation assays, actin/EGFR colocalization by immunofluorescence

    PMID:9314546

    Open questions at the time
    • Whether direct EGFR binding by TNC contributes was not tested
    • In vivo relevance in vascular remodeling not shown
  7. 2001 High

    Two discoveries redefined TNC's signaling capacity: its EGF-like repeats were shown to directly bind and activate EGFR (functioning as a matrix-tethered growth factor), and its binding to fibronectin's FNIII13 was shown to disrupt syndecan-4 coreceptor function, explaining TNC's anti-adhesive and pro-proliferative effects on the fibronectin matrix.

    Evidence EGFR autophosphorylation, ERK activation, and bead-tethered adhesion assays with EGF competition (EGFR); syndecan-4 rescue and FNIII13 competition on mixed FN/TNC substrata (syndecan-4)

    PMID:11470832 PMID:11731446

    Open questions at the time
    • Affinity of EGF-like repeats for EGFR much lower than EGF—physiological relevance of soluble presentation uncertain
    • Whether syndecan-4 displacement occurs in vivo not demonstrated
  8. 2004 High

    Placing TNC upstream of RhoA inactivation (via EGFR) and permissive for HGF/Rac-driven invasion established an epistatic pathway by which stromal TNC directs tumor cell morphological switching and invasive behavior.

    Evidence Collagen I/Matrigel invasion assays with dominant-negative/constitutively active Rho and Rac mutants, pharmacological inhibitors, myofibroblast co-culture

    PMID:15059978

    Open questions at the time
    • In vivo invasion assays not performed
    • Whether TNC acts solely through EGFR-EGF-like repeats or also through integrins in this context is unresolved
  9. 2009 High

    Identification of TNC as an endogenous TLR4 ligand—via its fibrinogen-like domain—fundamentally reframed TNC from a structural/adhesion molecule to a danger-associated molecular pattern (DAMP) that sustains chronic inflammation, as demonstrated by protection of Tnc-null mice from erosive arthritis and the role of periostin in incorporating TNC into ECM meshworks.

    Evidence Tnc-KO mice in arthritis model, TLR4-blocking antibodies and TLR4-deficient cells, human synovial cell stimulation (TLR4); periostin-null and TNC-null mouse phenocopying, domain-mapping binding assays (periostin)

    PMID:19561617 PMID:19887451

    Open questions at the time
    • Crystal structure of TNC fibrinogen-like domain bound to TLR4 not available
    • Whether periostin-mediated TNC incorporation amplifies TLR4 signaling not directly tested
  10. 2016 High

    Extension of the TLR4 mechanism to organ fibrosis (skin and lung) confirmed TNC as a general DAMP maintaining fibrosis amplification loops, while discovery of HIF1α-dependent transcriptional control downstream of IDH1 and tissue stiffness revealed a mechanosensitive feed-forward circuit in glioblastoma.

    Evidence TNC-KO mice in bleomycin skin/lung fibrosis models with fibroblast TLR4 signaling assays (fibrosis); IDH1 gain/loss-of-function xenografts with AFM stiffness measurements and HIF1α/miR-203 manipulation (glioblastoma)

    PMID:27256716 PMID:27820599

    Open questions at the time
    • Whether TLR4-TNC signaling is the sole driver or synergizes with integrin/EGFR pathways in fibrosis is unclear
    • Quantitative threshold of ECM stiffness required to activate HIF1α-TNC loop not defined
  11. 2019 Medium

    miR-9-5p was validated as a direct post-transcriptional suppressor of TNC in chondrocytes, linking miRNA dysregulation to TNC-driven cartilage pathology in osteoarthritis.

    Evidence Luciferase reporter assay confirming miR-9-5p binding to Tnc 3'UTR, gain/loss-of-function in OA mouse model

    PMID:31169312

    Open questions at the time
    • Single study from one lab
    • Whether miR-9-5p regulation of TNC operates in tissues beyond cartilage is unknown
  12. 2021 Medium

    miR-218 was confirmed as a second direct miRNA repressor of TNC, and TNC was placed within a TGFβ1/AKT/AP-1 positive feedback loop in glioma, further elucidating post-transcriptional control and downstream signaling.

    Evidence Dual-luciferase 3'UTR reporter, miR-218 overexpression/inhibition, nude mouse xenograft

    PMID:34558654

    Open questions at the time
    • Relative importance of miR-218 vs miR-9-5p in controlling TNC levels in different tissues not compared
    • Feedback loop not validated in non-glioma contexts
  13. 2024 High

    ChIP-based demonstration that Twist1 drives TNC expression indirectly through Prrx1 in fibroblasts provided the first two-step transcription factor cascade for TNC in kidney fibrosis, validated with fibroblast-specific Twist1 knockout mice.

