Affinage

LTBP2

Latent-transforming growth factor beta-binding protein 2 · UniProt Q14767

Round 2 corrected
Length
1821 aa
Mass
195.1 kDa
Annotated
2026-04-28
130 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LTBP2 is a large extracellular matrix glycoprotein of the fibrillin-LTBP superfamily that serves as a structural component of microfibrils and a multifunctional regulator of growth factor bioavailability, elastic fiber assembly, and connective tissue integrity. Unlike other LTBPs, LTBP2 does not stably bind TGF-β isoforms; instead it binds fibrillin-1 (Kd ~9 nM, Ca²⁺-dependent) and competes with the large latent TGF-β complex for fibrillin-1 binding, thereby modulating TGF-β storage and release, and also binds fibulin-5 (Kd ~27 nM), competing with tropoelastin to negatively regulate elastinogenesis (PMID:10930463, PMID:17293099, PMID:24148803, PMID:40654695). LTBP2 additionally binds FGF-2 with high affinity (Kd ~1 nM) to inhibit FGF-2-driven proliferation, interacts with heparan sulfate proteoglycans (syndecan-4, perlecan) and integrin α6β4, and signals through Akt/p38, NF-κB, and Src pathways in cell-type-dependent contexts (PMID:26263555, PMID:20382221, PMID:40245188, PMID:28991210). Loss-of-function mutations in LTBP2 cause primary congenital glaucoma and Weill-Marchesani syndrome in humans, and Ltbp2-null mice develop ectopia lentis from mechanically weakened ciliary zonular fibers, myxomatous mitral valve disease with dysregulated TGF-β signaling, and reduced fibrotic responses in the lung (PMID:19361779, PMID:22539340, PMID:33039488, PMID:39882270).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Identification of LTBP-2 as a novel ECM glycoprotein structurally related to LTBP-1 that associates with TGF-β1 precursor and the extracellular matrix established the founding member context for subsequent functional studies.

    Evidence cDNA cloning, recombinant co-transfection with TGF-β1, immunoprecipitation, and ECM association assay in COS cells

    PMID:7798248

    Open questions at the time
    • Physiological significance of the TGF-β1 association was unclear
    • In vivo ECM localization not determined
    • Binding stoichiometry and affinity not measured
  2. 2000 High

    Resolving a contradiction with the 1994/1998 findings, domain-swap mutagenesis demonstrated that LTBP-2 uniquely among LTBPs lacks TGF-β binding capacity due to absence of a critical motif in its third 8-Cys repeat, fundamentally redefining its functional identity.

    Evidence In vitro binding assays with purified 8-Cys repeat fragments and domain-swap mutagenesis introducing the LTBP-1 TGF-β-binding motif into LTBP-2

    PMID:10930463

    Open questions at the time
    • If not TGF-β binding, the primary biological function of LTBP-2 remained unknown
    • In vivo consequences of this distinction were untested
  3. 2003 High

    Mapping of dual adhesive and antiadhesive activities to the N-terminal proline-rich region of LTBP-2 revealed it as a cell-type-selective modulator of cell-matrix interactions operating through β1 integrins and heparan sulfate.

    Evidence Recombinant fragment adhesion assays, integrin-blocking antibodies, heparin inhibition on melanoma cells; antiadhesion and fibronectin-binding assays on fibroblasts

    PMID:12716902 PMID:14691143

    Open questions at the time
    • Specific integrin heterodimer(s) mediating the antiadhesive effect on fibroblasts were not defined
    • In vivo relevance of the adhesion/antiadhesion duality was not tested
  4. 2007 High

    Two landmark findings — high-affinity Ca²⁺-dependent binding of LTBP-2 to fibrillin-1 (Kd ~9 nM) with competition against LTBP-1, and binding to fibulin-5 to regulate elastic fiber assembly — established LTBP-2 as a structural microfibril component that indirectly controls TGF-β storage and elastogenesis.

    Evidence Solid-phase binding with Kd determination and competition assays for fibrillin-1; siRNA knockdown and recombinant rescue for fibulin-5/elastin deposition in human fibroblasts

    PMID:17293099 PMID:17581631

    Open questions at the time
    • Whether LTBP-2 displaces the large latent TGF-β complex from fibrillin-1 in vivo was not directly shown
    • Stoichiometry of LTBP-2 within microfibril bundles was unknown
  5. 2009 Medium

    Discovery that LTBP2 null mutations cause primary congenital glaucoma in humans, with LTBP-2 localized to the ciliary body, linked this structural ECM protein to a specific Mendelian ocular disease and anterior segment development.

