Affinage

THBS2

Thrombospondin-2 · UniProt P35442

Length
1172 aa
Mass
130.0 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

THBS2 encodes a secreted matricellular glycoprotein that functions as a central regulator of extracellular matrix assembly, composition, and mechanical properties by controlling collagen fibril organization and modulating MMP2/MMP9 activity and clearance (PMID:29631168, PMID:18455130, PMID:12792739). THBS2 signals through multiple cell-surface receptors—including integrin αvβ3, CD36, α2δ1, SDC4, ITGB1, and LRP1—to activate downstream MAPK, PI3K/AKT, Wnt/β-catenin, and Notch pathways, thereby regulating angiogenesis, fibroblast cytoskeletal organization via a Rac1–WAVE2–actin axis, synaptogenesis, and cancer-stroma crosstalk (PMID:34958892, PMID:36577792, PMID:20472562, PMID:33382873, PMID:40973793). THBS2 expression is post-transcriptionally controlled by m6A mRNA modification (METTL14/YTHDF2 and YTHDF3) and by miR-29a-3p/miR-29b-3p, and its secretion is regulated by O-fucosylation (PMID:40730238, PMID:39626342, PMID:36728807). A heterozygous missense mutation (p.Cys896Arg) in THBS2 causes a novel Ehlers-Danlos syndrome variant with vascular features, validated by CRISPR knock-in mice that recapitulate disorganized collagen and ECM abnormalities (PMID:38433265).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1991 High

    Identification of THBS2 as a second, distinct thrombospondin gene with tissue-specific expression patterns differing from TSP1 established that the thrombospondin family comprises structurally related but non-redundant members.

    Evidence cDNA cloning and genomic characterization in mouse tissues

    PMID:1712771

    Open questions at the time
    • No functional data on TSP2 protein activity
    • Tissue-level expression did not resolve cell-type specificity
  2. 2002 High

    Double TSP1/TSP2 knockout mice revealed that the two thrombospondins have distinct temporal roles in wound healing, with TSP1 dominating the inflammatory phase and TSP2 contributing separately, resolving the question of functional redundancy.

    Evidence Double-KO mouse wound healing model with immunohistochemistry

    PMID:12213711

    Open questions at the time
    • TSP2-specific wound healing mechanism undefined
    • No molecular mediators of TSP2's distinct wound role identified
  3. 2003 Medium

    Demonstration that TSP2 overexpression downregulates MMP2 and MMP9 while upregulating other MMPs established TSP2 as a selective modulator of matrix metalloproteinase expression, providing the first mechanistic link to ECM remodeling.

    Evidence Stable TSP2 overexpression in SW480 colon carcinoma cells with cDNA array and Western blot

    PMID:12792739

    Open questions at the time
    • Direct vs. indirect regulation of MMP transcription not distinguished
    • Single cell line limits generalizability
  4. 2008 High

    An intronic SNP causing exon 11 skipping produced a THBS2 variant with reduced MMP2/MMP9 binding, connecting alternative splicing to disrupted protease regulation and identifying a genetic mechanism for THBS2 functional variation.

    Evidence Genetic association combined with in vivo splicing assay and functional binding assay

    PMID:18455130

    Open questions at the time
    • Structural basis for exon 11-encoded domain's MMP interaction unknown
    • Effect of the splice variant on ECM architecture not tested
  5. 2010 High

    Discovery that TSP2 bridges Jagged1 and Notch3 ectodomains and potentiates Notch signaling through LRP1-dependent trans-endocytosis revealed a novel receptor-bridging mechanism, expanding TSP2's role beyond ECM remodeling to intercellular signaling.

    Evidence Co-IP, LRP1-KO fibroblast experiments, endocytosis assay, recombinant protein binding

    PMID:20472562

    Open questions at the time
    • Whether TSP2-Notch bridging occurs in vivo during development not shown
    • Stoichiometry and affinity of the ternary complex undefined
  6. 2012 Medium

    TSP2-null mice exhibited lower intraocular pressure with altered trabecular meshwork collagen fibril structure, extending TSP2's ECM-organizing role to a specific tissue with clinical relevance for aqueous humor dynamics.