    Evidence ChIP for Twist1 on Prrx1 promoter and Prrx1 on TNC promoter, fibroblast-specific Twist1-KO mice in UUO and IR injury

    PMID:39181396

    Open questions at the time
    • Whether Twist1→Prrx1→TNC cascade operates in fibrosis of other organs not tested
    • Direct versus Prrx1-mediated contribution of Twist1 not quantified
  14. 2025 Medium

    Discovery that ER stress activates CREB5 via a super-enhancer to directly drive TNC transcription and EMT in hepatocellular carcinoma added a stress-responsive transcriptional input to the growing regulatory network.

    Evidence ChIP-seq for super-enhancer, ChIP for CREB5 on TNC promoter, CRISPR-Cas9 KO and overexpression

    PMID:39915455

    Open questions at the time
    • Single study; independent replication needed
    • Whether CREB5-driven TNC activates TLR4 or EGFR in this context not examined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of TNC fibrinogen-like domain recognition by TLR4; how multiple receptor systems (integrins, EGFR, TLR4, annexin II) are spatially and temporally coordinated on a single hexabrachion; and the in vivo hierarchy among transcriptional (HIF1α, Twist1/Prrx1, CREB5) and post-transcriptional (miR-218, miR-9-5p) regulatory inputs across different tissue and disease contexts.
  • No co-crystal structure of TNC-TLR4 or TNC-EGFR
  • Relative signaling output from simultaneous engagement of multiple receptor types on a hexabrachion not quantified
  • Integrated regulatory model across tissues lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0005198 structural molecule activity 3 GO:0048018 receptor ligand activity 3
Localization
GO:0031012 extracellular matrix 4 GO:0005576 extracellular region 3
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ANXA2EGFRITGA2ITGA9ITGAVITGB1ITGB3POSTN