    Evidence Homozygosity mapping and Sanger sequencing in PCG families; immunohistochemistry of human anterior eye segment

    PMID:19361779

    Open questions at the time
    • Molecular mechanism by which LTBP-2 loss disrupts aqueous outflow was not determined
    • Whether glaucoma results from structural or signaling defects was unclear
  6. 2010 High

    Identification of multiple high-affinity heparin-binding sites and interactions with syndecan-4 and perlecan expanded the LTBP-2 interactome to heparan sulfate proteoglycans, providing a molecular basis for its cell-surface and basement membrane interactions.

    Evidence Solid-phase binding with recombinant fragments, synthetic peptide inhibition, Kd determination (~0.9 nM)

    PMID:20382221

    Open questions at the time
    • Functional consequence of syndecan-4/perlecan binding on signaling or ECM assembly was not tested
    • Whether HSPG interactions are required for LTBP-2 ECM incorporation was not addressed
  7. 2013 High

    Quantitative competition assays showing LTBP-2 displaces tropoelastin from fibulin-5 (comparable Kd values ~25 nM) and blocks elastinogenesis in chondrocytes established LTBP-2 as a negative modulator of elastic fiber assembly.

    Evidence Competitive solid-phase binding assays with Kd determination; exogenous LTBP-2 addition to chondrocyte elastogenesis cultures

    PMID:24148803

    Open questions at the time
    • In vivo elastic fiber phenotype of LTBP-2 deficiency in elastic tissues (aorta, lung) was not characterized at this point
    • Temporal regulation of competition was unknown
  8. 2014 High

    Ltbp2 knockout mice developed progressive lens luxation from ciliary zonule fiber failure, and recombinant LTBP-2 rescued microfibril formation in both knockdown cells and KO organ cultures, proving LTBP-2 is essential for zonular fiber integrity.

    Evidence Ltbp2−/− mice, siRNA in ciliary epithelial cells, recombinant protein rescue in vitro and organ culture, mutant protein secretion assay

    PMID:24908666

    Open questions at the time
    • Whether LTBP-2 is a load-bearing structural element or an assembly catalyst was unresolved
    • The mechanism by which human LTBP2 mutations cause glaucoma versus ectopia lentis was unexplained
  9. 2015 High

    Discovery that LTBP-2 binds FGF-2 with very high affinity (Kd ~1 nM) through central EGF-like repeats and completely blocks FGF-2-stimulated proliferation expanded LTBP-2's role from a structural/TGF-β modulator to a broader growth factor sequestrant.

    Evidence Solid-phase binding with recombinant fragments, Kd determination, FGF-2-stimulated fibroblast proliferation inhibition assay

    PMID:26263555

    Open questions at the time
    • In vivo significance of FGF-2 sequestration was not tested
    • Whether FGF-2 binding affects LTBP-2 matrix assembly or fibrillin interactions was unknown
  10. 2017 Medium

    A central bioactive fragment of LTBP-2 was shown to stimulate TGF-β1 transcription via Akt and p38 MAPK signaling, partially through αVβ3 integrin, revealing that LTBP-2 does not merely sequester growth factors but also actively triggers signaling cascades.

    Evidence Recombinant fragment addition to fibroblasts, ELISA, kinase inhibitors, phosphorylation Western blots, integrin-blocking antibodies

    PMID:28991210

    Open questions at the time
    • The direct receptor for the LTBP-2 fragment was not definitively identified
    • Whether this signaling occurs during normal ECM remodeling or only pathologically was unclear
    • Single lab finding not independently replicated
  11. 2020 High

    Mechanical testing of Ltbp2−/− ciliary zonules quantitatively demonstrated ~50% reduction in ultimate tensile strength and altered viscoelasticity, establishing LTBP-2 as a structural reinforcer required for long-term mechanical resilience rather than initial fiber formation.