    Evidence TSP2-null mouse tonometry, fluorophotometry, and transmission electron microscopy

    PMID:22930728

    Open questions at the time
    • Molecular mechanism linking TSP2 to collagen fibril diameter control not defined
    • Single KO model without rescue
  7. 2013 Medium

    Fracture studies in TSP2-null mice demonstrated that TSP2 controls vascular density and thereby oxygen availability, which dictates mesenchymal stem cell fate choice between endochondral and intramembranous ossification, linking TSP2's anti-angiogenic function to bone repair outcomes.

    Evidence TSP2-null mouse fracture model with computational modeling and pimonidazole hypoxia detection

    PMID:23775935

    Open questions at the time
    • Direct anti-angiogenic receptor mechanism in bone not identified
    • Computational model not validated by independent experiments
  8. 2016 Medium

    THBS2 was shown to interact with NOTCH1/2 ectodomains and inhibit JAG1-NOTCH2 signaling, positioning THBS2 as a modifier of Notch pathway output beyond the previously known Notch3 interaction and linking it to Alagille syndrome biology.

    Evidence Co-IP, THBS2-null mouse histology, GWAS in human cohort

    PMID:28090565

    Open questions at the time
    • Mechanism of THBS2-NOTCH2 inhibition vs. THBS2-Notch3 potentiation not reconciled
    • Functional rescue of Alagille phenotype by THBS2 modulation not demonstrated
  9. 2018 High

    Decellularized matrices from TSP2-KO mice showed altered collagen ultrastructure, reduced stiffness, and enhanced cell migration and vascularization, establishing that TSP2 directly shapes the physical and mechanical properties of the ECM.

    Evidence Scanning EM, mechanical testing, subcutaneous implantation, in vitro migration with TSP2-null fibroblast ECM

    PMID:29631168

    Open questions at the time
    • Molecular mechanism of TSP2-collagen crosslinking or assembly not defined
    • Contribution of MMP deregulation vs. direct structural role not separated
  10. 2019 Medium

    TSP2-KO mice showed impaired cochlear synapse recovery after noise exposure, and compensatory upregulation of TSP2 in TSP1-null inner ears established TSP2 as a synaptogenic factor in the auditory system with partial functional overlap with TSP1.

    Evidence TSP1/TSP2 KO mouse models with synaptic counting and auditory brainstem response

    PMID:30928339

    Open questions at the time
    • Receptor mediating TSP2 synaptogenesis in cochlea not identified
    • Whether TSP2 promotes synapse formation or maintenance not distinguished
  11. 2021 High

    Multiple studies converged on THBS2 as a stromal-tumor crosstalk mediator: TGF-β1 induces THBS2 in cancer-associated fibroblasts, which then activates integrin αvβ3/CD36-MAPK signaling on tumor cells, while THBS2 deficiency in cancer stem cells drives MMP-dependent matrix softening and stemness, revealing THBS2 as a bidirectional regulator of the tumor microenvironment.

    Evidence Quantitative proteomics, pathway inhibitor rescue, xenografts (PDAC and liver cancer models), MMP activity assays, histone modification analysis

    PMID:33717837 PMID:34958892

    Open questions at the time
    • Whether THBS2-mediated MMP clearance and receptor signaling operate independently or synergistically in tumors unclear
    • Therapeutic targeting of THBS2 in cancer not validated
  12. 2021 Medium

    THBS2 was shown to promote excitatory synaptogenesis via α2δ1/Rac1 signaling in peritumoral cortex and to drive fibrosis via TGF-β1/Smad2/3 signaling, defining two distinct receptor-pathway axes through which THBS2 exerts context-dependent effects.

    Evidence Glioma implantation with gabapentin rescue (synaptogenesis); THBS2 OE/KD with TGF-β inhibitor rescue in fibroblasts and bleomycin mouse model (fibrosis)

    PMID:33382873 PMID:34638915 PMID:37986676 PMID:40676074

    Open questions at the time
    • Structural basis for THBS2-α2δ1 interaction not resolved
    • Whether synaptogenic and fibrotic signaling share downstream effectors unknown
  13. 2022 High

    The TSP2–Rac1–WAVE2–actin axis was defined as the mechanism by which TSP2 controls fibroblast cytoskeletal organization, migration, and traction force, explaining how TSP2 deficiency alters cell-ECM mechanical coupling.

