Affinage

THBS2

Thrombospondin-2 · UniProt P35442

Length
1172 aa
Mass
130.0 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THBS2 (TSP2) is a secreted matricellular glycoprotein that governs extracellular matrix architecture, remodeling, and signaling, distinct in expression and function from the related thrombospondin TSP1 (PMID:1712771, PMID:12213711). A central activity is the negative regulation of matrix metalloproteinases: TSP2 binds and promotes clearance of MMP2 (and MMP9), and loss of this function increases MMP2-mediated proteoglycan cleavage and produces disorganized collagen fibers and abnormal cell morphology (PMID:38433265, PMID:18455130). Through this and direct ECM-structuring roles, TSP2 controls collagen fibril diameter, matrix stiffness and mechanical strength, with consequences for intraocular pressure regulation, matrix remodeling permissiveness, and cancer stem-cell-supporting matrix softness (PMID:22930728, PMID:29631168, PMID:33717837). A heterozygous missense mutation (p.Cys896Arg) causes a vascular-featured form of Ehlers-Danlos syndrome, recapitulated in CRISPR knock-in mice and mechanistically linked to attenuated MMP2 clearance (PMID:38433265). TSP2 also acts as a signaling ligand: it potentiates Notch signaling by binding Jagged1 and Notch ectodomains and driving LRP1-dependent trans-endocytosis (PMID:20472562, PMID:28090565), engages neuronal α2δ1/Rac1 signaling to control excitatory synapse formation and synaptic maintenance (PMID:33382873, PMID:36471420, PMID:30928339), and binds tumor-cell receptors including integrin αvβ3/CD36, SDC4, and ITGB1 to activate MAPK and PI3K/AKT pathways downstream of CAF-derived TSP2, promoting EMT and tumor progression (PMID:34958892, PMID:40973793, PMID:36728807). In fibroblasts, TSP2 promotes TGF-β1/Smad2/3-driven collagen synthesis in fibrosis (PMID:40676074) yet negatively regulates a Rac1–WAVE2–actin cytoskeletal axis and Wnt4/β-catenin pro-regenerative programs (PMID:36577792, PMID:41427771). Its expression is controlled transcriptionally (p53, NF-κB, Sp1 sites; CEBPB, XBP1) and post-transcriptionally (METTL14/YTHDF2 m6A stabilization, miR-29a-3p) (PMID:9249061, PMID:36728807, PMID:40293258, PMID:40730238).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1991 Medium

    Establishing that THBS2 is a distinct gene product from THBS1 with a divergent tissue expression pattern resolved whether the two thrombospondins were functionally interchangeable.

    Evidence cDNA cloning, sequence analysis, and tissue expression profiling in mouse

    PMID:1712771

    Open questions at the time
    • No functional or biochemical activity assigned at cloning
    • Protein-level localization and partners undefined
  2. 1997 Medium

    Mapping the human THBS2 promoter and tissue-specific transcription start sites explained how THBS2 expression is differentially regulated across tissues.

    Evidence Genomic sequencing, 5' RACE, and PCR-based transcription start site mapping

    PMID:9249061

    Open questions at the time
    • Functional contribution of each transcription factor site not tested
    • No link to physiological regulation
  3. 2002 High

    Genetic epistasis in double-null mice distinguished the non-redundant roles of TSP1 and TSP2, showing TSP1 dominates the wound-healing response.

    Evidence Single and double TSP1/TSP2 knockout mouse comparison with immunohistochemistry and cytokine measurement

    PMID:12213711

    Open questions at the time
    • Molecular basis of the TSP2-specific wound contribution not defined
    • Receptor/effector pathway not isolated
  4. 2003 Medium

    Demonstrating that TSP2 overexpression suppresses MMP2/MMP9 while inducing MMP12/MMP17 positioned TSP2 as an MMP-expression modulator in carcinoma cells.

    Evidence cDNA array and Western blot after stable TSP2 overexpression in SW480 colon carcinoma cells

    PMID:12792739

    Open questions at the time
    • Distinguishes expression effects from direct binding/clearance not addressed here
    • Single cell line
  5. 2008 High

    A functional splicing variant linked THBS2-MMP binding to human disease, showing exon-11 skipping reduces MMP2/MMP9 interaction and confers lumbar disc herniation susceptibility.

    Evidence Genetic association study, in vivo splicing assay, and THBS2-MMP binding assay in two Japanese populations

    PMID:18455130

    Open questions at the time
    • Structural basis of the THBS2-MMP interaction not resolved
    • Mechanism of clearance versus inhibition not separated
  6. 2010 High

    Identifying TSP2 as a Jagged1/Notch3 co-ligand that drives LRP1-dependent trans-endocytosis revealed a signaling, not purely structural, function for the matricellular protein.

    Evidence Co-IP/pulldown, LRP1-deficient fibroblast rescue, RAP inhibition, and endocytosis assays

    PMID:20472562

    Open questions at the time
    • In vivo relevance of Notch3 potentiation not established
    • Whether other Notch receptors are similarly modulated unknown at the time
  7. 2012 Medium

    Lower intraocular pressure and altered fibril diameter in TSP2-null mice established a role for TSP2 in trabecular meshwork ECM composition and aqueous outflow.