    Evidence Ltbp2 knockout mouse, tensile testing, 3D imaging, quasi-linear viscoelastic modeling, harmonic oscillator simulation of saccadic eye movement

    PMID:33039488

    Open questions at the time
    • The molecular mechanism of mechanical reinforcement (cross-linking, bundling, stiffening) was not defined
    • Whether this mechanical role extends to other microfibril-rich tissues was unknown
  12. 2023 Medium

    Multiple studies converged on a HIF-1α → LTBP2 → NF-κB/ERK fibrosis-promoting axis, showing HIF-1α directly binds the LTBP2 promoter and that LTBP2 activates NF-κB signaling in fibrotic contexts and interacts with LOXL1 to activate ERK in hepatic stellate cells.

    Evidence ChIP and dual-luciferase reporter assays for HIF-1α/promoter binding; co-immunoprecipitation of LTBP2-LOXL1; AAV6-mediated in vivo knockdown reducing liver fibrosis; siRNA studies in oral fibrosis models

    PMID:37382472 PMID:40244455

    Open questions at the time
    • Whether LTBP2-LOXL1 interaction is direct or bridged by ECM components needs confirmation beyond co-IP and docking
    • How extracellular LTBP2 activates intracellular NF-κB — the receptor/transducer is undefined
    • Replication in independent labs needed
  13. 2024 Medium

    Identification of integrin α6β4 as a functional cell-surface receptor for LTBP2, activating Src signaling to drive metastasis and chemoresistance in esophageal cancer, provided the first defined receptor-signaling axis for extracellular LTBP2.

    Evidence Co-immunoprecipitation of LTBP2 with integrin α6β4, Src phosphorylation assays, antagonistic antibody treatment in cancer cells

    PMID:40245188

    Open questions at the time
    • Binding site on LTBP2 for integrin α6β4 not mapped
    • Whether this receptor mediates LTBP2 signaling in non-cancer contexts is unknown
    • Single study without reciprocal knockout validation
  14. 2025 Medium

    Ltbp2 knockout mice showed myxomatous mitral valve disease with TGF-β target upregulation (RUNX2, periostin), and a human knockin of a MVP-segregating LTBP2 variant recapitulated this phenotype, establishing LTBP2 as a regulator of cardiac valve homeostasis via TGF-β pathway modulation.

    Evidence KO and knockin mouse models, echocardiography, histology, qPCR for TGF-β targets, exome sequencing with family segregation

    PMID:39882270

    Open questions at the time
    • Whether valve disease results from increased active TGF-β release or altered ECM mechanics is not resolved
    • Long-term progression and penetrance in heterozygotes not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of LTBP-2's mechanical reinforcement of microfibrils, the identity and hierarchy of cell-surface receptors mediating LTBP-2's intracellular signaling in non-cancer tissues, and why LTBP2 loss produces organ-specific phenotypes despite broad expression.
  • No atomic-resolution structure of LTBP-2 or its complexes exists
  • The receptor hierarchy (integrin α6β4, αVβ3, HSPGs) for LTBP2 signaling is not unified
  • Tissue-specific phenotypic selectivity in KO mice is mechanistically unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0098772 molecular function regulator activity 4 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0031012 extracellular matrix 8 GO:0005576 extracellular region 3
Pathway
R-HSA-1474244 Extracellular matrix organization 8 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4
Partners
FBLN5FBN1FGF2HSPG2ITGB4LOXL1SDC4