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The crystal structure of a fibronectin type III (FNIII) domain from tenascin-C was solved by multiwavelength anomalous diffraction (MAD) phasing of the selenomethionyl protein to 1.8 Å resolution, revealing a folding topology identical to extracellular domains of the human growth hormone receptor and CD4, and distinct from but related to immunoglobulin constant domains. An RGD sequence mediating cell adhesion was found in a tight turn on an exposed loop. X-ray crystallography (MAD phasing, selenomethionyl protein), 1.8 Å resolution Science High 1279805
1991 The complete primary structure of human tenascin-C was established by cDNA sequencing, identifying 14.5 EGF-like repeats and 15 fibronectin type III repeats (versus 11 in chicken). At least four different isoforms containing different numbers of FNIII repeats were identified by PCR, demonstrating alternative splicing of the TNC pre-mRNA. Monoclonal antibody BC-2 was mapped to an alternatively spliced FNIII repeat, while BC-4 recognized an EGF-like epitope present in all isoforms. cDNA sequencing, PCR amplification of splice variants, expression vector library screening, epitope mapping Nucleic Acids Research High 1707164
1993 Multiple integrins of the αv subtype mediate cell attachment to the third FNIII repeat of tenascin-C (cytotactin) containing the RGD tripeptide. However, mutation of RGD to RAD did not abolish attachment, and anti-β1 antibodies partially inhibited binding to intact TNC but not the FNIII repeat, indicating additional integrin receptors. Thus TNC engages multiple integrin receptor subtypes through partially RGD-dependent and -independent mechanisms. Recombinant fusion protein cell attachment assays, RGD peptide competition, anti-integrin blocking antibodies Proceedings of the National Academy of Sciences High 7694284
1993 Human umbilical vein endothelial cells attach to and spread on human tenascin-C via two distinct integrin receptors: α2β1 mediates cell spreading (inhibited by anti-α2 and anti-β1 antibodies), and αvβ3 mediates partial cell attachment via the SRRGDMS site (inhibited by LM609). Both integrins were affinity-purified on tenascin-C columns. The α2β1 binding site on TNC is distinct from the RGD site. Anti-integrin blocking antibodies, affinity chromatography on TNC-coated columns, radio-receptor binding assay Journal of Cell Science High 7693733
1994 The alternatively spliced segment of tenascin-C (TNfnA-D) binds specifically to annexin II on the cell surface of glioma and endothelial cells with ~2 nM affinity (~2–5 × 10^5 binding sites/cell). Annexin II was identified by Scatchard analysis, blot binding assays, affinity chromatography, and protein sequencing. Anti-annexin II antibodies blocked TNfnA-D binding to live cells, establishing annexin II as a cell-surface receptor for the alternatively spliced region of TNC. Radioligand binding assay, Scatchard analysis, affinity chromatography, protein sequencing, blocking antibodies Journal of Cell Biology High 7518469
1994 The integrin α9β1 mediates cell attachment to the third FNIII repeat of tenascin-C at a site that is not the RGD tripeptide: RGD peptide competition and RGD→RAD/RAA mutations did not inhibit α9β1 binding. α9β1 did not mediate attachment to fibronectin, laminin, vitronectin, fibrinogen, thrombospondin, or collagens, identifying tenascin-C as a specific ligand for this integrin. Stable transfection of α9 cDNA in 293 and SW480 cells, cell adhesion assays with recombinant TNC fragments, RGD peptide competition, mutagenesis of RGD site Journal of Biological Chemistry High 7523411
1995 The integrin α8β1 functions as a receptor for tenascin-C, fibronectin, and vitronectin. α8β1 binds to the RGD-containing third FNIII repeat of tenascin-C (eluted by GRGDSP peptide), localizes to focal contacts on fibronectin and vitronectin substrata, and mediates adhesion of α8-transfected 293 cells. Among RGD-containing ECM proteins, only tenascin was able to mediate adhesion via α8β1 in addition to fibronectin and vitronectin. Stable transfection of α8 cDNA, cell adhesion assays, affinity chromatography on fibronectin/vitronectin-Sepharose with RGD peptide elution, recombinant TNC fragment binding Journal of Biological Chemistry High 7559467
1997 Tenascin-C promotes survival and EGF-dependent growth of vascular smooth muscle cells (SMCs) through interaction with αvβ3 integrins. TNC-αvβ3 interaction redistributes filamentous actin to focal adhesion complexes that colocalize with EGF receptor clusters, increasing EGF-R tyrosine phosphorylation and activation. Cross-linking β3 integrins replicates TNC effects on EGF-R clustering and phosphorylation. MMP inhibition (GM6001) suppresses TNC expression; denatured collagen induces TNC in a β3-integrin-dependent manner. Exogenous TNC addition to SMCs, MMP inhibitor treatment, floating collagen gel assays, β3-integrin cross-linking, EGF-R phosphorylation assays, actin/EGF-R colocalization by immunofluorescence Journal of Cell Biology High 9314546
2001 Select EGF-like repeats of tenascin-C directly bind to and activate the EGF receptor (EGFR), inducing EGFR autophosphorylation and ERK/MAPK activation, and stimulating mitogenesis. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation to levels comparable to subsaturating EGF. When tethered to inert beads (simulating hexabrachion presentation), EGF-like repeats mediated EGFR-dependent adhesion. Specific EGFR binding was confirmed by immunofluorescence and EGFR cross-linking, both abolished by EGF competition. EGFR autophosphorylation assays, ERK/MAPK activation, mitogenesis assay, bead-mediated adhesion, immunofluorescence, EGF competition, EGFR cross-linking Journal of Cell Biology High 11470832