    Evidence Rebound tonometry, fluorophotometry, TEM, and immunofluorescence in TSP2-null versus WT mice

    PMID:22930728

    Open questions at the time
    • Molecular mediator linking TSP2 loss to fibril changes not identified
    • MMP involvement not tested in this tissue
  8. 2017 Medium

    Showing THBS2 binds NOTCH1/2 and inhibits JAG1-NOTCH2 interactions extended its Notch-modulating role and implicated it as a modifier in Alagille syndrome.

    Evidence Reporter mouse, co-IP, JAG1-NOTCH2 blocking assay, and Thbs2-null liver histology

    PMID:28090565

    Open questions at the time
    • Context-dependent potentiation versus inhibition of Notch not reconciled
    • Genetic modifier role not validated in patients
  9. 2018 Medium

    Decellularized TSP2-KO matrix established that TSP2 sets ECM mechanical properties and remodeling permissiveness, with degradation products being bioactive.

    Evidence SEM, mechanical testing, subcutaneous implantation, migration assays, and pepsin digestion of ECM

    PMID:29631168

    Open questions at the time
    • Identity of pro-migratory degradation fragments unknown
    • Direct molecular mechanism of stiffening not defined
  10. 2019 Low

    Linking TSP2 deficiency to oxygen-dependent MSC fate during fracture repair connected its angiogenic regulation to bone-forming pathway choice.

    Evidence Computational modeling validated against TSP2-null mouse IHC (pimonidazole hypoxia marker)

    PMID:23775935

    Open questions at the time
    • Largely a computational model with limited experimental validation
    • Direct molecular control of MSC differentiation by TSP2 not shown
  11. 2019 Medium

    Demonstrating TSP2 is required for cochlear afferent synapse recovery after noise revealed a synaptic-maintenance role distinct from TSP1.

    Evidence TSP2-null mice, auditory brainstem response, afferent synapse counting, and noise exposure

    PMID:30928339

    Open questions at the time
    • Receptor mediating cochlear synaptic effect not identified in this study
    • Cell source of TSP2 in cochlea unclear
  12. 2021 High

    Defining a CAF-derived TGF-β1-THBS2-integrin αvβ3/CD36-MAPK feedback circuit established TSP2 as a stromal signaling ligand driving tumor growth.

    Evidence Quantitative proteomics, RNA-ISH, co-culture, receptor/MEK/JNK inhibition rescue, and in vivo PDAC assays

    PMID:34958892

    Open questions at the time
    • Relative contribution of αvβ3 versus CD36 not dissected
    • Whether the same circuit operates in other tumor types unknown at the time
  13. 2021 Medium

    Showing TSP2 promotes peritumoral excitatory synaptogenesis and hyperexcitability via α2δ1/Rac1 connected its synaptogenic activity to glioma-associated epilepsy.

    Evidence TSP2 gain/loss glioma implantation in rats, synapse density quantification, epileptiform recordings, and gabapentin rescue

    PMID:33382873

    Open questions at the time
    • Downstream effectors of Rac1 in synapse assembly not defined here
    • Endogenous neuronal versus tumor source of TSP2 not separated
  14. 2021 Medium

    A CD133+ stem-cell feed-forward loop showed that reduced TSP2 (via H3 promoter modification) lowers MMP inhibition, softens matrix, and reinforces stemness.

    Evidence THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy, promoter ChIP, and xenografts

    PMID:33717837

    Open questions at the time
    • Identity of the histone-modifying enzyme not pinned down
    • Causality between softness and stemness only correlative in part
  15. 2022 High

    Identifying a TSP2-Rac1-WAVE2-actin axis that TSP2 negatively controls explained how TSP2 governs fibroblast morphology, migration, and contractility.

    Evidence TSP2 KO in diabetic fibroblasts, super-resolution and traction force microscopy, 3D contraction, and Rac1 activity assays

    PMID:36577792

    Open questions at the time
    • Receptor linking secreted TSP2 to intracellular Rac1 not identified
    • Generality beyond diabetic fibroblasts untested
  16. 2022 Medium

    Astrocyte-derived TSP2 binding α2δ1 to drive RGC axon degeneration and synaptic remodeling after ischemia extended the α2δ1 axis to retinal injury.

    Evidence TSP2 shRNA-AAV and gabapentin in rat retina, immunofluorescence, EM, Western blot, and ERG/visual assays

    PMID:36471420

    Open questions at the time
    • Whether axon degeneration is direct or downstream of synaptic change unclear
    • Signaling steps downstream of α2δ1 not mapped
  17. 2023 Medium

    Defining CEBPB-driven repression via miR-29a-3p and B3GALTL O-fucosylation control of secretion, plus a THBS2-ITGB1-PI3K/AKT axis, linked THBS2 regulation to breast cancer EMT.