    Evidence TSP2-KO fibroblasts with FRAP, traction force microscopy, Rac1 activity assay, and WAVE2-F-actin co-localization imaging; diabetic fibroblast rescue model

    PMID:36577792

    Open questions at the time
    • Receptor upstream of TSP2-Rac1 activation in fibroblasts not identified
    • Whether this axis operates in non-fibroblast cell types unknown
  14. 2023 Medium

    Post-transcriptional regulation of THBS2 was elucidated: CEBPB promotes miR-29a-3p to suppress THBS2 mRNA, while CEBPB also reduces B3GALTL-mediated O-fucosylation to limit THBS2 secretion; separately, YTHDF3 recognizes m6A modifications to promote THBS2 translation, establishing multi-layered regulation at mRNA and protein levels.

    Evidence ChIP, luciferase reporter assays, Co-IP (THBS2-ITGB1), RIP for m6A, YTHDF3 KD/OE in corneal epithelial cells and diabetic mouse cornea

    PMID:36728807 PMID:39626342

    Open questions at the time
    • Integration of O-fucosylation, m6A, and miRNA regulation under physiological conditions not tested
    • Which m6A sites are functionally critical not mapped at single-nucleotide resolution
  15. 2024 High

    A heterozygous THBS2 missense mutation (p.Cys896Arg) was identified as the cause of a novel Ehlers-Danlos syndrome variant, validated by CRISPR knock-in mice that recapitulate collagen disorganization and vascular ECM defects, providing the first Mendelian disease directly caused by THBS2 mutation.

    Evidence Human genetic analysis, CRISPR/Cas9 knock-in mouse, TEM, histology, bleeding time assay

    PMID:38433265

    Open questions at the time
    • Whether the mutation disrupts MMP clearance, collagen binding, or both not resolved
    • Penetrance and phenotypic spectrum in additional families not reported
  16. 2025 Medium

    THBS2 receptor repertoire expanded to include SDC4 on lung cancer cells and CD36 on CD8+ T cells; THBS2 binding to SDC4 drives EMT in lung adenocarcinoma, while tumor-secreted THBS2 suppresses CD36+CD8+ T cell cytotoxicity via AKT-mTOR signaling, revealing immunomodulatory functions.

    Evidence Spatial transcriptomics, multiplex IHC, protein-receptor binding assays, syngeneic mouse models, T-cell functional assays

    PMID:40293258 PMID:40973793

    Open questions at the time
    • Structural basis of THBS2-SDC4 interaction not determined
    • Whether THBS2's immunosuppressive effect is generalizable across tumor types unknown
  17. 2025 Medium

    METTL14-mediated m6A modification of THBS2 mRNA recognized by YTHDF2 was shown to stabilize THBS2 expression in diabetic kidney injury, and TSP2 knockdown reduced vascular smooth muscle cell proliferation and intimal hyperplasia in a sex-specific manner, expanding THBS2's roles to renal pathology and sex-dimorphic vascular biology.

    Evidence m6A-RIP, siRNA KD, HK-2 cell injury model; siRNA KD in VSMCs, carotid injury in male/female rats and mice

    PMID:40298323 PMID:40730238

    Open questions at the time
    • Whether YTHDF2 and YTHDF3 act on THBS2 mRNA at the same or distinct m6A sites is unresolved
    • Molecular basis of sex-specific TSP2 effects in vascular remodeling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of THBS2's selective receptor engagement across different cell types; how TSP2 simultaneously promotes and inhibits Notch signaling through different Notch paralogs; and whether TSP2's diverse context-dependent functions can be therapeutically targeted with domain-specific interventions.
  • No high-resolution structure of full-length TSP2 or TSP2-receptor complexes
  • Mechanism reconciling Notch3 potentiation vs. NOTCH2 inhibition undefined
  • No clinical trials or validated therapeutic targeting of THBS2

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1474244 Extracellular matrix organization 5 R-HSA-1643685 Disease 5 R-HSA-112316 Neuronal System 3
Partners
CD36ITGB1JAG1LRP1MMP2MMP9NOTCH3SDC4