2001 Tenascin-C directly binds to the 13th fibronectin type III repeat (FNIII13) of fibronectin, blocking syndecan-4 binding to fibronectin's HepII site. This inhibits integrin signaling (syndecan-4 coreceptor function) and disrupts cell adhesion while promoting tumor cell proliferation. Overexpression of syndecan-4 (but not syndecan-1 or -2) rescued the adhesion defect, and addition of FNIII13 restored adhesion and normalized proliferation. Mixed fibronectin/TNC substratum adhesion assays, syndecan overexpression (rescue experiment), recombinant FNIII13 competition, cell proliferation assays Cancer Research High 11731446
2004 Tenascin-C secreted by myofibroblasts promotes invasion of colon cancer cells by inactivating RhoA via the EGF-like repeats of TNC through EGFR signaling, creating a permissive signal for SF/HGF-activated Rac via c-Met. Myofibroblast-stimulated invasion is characterized by a morphological shift from round (high RhoA, low Rac) to elongated (low RhoA, high Rac) phenotype. Dominant-negative and constitutively active mutants of RhoA-ROCK and Rac, plus pharmacological modulators, confirmed this epistatic pathway: TNC acts upstream of RhoA inactivation, which is required for SF/HGF-Rac-driven invasion. In vitro invasion assay into collagen I/Matrigel, dominant-negative and constitutively active Rho/Rac mutants, pharmacological inhibitors of RhoA-ROCK and Rac, morphotype analysis, co-culture of myofibroblasts and cancer cells FASEB Journal High 15059978
2009 Tenascin-C is an endogenous activator of Toll-like receptor 4 (TLR4) that drives persistent synovial inflammation. Tnc-knockout mice show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of TNC promotes joint inflammation in vivo. In human synovial macrophages and fibroblasts, exogenous TNC induces proinflammatory cytokine synthesis specifically via TLR4 activation. TNC's fibrinogen-like domain was identified as the TLR4-activating region. Tnc knockout mice (in vivo arthritis model), intra-articular TNC injection, explant cultures from RA synovia, human macrophage/fibroblast stimulation with TNC, TLR4-blocking antibodies and TLR4-deficient cells Nature Medicine High 19561617
2009 Periostin promotes incorporation of tenascin-C into the extracellular matrix by acting as a molecular bridge: periostin possesses adjacent domains that bind to TNC and to fibronectin/type I collagen, thereby tethering TNC hexabrachions to ECM fibrils and stabilizing bifurcations to form a meshwork architecture. Both periostin-null and TNC-null mice exhibit a similar phenotype of confined tibial periostitis, and periostin deposition of TNC was demonstrated by in vitro binding assays. Periostin-null and TNC-null mouse phenotyping, in vitro protein-protein binding assays mapping periostin domains to TNC and fibronectin/collagen Journal of Biological Chemistry High 19887451
2011 TNC promoter activity is dynamically regulated during the cell cycle: live cell imaging of an NIH 3T3 line stably transfected with a TNC promoter-destabilized GFP reporter showed that TNC promoter activity increases during the last 40% of the cell cycle, and that the magnitude of this increase is proportional to promoter activity earlier in the cycle. Live cell phase-contrast and fluorescence microscopy, destabilized GFP reporter under TNC promoter, automated single-cell tracking over 62 h Cytometry Part A Medium 22045641
2013 Missense mutations in TNC (c.5317G>A, p.V1773M and c.5368A>T, p.T1796S), located in the conserved fibrinogen-like domain, co-segregate with autosomal dominant progressive nonsyndromic hearing loss (DFNA56) in two Chinese families. TNC is expressed in the basilar membrane and osseous spiral lamina of the cochlea, implicating it in cochlear structural integrity. Genome-wide linkage analysis, whole exome sequencing, Sanger sequencing validation, mass spectrometry genotyping, segregation analysis in 53 family members PLoS One Medium 23936043
2014 Mechanical stress upregulates expression of the alternatively spliced tenascin-C FNIIIA1 domain in osteosarcoma MG-63 cells through the mTOR/4E-BP1/S6K1 signaling pathway. Pharmacological inhibition of mTOR suppressed mechanical stress-induced A1 upregulation, and knockdown of 4E-BP1 and S6K1 reduced basal A1 expression. FNIIIA1 expression promoted MG-63 cell migration. Cyclic mechanical stress application, mTOR inhibitor treatment, siRNA knockdown of 4E-BP1 and S6K1, RT-PCR and Western blot, cell migration assay Molecules and Cells Medium 24598996
2016 Tenascin-C drives persistence of organ fibrosis by activating TLR4 signaling in fibroblasts. Exogenous TNC stimulates collagen gene expression and myofibroblast transformation via TLR4. Tenascin-C null mice show attenuation of both skin and lung fibrosis (bleomycin model) and accelerated fibrosis resolution. This identifies TNC as an endogenous danger signal that maintains a TLR4-dependent fibrosis amplification loop. Tenascin-C KO mice (skin and lung fibrosis models), exogenous TNC stimulation of fibroblasts, TLR4 signaling assays, collagen gene expression, myofibroblast transformation assays Nature Communications High 27256716