    Evidence Co-IP, ChIP, O-fucosylation analysis, PI3K/AKT Western blot, and rescue experiments

    PMID:36728807

    Open questions at the time
    • Relative importance of transcriptional versus secretory control not quantified
    • ITGB1 binding site not mapped
  18. 2024 High

    A human THBS2 missense mutation causing vascular Ehlers-Danlos syndrome, recapitulated in knock-in mice, established THBS2 as a Mendelian disease gene acting through impaired MMP2 clearance.

    Evidence Clinical phenotyping, TEM, CRISPR/Cas9 knock-in mice, histology, bleeding-time assays, and MMP2 clearance analysis

    PMID:38433265

    Open questions at the time
    • Structural consequence of p.Cys896Arg on trimerization not resolved
    • Why a heterozygous variant is sufficient not fully explained
  19. 2024 Medium

    Identifying a THBS2-SDC4-EMT axis in lung adenocarcinoma added syndecan-4 as a tumor-cell receptor for CAF-derived THBS2.

    Evidence Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, and binding/functional assays

    PMID:40973793

    Open questions at the time
    • Direct binding affinity not quantified
    • Downstream signaling from SDC4 not mapped
  20. 2024 Medium

    Showing THBS2 drives collagen synthesis through TGF-β1/Smad2/3 in IPF fibroblasts established a pro-fibrotic function in lung fibrosis.

    Evidence THBS2 overexpression/KD in IPF fibroblasts, TGF-β1 inhibitor, Western blot, qPCR, and bleomycin mouse model with exogenous THBS2

    PMID:40676074

    Open questions at the time
    • Receptor mediating TSP2-induced Smad activation not identified
    • Reconciliation with TSP2's negative regulation of regenerative pathways not addressed
  21. 2024 Medium

    METTL14/YTHDF2 m6A stabilization of THBS2 mRNA in renal tubular cells revealed an epitranscriptomic control point coupling THBS2 to diabetic injury.

    Evidence m6A-RIP-qPCR, METTL14 KD, THBS2 KD/overexpression, and apoptosis/fibrosis/ferroptosis readouts in HK-2 cells

    PMID:40730238

    Open questions at the time
    • In vivo relevance of m6A control not established
    • Downstream effectors of THBS2 in tubular damage unclear
  22. 2025 Medium

    Demonstrating that TSP2 loss upregulates TGF-β3 and Wnt4/β-catenin to enhance fibroblast proliferation/migration defined TSP2 as a negative regulator of pro-regenerative dermal programs.

    Evidence Bulk RNA-seq of WT versus TSP2-KO fibroblasts, CRISPR KO validation, and proliferation/migration/reporter assays

    PMID:41427771

    Open questions at the time
    • Mechanism by which secreted TSP2 suppresses these pathways not defined
    • In vivo regeneration phenotype not shown
  23. 2025 Medium

    Linking TCA-cycle blockade to ER-stress/XBP1 suppression of THBS2 transcription connected THBS2 secretion to suppression of CD36+CD8+ T-cell antitumor immunity.

    Evidence CPI-613 treatment, XBP1 ChIP/reporter, THBS2 ELISA, T-cell functional assays, and syngeneic orthotopic mouse model

    PMID:40293258

    Open questions at the time
    • Direct effect of THBS2 on T cells versus indirect not fully separated
    • Receptor on T cells mediating the effect not identified
  24. 2026 Medium

    AAV-mediated depletion of THBS2+ fibroblasts revealed a stage-specific pro-tumorigenic role acting through THBS2-CD36 and THBS2-SDC1 pathways in colorectal cancer.

    Evidence Multiplex immunostaining, AAV fibroblast depletion mouse model, and multi-omics spatial analysis

    PMID:41640327

    Open questions at the time
    • Opposing effects on polyp versus tumor formation mechanistically unresolved
    • Direct THBS2-SDC1 binding not biochemically validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same secreted TSP2 molecule selects among its many receptors (LRP1, α2δ1, αvβ3/CD36, SDC4, SDC1, ITGB1) and switches between MMP clearance, Notch modulation, synaptogenesis, and pro/anti-fibrotic signaling in a context-dependent manner remains unresolved.
  • No structural model relating TSP2 domains to receptor selectivity
  • No unified framework reconciling pro- and anti-regenerative/fibrotic roles
  • Receptors linking secreted TSP2 to intracellular Rac1/WAVE2 control not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 4 GO:0005198 structural molecule activity 3
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 4
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 2
Partners
CD36ITGB3JAG1LRP1MMP2MMP9NOTCH3SDC4