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 LTBP-2 is a novel ~240 kDa extracellular matrix protein structurally related to LTBP-1, composed of 20 EGF-like repeats and four 8-cysteine repeats. Co-transfection experiments showed that LTBP-2 forms a high molecular weight complex with the TGF-β1 precursor, and a considerable fraction associates with extracellular matrix. cDNA cloning, recombinant protein expression in COS cells, co-transfection with TGF-β1 cDNA, immunoprecipitation, ECM association assay The Journal of biological chemistry High 7798248
1998 The 8-Cys (TGF-bp) repeats of LTBP-2 are capable of covalently binding latent TGF-β1, demonstrated by immunoprecipitation and SDS-PAGE. Specifically, the second and third TGF-bp repeats of LTBP-2 can form covalent bonds with the latent TGF-β1 complex, analogous to LTBP-3. Immunoprecipitation, SDS-PAGE, autoradiography of radiolabeled proteins Biochimica et biophysica acta Medium 9602168
1998 Recombinant LTBP-2 assembles into fibrillar structures in fibroblast extracellular matrix. Proteolytic processing by plasmin or elastase releases an ~160-kDa fragment from matrix-bound LTBP-2, with cleavage sites localized to proline-rich regions in the N-terminal portion of LTBP-2, indicating that the matrix-binding site resides in the N-terminal ~500 amino acids. Recombinant protein expression in CHO cells, purification, biotinylation, matrix assembly assay, plasmin/elastase digestion, N-terminal amino acid sequencing of cleavage products The Journal of biological chemistry High 9685426
2000 LTBP-2 does not bind any TGF-β isoform through its 8-Cys repeats, distinguishing it from LTBP-1 and LTBP-3. A specific short TGF-β binding motif present in the 3rd 8-Cys repeat of LTBP-1 is absent in the corresponding repeat of LTBP-2; introduction of this motif into LTBP-2's 3rd 8-Cys repeat confers TGF-β·LAP binding ability, demonstrating that the motif is necessary and sufficient for TGF-β binding. In vitro binding assays with purified 8-Cys repeat fragments, domain-swap mutagenesis, molecular modeling Molecular biology of the cell High 10930463
2003 LTBP-2 functions as an adhesion protein selectively for melanoma cells. The adhesive site is located in the N-terminal region of LTBP-2. Adhesion was blocked by anti-β1 integrin antibody and by antibodies against integrin subunits α3 and α6, and also by heparin, implicating β1 integrins (particularly α3β1 and α6β1) and heparan sulfate in the interaction. LTBP-2 also supported melanoma cell migration. Recombinant protein adhesion assays, recombinant fragment mapping, function-blocking integrin antibodies, heparin inhibition, immunofluorescence localization of integrins, modified Boyden chamber migration assay The Journal of biological chemistry High 12716902
2003 LTBP-2 exerts antiadhesive effects on fibroblasts adhering to fibronectin. Fibroblasts plated on LTBP-2/fibronectin substrate showed markedly reduced actin stress fibers and a less adherent morphology compared to fibronectin alone. LTBP-2 did not affect adhesion to collagen type I. The antiadhesive and adhesion-mediating activities mapped to the same N-terminal proline-rich region of LTBP-2, which also bound fibronectin in vitro. Quantitative cell adhesion assays, recombinant fragment analysis, actin cytoskeleton imaging (phalloidin staining), in vitro fibronectin binding assay The Journal of cell biology High 14691143
2007 LTBP-2 specifically binds the amino-terminal region of fibrillin-1 but not fibrillin-2, in a Ca2+-dependent manner (Kd = 9.4 nM). The major fibrillin-1 binding site resides near the C-terminus of LTBP-2. LTBP-2 and LTBP-1 compete for the same or adjacent binding site on fibrillin-1, suggesting LTBP-2 can act as a negative modulator of latent TGF-β complex storage on microfibrils. Solid phase binding assays, overlay blotting, recombinant fragment competition assays, EDTA/Ca2+ modulation, Kd calculation, immunohistochemistry of developing human aorta Matrix biology High 17293099
2007 LTBP-2 binds fibulin-5 (DANCE) and regulates elastic fiber assembly. Downregulation of LTBP-2 in human skin fibroblasts induces fibrillin-1-independent fibrillar deposition of fibulin-5 and elastin. Recombinant LTBP-2 promotes deposition of fibulin-5 onto fibrillin-1 microfibrils, indicating LTBP-2 regulates targeting of fibulin-5 to appropriate microfibrils for elastic fiber assembly. Yeast two-hybrid (implied by 'identification'), protein binding assays, siRNA knockdown of LTBP-2 in human fibroblasts, elastogenesis assay with confocal microscopy, recombinant LTBP-2 add-back experiment The EMBO journal High 17581631