2016 In glioblastoma, tissue stiffness and TNC expression form a positive feedback loop with IDH1 and HIF1α: mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression, decreasing ECM stiffness and mechanosignalling. HIF1α directly drives TNC expression; recurrent IDH1-mutant tumors bypass this suppression via reduced miR-203-mediated suppression of HIF1α and TNC. Gain- and loss-of-function xenograft manipulations confirmed that IDH1 mutation reduces TNC-ECM stiffness and tumor aggression. IDH1 gain- and loss-of-function xenograft models, atomic force microscopy (ECM stiffness), HIF1α manipulation, miR-203 functional studies, patient glioma sample analysis Nature Cell Biology High 27820599
2008 EMMPRIN (CD147) overexpression in oral squamous cell carcinoma (SCC) cells promotes tenascin-C deposition in co-cultures with peritumoral fibroblasts, in an MMP-dependent manner (suppressed by the broad-spectrum MMP inhibitor GM6001). EMMPRIN knockdown by siRNA reduced both cell migration and TNC deposition, while EMMPRIN overexpression increased MMP-2, -3, -9 expression and TNC deposition several-fold, establishing an EMMPRIN→MMP→TNC deposition axis. EMMPRIN retroviral overexpression, siRNA knockdown, co-culture with fibroblasts, MMP inhibitor (GM6001) treatment, TNC deposition quantification, cell migration assay Anticancer Research Medium 18751374
2019 NG2 proteoglycan binds to tenascin-C via its core protein (chondroitinase treatment did not reduce binding), in a concentration-dependent and saturable manner demonstrated by solid-phase binding assay. Decorin did not bind tenascin-C and could not inhibit NG2-tenascin binding, indicating NG2 uses a distinct domain for tenascin that differs from its collagen-binding region. Solid-phase binding assay with purified NG2, chondroitinase treatment, decorin competition assay Journal of Biological Chemistry Medium 8824254
2020 Novel TNC-USP6 gene fusions were identified in two cases of primary aneurysmal bone cyst (ABC) by next-generation sequencing, confirmed by RT-PCR and Sanger sequencing. TNC serves as a novel fusion partner driving USP6 rearrangement in this neoplasm. Next-generation sequencing (NGS), RT-PCR, Sanger sequencing Genes, Chromosomes & Cancer Medium 32011035
2021 In diabetic kidney disease, TNC activates the TLR4/NF-κB p65 pathway in rat glomerular mesangial cells under high glucose conditions, leading to upregulation of miR-155-5p, and downstream increases in CTGF and fibronectin (fibrosis markers). TNC knockdown reduced TLR4, p-NF-κB p65, miR-155-5p, CTGF, and fibronectin levels. Metformin treatment reduced TNC, p-NF-κB p65, CTGF, and FN protein levels. TNC knockdown in rat mesangial cells, high glucose stimulation, Western blot, qPCR, ELISA for TNC, immunohistochemistry in diabetic rat glomeruli World Journal of Diabetes Medium 33520106
2021 miR-218 targets the 3'UTR of TNC mRNA (confirmed by dual-luciferase reporter assay), suppressing TNC protein expression. Loss of TNC reduces AKT phosphorylation and JNK phosphorylation (AP-1 transcriptional activity), which decreases TGFβ1 expression. TGFβ1 in turn activates the TNC/AKT/AP-1 axis, forming a positive feedback loop. miR-218 overexpression inhibited glioma cell proliferation, migration, invasion, and tumor growth in nude mice, and induced apoptosis. Dual-luciferase reporter (3'UTR binding), Western blot (AKT/JNK phosphorylation), miR-218 overexpression/inhibition, in vivo nude mouse xenograft, colony formation, invasion assays International Journal of Molecular Medicine Medium 34558654
2024 Transcription factor Twist1 promotes kidney fibrosis by driving TNC expression through an indirect mechanism: Twist1 directly binds the Prrx1 promoter to upregulate Prrx1, and Prrx1 in turn directly binds the TNC promoter to upregulate TNC expression. Fibroblast-specific Twist1 knockout mice showed reduced Prrx1 and TNC protein, decreased interstitial ECM deposition, and less kidney inflammation in UUO and ischemia-reperfusion fibrosis models. TGF-β1 induces Twist1 in fibroblasts. Chromatin immunoprecipitation (Twist1 binding to Prrx1 promoter; Prrx1 binding to TNC promoter), fibroblast-specific Twist1 KO mice (UUO and IR injury models), TGF-β1 stimulation, gain/loss-of-function experiments Kidney International High 39181396
2025 CREB5, activated by endoplasmic reticulum stress (ERS) via a super-enhancer, directly binds the TNC promoter to upregulate TNC transcription, thereby promoting epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. ChIP-seq identified the ERS-related super-enhancer, and CREB5 overexpression increased TNC expression and EMT markers; CREB5 knockdown reduced them. This CREB5/TNC axis is activated downstream of ERS. ChIP-seq (super-enhancer identification), ChIP (CREB5 binding to TNC promoter), RT-qPCR, Western blot, CRISPR-Cas9 KO and overexpression, TCGA dataset analysis, tissue arrays Cell Death & Disease Medium 39915455
2019 miR-9-5p directly targets and suppresses Tnc (tenascin-C) expression in chondrocytes; the miR-9-5p binding site on Tnc was confirmed by luciferase reporter assay. In an OA mouse model following tibial plateau fracture, miR-9-5p was downregulated while Tnc was upregulated. Overexpression of miR-9-5p or Tnc knockdown inhibited chondrocyte apoptosis and promoted proliferation, migration, and cartilage remodeling. Luciferase reporter assay (miR-9-5p/Tnc 3'UTR), gain/loss-of-function in OA mouse model and in vitro, Western blot, Mankin scoring of cartilage Journal of Cellular Physiology Medium 31169312