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 THBS2 (TSP2) is the product of a separate gene (Thbs2) distinct from THBS1, expressed in a variety of mouse tissues in a pattern that differs from TSP1, establishing that two functionally distinct thrombospondin proteins exist in the same organism. cDNA cloning, sequence analysis, tissue expression profiling The Journal of biological chemistry Medium 1712771
1997 The human THBS2 promoter contains binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection contribute to differential THBS2 expression across tissues. Genomic sequencing, 5' RACE, PCR-based transcription start site mapping Gene Medium 9249061
2002 In double-TSP1/TSP2-null mice, the wound-healing defect (delayed healing, impaired macrophage recruitment, reduced MCP-1, and non-excessive vascularization) phenocopies TSP1-null mice rather than TSP2-null mice, demonstrating that TSP1 dominates over TSP2 in dictating the wound-healing response and that the two proteins have distinct temporal and spatial roles. Genetic epistasis using double-knockout mouse model, immunohistochemistry, cytokine measurement The American journal of pathology High 12213711
2003 Overexpression of TSP2 in the SW480 colon carcinoma cell line downregulates MMP2 and MMP9 expression and protein production, while upregulating MMP12 and MMP17, establishing TSP2 as a modulator of MMP expression. cDNA array and Western blot following stable TSP2 overexpression in SW480 cells Oncology reports Medium 12792739
2008 An intronic SNP in THBS2 (IVS10-8C→T; rs9406328) in a polypyrimidine tract causes allele-dependent skipping of exon 11 in vivo; the exon-11-skipped isoform shows decreased interaction with MMP2 and MMP9, linking THBS2 alternative splicing to reduced MMP regulation and susceptibility to lumbar disc herniation. Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP2/9 interaction) American journal of human genetics High 18455130
2010 TSP2 enhances Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this potentiation requires LRP1 expression in the signal-sending cell, is blocked by RAP (an LRP1 inhibitor), and TSP2 stimulates Notch3 endocytosis into WT but not LRP1-deficient fibroblasts, indicating TSP2 drives Notch trans-endocytosis via LRP1. Co-IP / pulldown (Notch3 and Jagged1 binding to LRP1 85-kDa B-chain), LRP1-deficient fibroblast rescue assay, RAP inhibition, endocytosis assay The Journal of biological chemistry High 20472562
2012 TSP2-null mice exhibit lower intraocular pressure (~7% less than WT) with enhanced aqueous outflow and larger collagen fibril diameters in the iridocorneal angle, establishing that TSP2 regulates extracellular matrix composition in the trabecular meshwork and thereby modulates intraocular pressure. Rebound tonometry, fluorophotometry (aqueous turnover), transmission electron microscopy, immunofluorescence in TSP2-null vs WT mice Investigative ophthalmology & visual science Medium 22930728
2013 Increased angiogenic progression due to TSP2 deficiency regulates mesenchymal stem cell (MSC) bipotential differentiation during fracture repair, shifting fate toward intramembranous ossification and reducing endochondral ossification, with oxygen availability as a key downstream mediator. Computational modeling validated against TSP2-null mouse experimental data (immunohistochemistry for hypoxia marker pimonidazole) Journal of orthopaedic research Low 23775935
2016 THBS2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and Thbs2-null livers show increased microvessels in portal regions, implicating THBS2 as a modifier of JAG1–Notch2 signaling in Alagille syndrome. Reporter mouse line, co-immunoprecipitation (THBS2–NOTCH1/2 interaction), JAG1–NOTCH2 blocking assay, Thbs2-null mouse histology Cellular and molecular gastroenterology and hepatology Medium 28090565
2018 Decellularized matrix derived from TSP2-KO skin has altered ECM structure (reduced elastic modulus and tensile strength), promotes enhanced vascularization and host cell infiltration upon implantation, and releases pro-migratory degradation products, establishing that TSP2 regulates ECM mechanical properties and remodeling permissiveness. Scanning electron microscopy, mechanical testing, subcutaneous implantation in mouse, in vitro migration assay, pepsin digestion of ECM Biomaterials Medium 29631168
2019 TSP2 is required for normal cochlear afferent synaptic connections; TSP2-null mice show impaired recovery of afferent synaptic counts and ABR wave amplitudes after noise exposure at mid-to-high frequencies, with peripheral neuronal damage and audiogenic seizures, a phenotype not observed in TSP1-null mice. KO mouse model, auditory brainstem response (ABR), afferent synapse counting, noise exposure paradigm Neuroscience Medium 30928339
2020 THBS2 inhibits MMP9 production in pancreatic neuroendocrine tumor cells by suppressing the transcriptional activity of CUX1; forced THBS2 expression inhibits pNET cell proliferation and migration, and this effect is mediated through the CUX1/MMP9 cascade. THBS2 overexpression, CUX1 transcriptional activity reporter assay, Western blot, proliferation and migration assays Oncology letters Medium 32194660
2021 Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts (CAFs) to induce THBS2 expression via the p-Smad2/3 pathway; CAF-derived THBS2 then binds membrane receptors integrin αvβ3 and CD36 on PDAC cells, activating the MAPK pathway (MEK/JNK) to promote tumor growth and adhesion in a TGF-β1–THBS2–integrin αvβ3/CD36–MAPK feedback circuit. Quantitative proteomics, IHC, RNA ISH in mouse models; co-culture experiments; integrin/CD36/MEK/JNK inhibition rescue assays; in vitro and in vivo functional assays Cancer letters High 34958892