2009 LTBP-2 matrix association depends on fibrillin-1. In cultured human embryonic lung fibroblasts, LTBP-2 was not deposited into ECM until after fibronectin and fibrillin-1 networks formed. LTBP-2 failed to assemble into ECM of fibronectin-deficient mouse fibroblasts. Lentiviral shRNA silencing of fibrillin-1 profoundly disrupted LTBP-2 deposition, demonstrating fibrillin-1 is required for LTBP-2 ECM incorporation. Metabolic labeling, immunoprecipitation, temporal ECM assembly analysis, fibronectin-null fibroblasts, lentiviral shRNA knockdown of fibrillin-1, immunofluorescence co-localization Journal of cellular physiology High 19681046
2009 Null mutations in LTBP2 cause primary congenital glaucoma. LTBP2 protein was localized to the anterior segment of the eye, specifically at the ciliary body and ciliary processes, suggesting a structural role in maintaining ciliary muscle tone and normal anterior chamber development. Homozygosity mapping, Sanger sequencing of LTBP2 in PCG families, immunohistochemistry of anterior eye segment American journal of human genetics Medium 19361779
2010 LTBP-2 has multiple heparin/heparan sulfate binding sites. Solid-phase assays identified high-affinity binding to heparin (Kd ~0.9 nM for full-length LTBP-2). Three major heparin-binding sequences reside in the N-terminal fragment, including the sequence LTEKIKKIKIV in the first large cysteine-free domain adjacent to the fibulin-5 binding site. LTBP-2 interacts with cell-surface syndecan-4 and basement membrane perlecan heparan sulfate chains. Solid-phase heparin-albumin conjugate binding assays, recombinant fragment analysis, synthetic peptide inhibition, Kd determination, EDTA/EGTA modulation, specificity controls with chondroitin sulfate Matrix biology High 20382221
2012 LTBP2 mutations cause Weill-Marchesani syndrome. The homozygous missense mutation p.Val1177Met in LTBP2 was shown to cause autosomal recessive WMS/WM-like syndrome. Electron and fluorescence microscopy of patient skin showed disruptions of the microfibrillar network in the ECM, directly linking LTBP2 dysfunction to microfibrillar network integrity. Homozygosity mapping, Sanger sequencing, light/fluorescent/electron microscopy of patient ECM Human mutation Medium 22539340
2013 LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, acting as a negative modulator of elastinogenesis. LTBP-2 bound fibulin-5 with Kd = 26.5 nM (similar affinity to tropoelastin-fibulin-5, Kd = 24.7 nM) and inhibited the tropoelastin-fibulin-5 interaction in a dose-dependent manner. LTBP-2 also significantly inhibited tropoelastin binding to heparin. Addition of exogenous LTBP-2 to chondrocyte cultures blocked elastinogenesis concentration-dependently. Solid-phase competitive binding assays, Kd calculation, confocal co-localization in fibroblast matrix, ear cartilage chondrocyte elastogenesis assay Matrix biology High 24148803
2014 LTBP-2 is essential for formation of ciliary zonule microfibrils. Ltbp2−/− mice developed lens luxation due to compromised ciliary zonule formation. siRNA knockdown of LTBP2 in human ciliary epithelial cells disrupted microfibril meshwork formation. Supplementation with recombinant LTBP-2 rescued microfibril meshwork formation in knockdown cells and restored unfragmented bundled ciliary zonules in Ltbp2−/− mouse eyes under organ culture. Human mutant LTBP-2 proteins, despite retaining fibrillin-1-binding domains, failed to be secreted due to conformational alteration. Ltbp2 knockout mouse generation, siRNA knockdown in ciliary epithelial cells, recombinant LTBP-2 rescue in vitro and organ culture, secretion assay of mutant proteins Human molecular genetics High 24908666
2015 LTBP-2 has a single high-affinity binding site for FGF-2 (Kd = 1.1 nM) located in a central region consisting of six tandem EGF-like motifs (EGFs 9-14). This region also contains a heparin/heparan sulfate-binding site. LTBP-2 completely blocked FGF-2-stimulated fibroblast proliferation at 5-fold molar excess, demonstrating it is a potent inhibitor of FGF-2 bioactivity. Solid-phase binding assays, recombinant fragment mapping, Kd determination, FGF-2-stimulated fibroblast proliferation assay, confocal co-localization in keloid tissue PloS one High 26263555