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 THBS2 is the product of a second, distinct thrombospondin gene (Thbs2) expressed in multiple mouse tissues in a pattern that differs from TSP1, establishing that two structurally related but distinct TSP proteins exist in the same organism. cDNA cloning, genomic characterization, tissue expression analysis The Journal of biological chemistry High 1712771
1997 The human THBS2 gene promoter contains putative binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection (exons 1A/1B separated by a small intron) contribute to differential THBS2 expression across tissues. Genomic sequencing, 5' RACE, PCR mapping of transcription start sites Gene Medium 9249061
2002 In double TSP1/TSP2-null mice, the wound-healing phenotype is dominated by loss of TSP1 (delayed healing, impaired inflammation, reduced macrophage recruitment and MCP-1) rather than loss of TSP2, demonstrating that TSP1 and TSP2 have distinct temporal/spatial roles in wound healing with TSP1 dictating inflammatory-phase outcomes. Double-knockout mouse model, immunohistochemistry, wound healing assay 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, identifying TSP2 as a multifunctional modulator of matrix metalloproteinase activity. cDNA array, Western blot, stable gene overexpression in cell line Oncology reports Medium 12792739
2008 An intronic SNP in THBS2 (IVS10-8C→T; rs9406328) in a polypyrimidine tract causes increased skipping of exon 11, and this exon-skipping variant results in decreased THBS2 interaction with MMP2 and MMP9, linking alternative splicing of THBS2 to disrupted MMP regulation and susceptibility to lumbar-disc herniation. Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP interaction) American journal of human genetics High 18455130
2010 TSP2 potentiates Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this activity requires LRP1 expression in the signal-sending cell, as TSP2 stimulates Notch3 trans-endocytosis into wild-type but not LRP1-deficient fibroblasts, and recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain. Co-immunoprecipitation, receptor-associated protein inhibition, fibroblast LRP1 KO experiments, endocytosis assay, recombinant protein binding The Journal of biological chemistry High 20472562
2012 TSP2-null mice exhibit lower intraocular pressure than wild-type, associated with increased aqueous outflow facility and larger collagen fibril diameters in the trabecular meshwork, indicating TSP2 regulates ECM structure and aqueous humor outflow in the eye. TSP2-null mouse model, tonometry, fluorophotometry, transmission electron microscopy, immunofluorescence Investigative ophthalmology & visual science Medium 22930728
2013 TSP2 regulates bone fracture repair by controlling vascular density: increased angiogenesis in TSP2-null mice leads to higher oxygen availability, which shifts mesenchymal stem cell fate from endochondral to intramembranous ossification. TSP2-null mouse fracture model, computational modeling, immunohistochemical pimonidazole hypoxia detection Journal of orthopaedic research Medium 23775935
2016 THBS2 interacts with NOTCH1 and NOTCH2 ectodomains and can inhibit JAG1-NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and THBS2-null mice show increased microvessels in portal regions, placing THBS2 as a modifier of JAG1-NOTCH2 signaling relevant to Alagille syndrome. Co-immunoprecipitation/protein interaction assay, reporter mouse line, THBS2-null mouse histology, GWAS in human cohort Cellular and molecular gastroenterology and hepatology Medium 28090565
2018 Decellularized matrix from TSP2-KO mice has altered collagen fibril structure, reduced mechanical stiffness, and promotes greater cell migration and vascularization compared to WT matrix; cell-derived ECM from TSP2-null fibroblasts is more permissive to fibroblast migration, demonstrating TSP2 directly regulates ECM physical properties and cell migration. Scanning electron microscopy, mechanical testing, subcutaneous implantation, in vitro migration assay with TSP2-null fibroblast ECM Biomaterials High 29631168
2019 TSP2-null mice show unique and overlapping roles with TSP1 in cochlear synapse maintenance; TSP2 KO mice exhibit worse recovery of afferent synaptic counts and ABR following noise exposure specifically at mid-to-high frequencies, and TSP2 protein levels are elevated in TSP1-null inner ears, suggesting functional compensation. TSP1/TSP2 KO mouse models, synaptic counting, auditory brainstem response measurement Neuroscience Medium 30928339