2021 In glioma, TSP2 promotes excitatory synapse formation in the peritumoral cortex and induces hyperexcitability via the α2δ1/Rac1 signaling pathway; gabapentin (an α2δ1 antagonist) inhibited epileptiform discharges in the peritumoral cortex. TSP2-overexpressing/KO glioma cell implantation in rats, spine/synapse density quantification, EEG-like epileptiform discharge recording, gabapentin pharmacological rescue Journal of neuropathology and experimental neurology Medium 33382873
2021 TSP2 deficiency in liver cancer stem cells (CD133+) leads to reduced MMP activity inhibition, increased collagen degradation, and a softer matrix; a positive feed-forward loop exists where a soft-spot microenvironment enriches CD133+ cells that secrete less THBS2 due to histone H3 modification at the THBS2 promoter, maintaining local matrix softness and enhancing stemness. THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy (matrix stiffness), histone modification ChIP at THBS2 promoter, in vivo xenograft Advanced science Medium 33717837
2022 TSP2 deficiency in diabetic fibroblasts rescues cytoskeletal disorganization by restoring active Rac1 levels and WAVE2–F-actin co-localization, identifying a TSP2–Rac1–WAVE2–actin regulatory axis that controls fibroblast morphology, migration, traction force, and 3D contractility. TSP2 KO in diabetic fibroblasts, super-resolution microscopy, traction force microscopy, 3D contraction assay, Rac1 activity assay, WAVE2 co-localization imaging Scientific reports High 36577792
2022 Astrocyte-derived TSP2 binds α2δ1 to mediate retinal ganglion cell axon degeneration, compensatory synaptic remodeling in the inner plexiform layer, and visual dysfunction following ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) and competitive inhibition of TSP2–α2δ1 binding by gabapentin both alleviated these effects. TSP2 shRNA-AAV transduction in rat retina, gabapentin injection, immunofluorescence, electron microscopy, Western blot, ERG/visual function assays Cell & bioscience Medium 36471420
2023 CEBPB inhibits THBS2 expression by facilitating miR-29a-3p transcription; additionally, CEBPB inhibits B3GALTL transcription to reduce O-fucosylation and secretion of THBS2; secreted THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT. Co-IP (THBS2–ITGB1 interaction), ChIP (CEBPB binding to miR-29a-3p and B3GALTL promoters), O-fucosylation analysis, PI3K/AKT pathway Western blot, rescue experiments Human molecular genetics Medium 36728807
2024 A heterozygous missense mutation in THBS2 (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features in humans; CRISPR/Cas9 knock-in mice bearing the same mutation recapitulate the phenotype. Mechanistically, THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage and causing ECM abnormalities including disorganized collagen fibers and abnormal fibroblast/endothelial cell morphology. Clinical phenotyping, TEM, CRISPR/Cas9 KI mouse generation, histology, bleeding time assays, MMP2 clearance mechanistic analysis European journal of human genetics High 38433265
2024 THBS2 secreted by matrix CAFs (mCAFs) directly binds to SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition (EMT) programs in lung adenocarcinoma, establishing the THBS2–SDC4–EMT axis as a mediator of CAF-tumor crosstalk. Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, in vitro and in vivo binding/functional assays Oncogene Medium 40973793
2024 THBS2 promotes collagen synthesis in IPF fibroblasts through the TGF-β1/Smad2/3 signaling pathway; THBS2 overexpression increases COL1A1, COL1A2, COL3A1, LOX, and LOXL2, and THBS2 knockdown attenuates these effects; exogenous THBS2 protein aggravates bleomycin-induced pulmonary fibrosis in mice. THBS2 overexpression/KD in IPF fibroblasts, TGF-β1 inhibitor (SB525334), Western blot, qPCR, bleomycin mouse model with exogenous THBS2 protein Scientific reports Medium 40676074
2024 METTL14 stabilizes THBS2 mRNA via m6A modification recognized by YTHDF2; METTL14 knockdown reduces THBS2 expression and alleviates high-glucose-induced HK-2 cell damage (apoptosis, fibrosis, inflammation, ferroptosis), while THBS2 overexpression negates these protective effects. m6A-RIP-qPCR (THBS2 interaction with METTL14 and YTHDF2), METTL14 KD, THBS2 KD/overexpression, CCK-8, flow cytometry, ELISA, Western blot Experimental and clinical endocrinology & diabetes Medium 40730238
2025 TSP2 deficiency in dermal fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 cells confirmed that TSP2 negatively regulates these pro-regenerative pathways. Bulk RNA sequencing of WT vs TSP2-KO primary fibroblasts, CRISPR/Cas9 KO validation, proliferation and migration assays, pathway reporter assays FASEB journal Medium 41427771
2025 Blocking the TCA cycle in HNSCC cells (via CPI-613) induces ER stress, which directly suppresses THBS2 transcription through spliced XBP1; reduced secretion of THBS2 enhances CD36+CD8+ T-cell proliferation and cytotoxicity by upregulating AKT-mTOR signaling, enhancing antitumor immunity in a syngeneic orthotopic mouse model. CPI-613 treatment, ChIP/reporter assay (XBP1 binding to THBS2 promoter), THBS2 secretion ELISA, T-cell functional assays, syngeneic mouse model Cancer research Medium 40293258
2025 THBS2 interacts with INHBA to activate the FAK/PI3K/AKT signaling pathway in prostate cancer cells, promoting proliferation, migration, invasion, and EMT; INHBA knockdown reverses the oncogenic effects of THBS2 overexpression. STRING protein interaction analysis, Western blot co-expression, INHBA siRNA rescue, FAK/PI3K/AKT pathway Western blot, functional assays (CCK-8, wound healing, Transwell) Analytical cellular pathology Low 41810913
2026 THBS2+ fibroblasts interact with colorectal cancer cells via THBS2–CD36 and THBS2–SDC1 pathways; depletion of THBS2+ fibroblasts in an AAV-mediated mouse model enhanced polyp formation but suppressed tumor formation, establishing a stage-specific pro-tumorigenic role for THBS2+ fibroblasts in CRC malignant transformation. Multiplex immunostaining, AAV-mediated THBS2+ fibroblast depletion mouse model, multi-omics spatial analysis The Journal of pathology Medium 41640327