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
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
1984 T and Tn, general carcinoma autoantigens. Science (New York, N.Y.) 899 6729450
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2009 Tn-seq: high-throughput parallel sequencing for fitness and genetic interaction studies in microorganisms. Nature methods 730 19767758
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2009 Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature medicine 591 19561617
2000 The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Developmental dynamics : an official publication of the American Association of Anatomists 521 10842355
2020 Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet (London, England) 519 32305093
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
1992 Structure of a fibronectin type III domain from tenascin phased by MAD analysis of the selenomethionyl protein. Science (New York, N.Y.) 473 1279805
2003 Tenascins: regulation and putative functions during pathological stress. The Journal of pathology 442 12845616
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2004 Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 313 15059978
1997 Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. The Journal of cell biology 292 9314546
2011 The Tn antigen-structural simplicity and biological complexity. Angewandte Chemie (International ed. in English) 291 21259410
2016 Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression. Nature cell biology 272 27820599
2007 Myofibre damage in human skeletal muscle: effects of electrical stimulation versus voluntary contraction. The Journal of physiology 263 17584833
2016 Tenascin-C drives persistence of organ fibrosis. Nature communications 241 27256716
2008 Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer research 240 18339842
2009 Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. The Journal of biological chemistry 233 19887451
2001 Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. The Journal of cell biology 233 11470832
2010 Proteomics characterization of extracellular space components in the human aorta. Molecular & cellular proteomics : MCP 231 20551380
2001 Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation. Cancer research 222 11731446
1993 Multiple integrins mediate cell attachment to cytotactin/tenascin. Proceedings of the National Academy of Sciences of the United States of America 220 7694284
2005 Protein glycosylation: chaperone mutation in Tn syndrome. Nature 213 16251947
1994 Cell surface annexin II is a high affinity receptor for the alternatively spliced segment of tenascin-C. The Journal of cell biology 204 7518469
2014 Extracellular matrix signatures of human primary metastatic colon cancers and their metastases to liver. BMC cancer 203 25037231
1991 Human tenascin: primary structure, pre-mRNA splicing patterns and localization of the epitopes recognized by two monoclonal antibodies. Nucleic acids research 198 1707164
1995 The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. The Journal of biological chemistry 189 7559467
2017 Characterization of the Extracellular Matrix of Normal and Diseased Tissues Using Proteomics. Journal of proteome research 185 28675934
1993 Endothelial cell attachment and spreading on human tenascin is mediated by alpha 2 beta 1 and alpha v beta 3 integrins. Journal of cell science 185 7693733
1994 The integrin alpha 9 beta 1 mediates cell attachment to a non-RGD site in the third fibronectin type III repeat of tenascin. The Journal of biological chemistry 182 7523411
2011 Protein interactome reveals converging molecular pathways among autism disorders. Science translational medicine 180 21653829
2012 Proteomics analysis of cardiac extracellular matrix remodeling in a porcine model of ischemia/reperfusion injury. Circulation 179 22261194
1996 Binding of the NG2 proteoglycan to type VI collagen and other extracellular matrix molecules. The Journal of biological chemistry 176 8824254
2016 The Role of Sialyl-Tn in Cancer. International journal of molecular sciences 171 26927062
2016 Tumor-associated antigens: Tn antigen, sTn antigen, and T antigen. HLA 171 27679419
2013 Tn and sialyl-Tn antigens, aberrant O-glycomics as human disease markers. Proteomics. Clinical applications 132 23857728
2014 The Cosmc connection to the Tn antigen in cancer. Cancer biomarkers : section A of Disease markers 126 24643043
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