2019 TSP2 deficiency in diabetic fibroblasts is associated with decreased active Rac1 and loss of WAVE2-F-actin co-localization; deletion of TSP2 in diabetic fibroblasts rescues cytoskeletal disorganization, restoring normal Rac1 activity, WAVE2-F-actin co-localization, cell morphology, migration speed, traction force, and contractility. TSP2-KO in diabetic fibroblast model, advanced microscopy (FRAP, traction force), Rac1 activity assay, F-actin/WAVE2 co-localization imaging Scientific reports High 36577792
2021 Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts to induce THBS2 expression via p-Smad2/3; CAF-derived THBS2 then binds membrane receptors integrin αvβ3/CD36 on PDAC cells to activate the MAPK pathway, promoting tumor growth and adhesion, forming a TGF-β1→THBS2→integrin αvβ3/CD36→MAPK feedback circuit. RNA in situ hybridization, quantitative proteomics, IHC, pathway inhibitor rescue experiments (anti-integrin αvβ3, CD36, MEK, JNK), in vitro and in vivo functional assays Cancer letters High 34958892
2021 Glioma-derived TSP2 promotes excitatory synapse formation in peritumoral cortex via the α2δ1/Rac1 signaling pathway; TSP2 overexpression increases spine and excitatory synapse density and epileptiform discharge frequency, while the α2δ1 antagonist gabapentin inhibits these effects. Stereotactic glioma cell implantation (WT, TSP2-OE, TSP2-KO C6 cells), EEG recording, spine/synapse density quantification, gabapentin pharmacological rescue Journal of neuropathology and experimental neurology Medium 33382873
2021 THBS2 deficiency in CD133+ liver cancer stem cells promotes collagen degradation and matrix softening by increasing MMP activity; a positive feed-forward loop exists where a soft-spot ECM microenvironment enriches THBS2-deficient CD133+ cells through histone H3 modification at the THBS2 promoter, maintaining localized ECM softness and enhancing stemness. Cancer stem cell isolation, ECM stiffness measurement, MMP activity assay, chromatin/histone modification analysis, in vivo xenograft Advanced science Medium 33717837
2021 miR-29a-3p directly targets THBS2 and regulates its expression; reduced miR-29a-3p in PAH leads to elevated THBS2, which promotes cardiac fibrosis progression. Dual luciferase reporter assay, cell culture and mouse PAH model, qRT-PCR, Western blot International journal of molecular sciences Medium 34638915
2022 TSP2 deficiency in fibroblasts leads to cytoskeletal disorganization through the TSP2-Rac1-WAVE2-actin axis; TSP2-null fibroblasts show decreased active Rac1, disrupted WAVE2-F-actin co-localization, and produce thickened, less porous ECM that hinders normal fibroblast migration. TSP2 KO fibroblasts, multiple microscopy modalities, Rac1 activity assay, CDM analysis, traction force microscopy Scientific reports High 36577792
2022 Astrocyte-derived TSP2 binds α2δ1 to mediate degeneration of retinal ganglion cell axons and compensatory synaptic remodeling in the inner plexiform layer after retinal ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) or competitive inhibition of TSP2-α2δ1 binding (gabapentin) alleviated synaptic/neurite alteration and visual dysfunction. Viral transduction (TSP2 shRNA-AAV), intravitreal drug injection (gabapentin, fluorocitrate), Western blot, immunofluorescence, electron microscopy, visual function testing Cell & bioscience Medium 36471420
2023 THBS2 promotes fibroblast proliferation and migration and increases collagen synthesis (COL1A1, COL1A2, COL3A1) via the TGF-β1/Smad2/3 signaling pathway in IPF; THBS2 also promotes inflammatory cytokine secretion (IL-1β, IL-6, IL-8); exogenous THBS2 protein aggravates bleomycin-induced fibrosis in mice. THBS2 overexpression/knockdown in IPF fibroblasts, exogenous protein administration, TGF-β1 inhibitor rescue, bleomycin mouse model, Western blot Scientific reports Medium 40676074
2023 CEBPB facilitates miR-29a-3p transcription which negatively regulates THBS2 expression; CEBPB also inhibits B3GALTL transcription to reduce THBS2 O-fucosylation and secretion; THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT. ChIP, luciferase reporter assay, Western blot, rescue experiments, Co-IP (THBS2-ITGB1 interaction) Human molecular genetics Medium 36728807