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. The American journal of pathology 260 12213711
2019 Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma. Angiogenesis 148 30993566
2010 Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1. BMC medical genomics 130 21047417
1991 A second, expressed thrombospondin gene (Thbs2) exists in the mouse genome. The Journal of biological chemistry 114 1712771
2018 Silencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k-Akt signaling pathway. Journal of cellular biochemistry 104 29143985
2008 A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. American journal of human genetics 94 18455130
2003 Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 90 12796396
2017 MicroRNA-221-3p, a TWIST2 target, promotes cervical cancer metastasis by directly targeting THBS2. Cell death & disease 87 29242498
2021 Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin αvβ3/CD36-mediated activation of the MAPK pathway. Cancer letters 84 34958892
2022 Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 77 35547750
2024 THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Molecular cancer 67 39732719
2016 Differential Expression Pattern of THBS1 and THBS2 in Lung Cancer: Clinical Outcome and a Systematic-Analysis of Microarray Databases. PloS one 67 27513329
2012 Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures. Investigative ophthalmology & visual science 53 22930728
2019 MiR-106a aggravates sepsis-induced acute kidney injury by targeting THBS2 in mice model. Acta cirurgica brasileira 49 31432993
2014 Secretome profiling of primary cells reveals that THBS2 is a salivary biomarker of oral cavity squamous cell carcinoma. Journal of proteome research 49 24708169
2021 Chemotherapy-Enriched THBS2-Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 45 33717837
1999 Thrombospondin-2 (TSP2) expression is inversely correlated with vascularity in glioma. European journal of cancer (Oxford, England : 1990) 38 10448307
2021 miR-29a-3p/THBS2 Axis Regulates PAH-Induced Cardiac Fibrosis. International journal of molecular sciences 36 34638915
2018 Decellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds. Biomaterials 36 29631168
2016 THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome. Cellular and molecular gastroenterology and hepatology 34 28090565
2010 Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling. The Journal of biological chemistry 34 20472562
2020 Circular RNA circ_0020123 promotes non-small cell lung cancer progression by sponging miR-590-5p to regulate THBS2. Cancer cell international 33 32831647
2019 MiR-93-5p promotes cervical cancer progression by targeting THBS2/MMPS signal pathway. European review for medical and pharmacological sciences 33 31298364
2013 The role of oxygen as a regulator of stem cell fate during fracture repair in TSP2-null mice. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 30 23775935
2013 Expression at a 20L scale and purification of the extracellular domain of the Schistosoma mansoni TSP-2 recombinant protein: a vaccine candidate for human intestinal schistosomiasis. Human vaccines & immunotherapeutics 30 23899507
1997 Analysis of the promoter and transcription start sites of the human thrombospondin 2 gene (THBS2). Gene 30 9249061
2024 The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization. Journal of experimental & clinical cancer research : CR 29 39020380
2023 Systematic analysis of integrated bioinformatics to identify upregulated THBS2 expression in colorectal cancer cells inhibiting tumour immunity through the HIF1A/Lactic Acid/GPR132 pathway. Cancer cell international 29 37884956
2020 Inhibiting role of long non-coding RNA LINC01197 in inflammation in rheumatoid arthritis through the microRNA-150/THBS2 axis. Experimental cell research 29 32540401
2021 Circ_0091702 serves as a sponge of miR-545-3p to attenuate sepsis-related acute kidney injury by upregulating THBS2. Journal of molecular histology 27 34101064
2020 Structure and function of bacteriophage CBA120 ORF211 (TSP2), the determinant of phage specificity towards E. coli O157:H7. Scientific reports 26 32958885
2023 Mesenchymal stem cell-derived extracellular vesicles transfer miR-598 to inhibit the growth and metastasis of non-small-cell lung cancer by targeting THBS2. Cell death discovery 25 36609437
2023 CEBPB regulates the migration, invasion and EMT of breast cancer cells by inhibiting THBS2 expression and O-fucosylation. Human molecular genetics 25 36728807
2022 THBS2 promotes cell migration and invasion in colorectal cancer via modulating Wnt/β-catenin signaling pathway. The Kaohsiung journal of medical sciences 24 35315209
2020 LINC01235-TWIST2 feedback loop facilitates epithelial-mesenchymal transition in gastric cancer by inhibiting THBS2. Aging 24 33206629
2021 The Integrative Analysis of Thrombospondin Family Genes in Pan-Cancer Reveals that THBS2 Facilitates Gastrointestinal Cancer Metastasis. Journal of oncology 23 34804159
2021 Glioma-Derived TSP2 Promotes Excitatory Synapse Formation and Results in Hyperexcitability in the Peritumoral Cortex of Glioma. Journal of neuropathology and experimental neurology 21 33382873
2020 THBS2, a microRNA-744-5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors. Oncology letters 20 32194660
2011 Requirement of a Tsp2-type tetraspanin for laccase repression and stress resistance in the basidiomycete Cryptococcus neoformans. Applied and environmental microbiology 20 22020508
2010 Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population. Journal of human genetics 20 20485444
2024 THBS1 and THBS2 Enhance the In Vitro Proliferation, Adhesion, Migration and Invasion of Intrahepatic Cholangiocarcinoma Cells. International journal of molecular sciences 18 38339060
2024 Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice. European journal of human genetics : EJHG 18 38433265
2016 Associations of THBS2 and THBS4 polymorphisms to gastric cancer in a Southeast Chinese population. Cancer genetics 18 27160021
2013 Biophysical and formulation studies of the Schistosoma mansoni TSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis. Human vaccines & immunotherapeutics 18 23880663
2015 DNA Vaccine Encoding the Chimeric Form of Schistosoma mansoni Sm-TSP2 and Sm29 Confers Partial Protection against Challenge Infection. PloS one 17 25942636
2022 Tsp2 Facilitates Tumor-associated Fibroblasts Formation and Promotes Tumor Progression in Retroperitoneal Liposarcoma. International journal of biological sciences 16 35982904
2009 NF-kappaB blockade upregulates Bax, TSP-1, and TSP-2 expression in rat granulation tissue. Journal of molecular medicine (Berlin, Germany) 16 19189070
2023 LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway. Cancer cell international 15 38110984
2020 Circ-AK2 is associated with preeclampsia and regulates biological behaviors of trophoblast cells through miR-454-3p/THBS2. Placenta 14 33129036
2019 TSP2 acts as a suppresser of cell invasion, migration and angiogenesis in medulloblastoma by inhibiting the Notch signaling pathway. Brain research 14 31063715
2008 Microvessel density and CpG island methylation of the THBS2 gene in malignant ovarian tumors. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 14 18955754
2023 Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma. Histopathology 12 38155475
2022 circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network. Open medicine (Warsaw, Poland) 12 35415249
2016 New Markers in Atherosclerosis: Thrombospondin-2 (THBS-2) and Leukocyte Cell-Derived Chemotaxin-2 (LECT-2); An Immunohistochemical Study. Medical science monitor : international medical journal of experimental and clinical research 12 28039493
2023 Machine learning and single-cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P-Smad2/3 signalling pathway in hypertrophic scar. International wound journal 11 37986676
2003 Overexpression of the thrombospondin 2 (TSP2) gene modulated by the matrix metalloproteinase family expression and production in human colon carcinoma cell line. Oncology reports 10 12792739
2023 MiR-214-3p suppresses cervical cancer cell metastasis by downregulating THBS2. Cellular and molecular biology (Noisy-le-Grand, France) 9 37807313
2022 Circ-OPHN1 suppresses the proliferation, migration, and invasion of trophoblast cells through mediating miR-558/THBS2 axis. Drug development research 9 35277867
2009 Association of polymorphisms of THBS2 and HSPA8 with hypertension in Japanese individuals with chronic kidney disease. Molecular medicine reports 9 21475814
2024 THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway. American journal of cancer research 8 39113869
2022 Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction. Scientific reports 8 36577792
2019 A population-based study identifies an association of THBS2 with intervertebral disc degeneration. Osteoarthritis and cartilage 8 31233787
2001 Antisense oligonucleotide ISIS 2922 targets IE-expression and prevents HCMV-IE-induced suppression of TSP-1 and TSP-2 expression. Nucleosides, nucleotides & nucleic acids 8 11563036
2025 Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling. Cancer research 7 40293258
2024 YTHDF3 suppresses declines in corneal epithelial wound healing through upregulating the Wnt/β-catenin signaling pathway and THBS2 expression in diabetic corneas. International journal of biological macromolecules 7 39626342
2023 Transcription Analysis of the THBS2 Gene through Regulation by Potential Noncoding Diagnostic Biomarkers and Oncogenes of Gastric Cancer in the ECM-Receptor Interaction Signaling Pathway: Integrated System Biology and Experimental Investigation. International journal of genomics 7 38162289
2022 Circ_0007580 knockdown strengthens the radiosensitivity of non-small cell lung cancer via the miR-598-dependent regulation of THBS2. Thoracic cancer 7 35044104
2021 Robust Immune Response Induced by Schistosoma mansoni TSP-2 Antigen Coupled to Bacterial Outer Membrane Vesicles. International journal of nanomedicine 7 34712047
2019 TSP1 and TSP2 Have Unique and Overlapping Roles in Protecting against Noise-Induced Auditory Synaptopathy. Neuroscience 7 30928339