2023 THBS2 promotes hypertrophic scar fibroblast proliferation and migration through the TGFβ1/P-Smad2/3 signaling pathway, as established by single-cell sequencing analysis, immunofluorescence localization, and functional assays. scRNA-seq, machine learning, CCK8/wound healing assay, Western blot, immunofluorescence, qRT-PCR International wound journal Medium 37986676
2024 A heterozygous THBS2 missense mutation (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features; CRISPR/Cas9 knock-in mice bearing the same mutation replicate the human phenotype including disorganized collagen fibers and abnormal ECM near blood vessels, consistent with THBS2's known role in mediating MMP2 clearance to regulate ECM. Human genetic analysis, CRISPR/Cas9 KI mouse model, TEM, histology, bleeding time assay European journal of human genetics High 38433265
2024 THBS2 promotes gastric cancer progression and cancer stem cell-like characteristics through the Notch signaling pathway by regulating Notch3, HEY1, and HES1 proteins; miR-29b-3p directly targets the 3'-UTR of THBS2 mRNA to suppress its expression. Dual-luciferase reporter assay, Western blot, xenograft and metastasis assay in nude mice American journal of cancer research Medium 39113869
2024 YTHDF3 promotes THBS2 translation by recognizing m6A modification sites in the coding region of THBS2; THBS2 promotes corneal epithelial cell proliferation and migration by activating the Wnt/β-catenin signaling pathway, and enforced THBS2 expression accelerates corneal wound healing in diabetic mice. m6A-mRNA microarray, RIP assay, YTHDF3 KD/OE, THBS2 OE in cells and diabetic mouse cornea, Wnt/β-catenin pathway analysis International journal of biological macromolecules Medium 39626342
2025 THBS2 secreted by matrix CAFs directly binds SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition programs in lung adenocarcinoma, as demonstrated by spatial transcriptomics, multiplex IHC, and in vivo/in vitro binding experiments. scRNA-seq, spatial transcriptomics, multiplex IHC, in vivo and in vitro functional experiments, protein-receptor binding assay Oncogene Medium 40973793
2025 TSP2 deficiency in fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 fibroblasts confirmed that TSP2 negatively regulates these pro-regenerative pathways. Bulk RNA sequencing of WT vs TSP2 KO fibroblasts, CRISPR/Cas9 KO in NIH3T3, functional proliferation/migration assays FASEB journal Medium 41427771
2025 Blocking the TCA cycle in HNSCC cells with CPI-613 induces ER stress, leading to increased spliced XBP1 which directly suppresses THBS2 transcription; reduced THBS2 secretion then enhances proliferation and cytotoxicity of tumor-infiltrating CD36+CD8+ T cells via AKT-mTOR signaling. CPI-613 treatment, ER stress induction assay, XBP1 transcriptional reporter, T-cell proliferation/cytotoxicity assay, syngeneic mouse model Cancer research Medium 40293258
2025 TSP2 siRNA knockdown reduces vascular smooth muscle cell (VSMC) proliferation and migration in vitro and reduces intimal hyperplasia in male but not female rats and mice after carotid injury, demonstrating a sex-specific role for TSP2 in vascular remodeling. siRNA knockdown, VSMC proliferation/chemotaxis assay, carotid balloon injury rat model, carotid ligation mouse model, adeno-associated virus siRNA delivery American journal of physiology. Heart and circulatory physiology Medium 40298323
2025 METTL14 promotes m6A modification of THBS2 mRNA, which is recognized by YTHDF2 to stabilize THBS2 expression; elevated THBS2 in high-glucose conditions exacerbates HK-2 cell injury (apoptosis, fibrosis, inflammation, ferroptosis), and METTL14 knockdown is protective through reduction of THBS2. m6A-RIP assay, RIP-qPCR, siRNA knockdown, CCK-8, flow cytometry, ELISA, Western blot Experimental and clinical endocrinology & diabetes Medium 40730238
2025 LXN positively correlates with THBS2 and LXN knockdown downregulates THBS2; the LXN-THBS2 signaling axis activates the TLR4-TGF-β/FAK pathway through autocrine THBS2 signaling to promote hepatic stellate cell activation and liver fibrosis. AAV9-mediated LXN knockdown in mouse liver fibrosis model, siRNA in LX-2 cells, qPCR, Western blot, IHC, immunofluorescence Frontiers in bioscience Low 41761978