2019 TSP1 and TSP2 deficiencies affect LOX protein distribution in the femoral diaphysis and pro-peptide removal in marrow-derived mesenchymal stem cells in vitro. Connective tissue research 7 30939949
2018 Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model. International archives of allergy and immunology 7 29393209
2013 Variants within the COMP and THBS2 genes are not associated with Achilles tendinopathy in a case-control study of South African and Australian populations. Journal of sports sciences 7 23875975
2023 Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2. Frontiers in oncology 6 38156105
2022 Circ_0079530 stimulates THBS2 to promote the malignant progression of non-small cell lung cancer by sponging miR-584-5p. Histology and histopathology 6 36382967
2014 Complex brain malformations associated with chromosome 6q27 gain that includes THBS2, which encodes thrombospondin 2, an astrocyte-derived protein of the extracellular matrix. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 6 25299246
2025 Cancer-associated fibroblasts drive lung adenocarcinoma progression via THBS2-mediated epithelial-mesenchymal transition. Oncogene 5 40973793
2024 A longitudinal population-based study identifies THBS2 as a susceptibility gene for intervertebral disc degeneration. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 5 38918228
2022 Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury. Cell & bioscience 5 36471420
2019 Molecular characterization and functional analysis of Japanese flounder (Paralichthys olivaceus) thbs2 in response to lymphocystis disease virus. Fish & shellfish immunology 5 31330254
2023 Hsa_circ_0015382 is involved in the pathogenesis of preeclampsia by mediating THBS2 expression. American journal of reproductive immunology (New York, N.Y. : 1989) 4 37641374
2023 Serum THBS2 is a potential biomarker for the diagnosis of non-small cell lung cancer. Journal of cancer research and clinical oncology 4 37658862
2025 Enhanced THBS2 promotes collagen synthesis and inflammatory secretome of fibroblasts in idiopathic pulmonary fibrosis. Scientific reports 3 40676074
2024 Carbon black induced pulmonary fibrosis through piR-713551/PIWIL4 targeting THBS2 signal pathway. Journal of environmental sciences (China) 3 40246476
2023 COL3A1, CXCL8, VCAN, THBS2, and COL1A2 are correlated with the onset of biliary atresia. Medicine 3 36930067
2025 Identification of the "Collagen-Macrophage" sub-category of patients with colorectal cancer as an extension of the CMS4 subtype with THBS2 as a therapeutic target. BMC gastroenterology 2 40340827
2025 Identification of the M2 Macrophage-associated Gene THBS2 as a Predictive Marker for Inflammatory Cancer Transformation. Inflammatory bowel diseases 1 39045635
2025 Hirudo extract ameliorates proliferative vitreoretinopathy by promoting autophagy and attenuating the THBS2/PI3K/Akt pathway. Scientific reports 1 39779937
2024 Schistosoma heamatobium tetraspanins TSP-2 and TSP-6 induce Dendritic Cells maturation, cytokine production and T helper cells differentiation in vitro. Microbes and infection 1 39549890
2008 [Gene synthesis, expression and immunogenicity analysis of TSP2 hydrophilic domain(TSP2HD) of Schistosoma japonicum]. Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases 1 19160958
2026 Roles of THBS2+ fibroblasts in malignant transformation of colorectal polyp to cancer. The Journal of pathology 0 41640327
2026 LXN-THBS2 Signaling Axis Regulates Hepatic Stellate Cell Activation and Promotes the Development of Liver Fibrosis. Frontiers in bioscience (Landmark edition) 0 41761978
2026 THBS2 Promotes Prostate Cancer Malignancy via INHBA-Dependent FAK/PI3K/AKT Signaling Activation. Analytical cellular pathology (Amsterdam) 0 41810913
2026 Artesunate protects against ischemic stroke through THBS2/CD36/TLR4 pathway. International immunopharmacology 0 41903303
2026 Transcriptomic and Proteomic Analyses Identify THBS2, VWF, NFASC, and AKR1B10 as Diagnostic Biomarkers for Advanced Fibrosis in NAFLD. Journal of inflammation research 0 42211234
2025 TSP-1, TSP-2, and TSP-5 demonstrate sexual dimorphism in intimal hyperplasia in rats and mice. American journal of physiology. Heart and circulatory physiology 0 40298323
2025 METTL14 Promotes HK-2 Cell Injury in Diabetic Nephropathy Through the Regulation of THBS2 Expression in an m6A-YTHDF2-Dependent Manner. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 0 40730238
2025 CircP4HA3/miR-5001-5p/THBS2 axis promotes chondrocyte senescence and cartilage degradation during osteoarthritis progression. International immunopharmacology 0 41187421
2025 Integrative multi-omics and Mendelian randomization identify WWOX and THBS2 as potential therapeutic targets in mature T/NK-cell lymphoma. Journal of translational medicine 0 41254692
2025 TSP2 Deficiency Promotes Fibroblast Proliferation and Migration With Enhanced WNT4/β-Catenin/TGFb3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41427771
2011 [Effects of TSP2-8 and CUB1+2 domains on secretion direction of von Willebrand factor-cleaving protease]. Zhongguo shi yan xue ye xue za zhi 0 21867624

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