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 259 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 129 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 103 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 86 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 82 34958892
2022 Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 76 35547750
2016 Differential Expression Pattern of THBS1 and THBS2 in Lung Cancer: Clinical Outcome and a Systematic-Analysis of Microarray Databases. PloS one 67 27513329
2024 THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Molecular cancer 59 39732719
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) 43 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 35 34638915
2018 Decellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds. Biomaterials 35 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
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
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 27 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 26 37884956
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 26 34101064
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
2020 Structure and function of bacteriophage CBA120 ORF211 (TSP2), the determinant of phage specificity towards E. coli O157:H7. Scientific reports 25 32958885
2023 CEBPB regulates the migration, invasion and EMT of breast cancer cells by inhibiting THBS2 expression and O-fucosylation. Human molecular genetics 24 36728807
2020 LINC01235-TWIST2 feedback loop facilitates epithelial-mesenchymal transition in gastric cancer by inhibiting THBS2. Aging 24 33206629
2022 THBS2 promotes cell migration and invasion in colorectal cancer via modulating Wnt/β-catenin signaling pathway. The Kaohsiung journal of medical sciences 23 35315209
2021 The Integrative Analysis of Thrombospondin Family Genes in Pan-Cancer Reveals that THBS2 Facilitates Gastrointestinal Cancer Metastasis. Journal of oncology 22 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
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
2020 THBS2, a microRNA-744-5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors. Oncology letters 19 32194660
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
2024 Heterozygous THBS2 pathogenic variant causes Ehlers-Danlos syndrome with prominent vascular features in humans and mice. European journal of human genetics : EJHG 17 38433265
2016 Associations of THBS2 and THBS4 polymorphisms to gastric cancer in a Southeast Chinese population. Cancer genetics 17 27160021
2015 DNA Vaccine Encoding the Chimeric Form of Schistosoma mansoni Sm-TSP2 and Sm29 Confers Partial Protection against Challenge Infection. PloS one 17 25942636
2024 THBS1 and THBS2 Enhance the In Vitro Proliferation, Adhesion, Migration and Invasion of Intrahepatic Cholangiocarcinoma Cells. International journal of molecular sciences 16 38339060
2009 NF-kappaB blockade upregulates Bax, TSP-1, and TSP-2 expression in rat granulation tissue. Journal of molecular medicine (Berlin, Germany) 16 19189070
2022 Tsp2 Facilitates Tumor-associated Fibroblasts Formation and Promotes Tumor Progression in Retroperitoneal Liposarcoma. International journal of biological sciences 15 35982904
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 14 38110984
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
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
2020 Circ-AK2 is associated with preeclampsia and regulates biological behaviors of trophoblast cells through miR-454-3p/THBS2. Placenta 12 33129036
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 Infiltrative pattern of invasion is independently associated with shorter survival and desmoplastic stroma markers FAP and THBS2 in mucinous ovarian carcinoma. Histopathology 11 38155475
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 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 9 37986676
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
2023 MiR-214-3p suppresses cervical cancer cell metastasis by downregulating THBS2. Cellular and molecular biology (Noisy-le-Grand, France) 8 37807313
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
2024 THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway. American journal of cancer research 7 39113869
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
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 6 39626342
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
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
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 4 38918228
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 Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling. Cancer research 3 40293258
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
2025 Enhanced THBS2 promotes collagen synthesis and inflammatory secretome of fibroblasts in idiopathic pulmonary fibrosis. Scientific reports 1 40676074
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 Artesunate protects against ischemic stroke through THBS2/CD36/TLR4 pathway. International immunopharmacology 0 41903303
2026 The Clinical Role of miR-744-5p in Osteoarthritis and Its Regulation of Chondrocyte Inflammation Through the Modulation of Thrombospondin-2 (THBS2) Expression. International journal of rheumatic diseases 0 41906361
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 Neuroprotective Role of THBS2 in Experimental Spinal Cord Injury Via its Anti-neuroinflammatory and Anti-apoptotic Properties. Biochemical genetics 0 40571842
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