2015 LTBP-2 modulates NF-κB p65 signaling in nasopharyngeal carcinoma cells. Re-expression of LTBP-2 reduced phosphorylation of p65 at Serine 536, inhibited nuclear translocation of phosphorylated p65, and impaired p65 DNA-binding ability, resulting in downregulation of p65-related gene expression and tumor suppression. Loss- and gain-of-function (siRNA/overexpression), Western blotting for p-p65(Ser536), nuclear fractionation, DNA-binding assay (EMSA implied), colony formation, angiogenesis and EMT assays PloS one Medium 25974126
2016 A 4-bp insertion in exon 8 of LTBP2 causing a frameshift causes primary congenital glaucoma in domestic cats, with histologically confirmed arrest of aqueous humor outflow pathway development. This establishes the feline model as the first spontaneous non-rodent model of PCG linked to LTBP2 mutation and confirms LTBP2's role in anterior segment development. Candidate gene linkage analysis (LOD 18.38), Sanger sequencing, ophthalmic phenotyping, histology of anterior segment PloS one Medium 27149523
2017 A central bioactive region of LTBP-2 (an 8-Cys motif flanked by four EGF-like repeats) stimulates TGF-β1 expression and secretion in fibroblasts via phosphorylation of both Akt and p38 MAPK signaling pathways. The TGF-β1 increase was due to transcriptional upregulation (not displacement of matrix-stored TGF-β1). Anti-αVβ3 integrin antibodies partially inhibited this effect, suggesting a direct or indirect role for αVβ3 integrin as receptor. Exogenous recombinant LTBP-2 and fragment addition to fibroblasts, ELISA for TGF-β1, kinase inhibitor experiments, phosphorylation Western blots (Akt, p38), function-blocking integrin antibodies International journal of molecular sciences Medium 28991210
2018 LTBP2 knockdown in trabecular meshwork cells affected TGFβ and BMP signaling pathways, ECM gene expression, and apoptosis. Effects of LTBP2 knockdown paralleled those of oxidative stress induction, suggesting LTBP2 mediates its effects on trabecular meshwork ECM and apoptosis through TGFβ and BMP signaling pathway activation. siRNA knockdown, TGFβ2 and gremlin treatment, canonical TGFβ and BMP signaling assays, ECM gene expression analysis, apoptosis assays in primary human trabecular meshwork cells Gene Medium 29908281
2019 LTBP2 knockdown in a rat dilated cardiomyopathy model reversed myocardial oxidative stress injury, fibrosis, and remodeling. The protective effects were mediated by downregulation of the NF-κB signaling pathway (reduced p65 and p52 levels). Activation of NF-κB pathway reversed the benefits of LTBP2 silencing, placing LTBP2 upstream of NF-κB in this context. siRNA knockdown in vivo (DCM rat model) and in vitro, NF-κB pathway activator co-treatment, hemodynamic measurements, collagen/ROS/cytokine quantification, Western blotting Acta physiologica Medium 31512380
2020 LTBP-2 is required for mechanical strength and longevity of ciliary zonular fibers but not for their initial formation. In Ltbp2−/− mice, zonular fibers appeared structurally normal at birth but began to rupture by 2 months, with fully penetrant ectopia lentis by 6 months. LTBP-2 absence reduced ultimate tensile strength by ~50% and significantly altered viscoelastic behavior. Modeling indicated mutant fibers are prone to failure during saccadic eye movement. Ltbp2 knockout mouse, 3D zonule imaging, in vivo OCT imaging, mechanical tensile testing, quasi-linear viscoelastic modeling, harmonic oscillator simulation Matrix biology High 33039488
2020 LTBP2 mutation in an LTBP2/TCTN3 double-heterozygous patient delayed cardiomyocyte development. Using CRISPR/Cas9-generated human pluripotent stem cells carrying the LTBP2 mutation (p.Asp736Asn), differentiation into cardiomyocytes showed delayed CM development compared to wild type, with enrichment of pathways related to cardiac development and congenital heart disease. CRISPR/Cas9 gene editing of hPSCs, hPSC differentiation into cardiomyocytes, transcriptomics at differentiation days 0/9/13, pathway enrichment analysis Journal of cellular and molecular medicine Low 33098376
2023 Ltbp2−/− mice exhibit multiple organ phenotypes including altered body weight and fat mass, and effects on bone and skin development, with reduced tissue strength. Notably, tissues expressing high Ltbp2 levels, such as aorta and lung, showed no developmental or homeostatic phenotype, indicating tissue-specific roles for LTBP2 in ECM and signaling. Ltbp2 knockout mouse analysis, body composition measurement, bone and skin mechanical testing, histology Developmental dynamics Medium 37688792
2023 HIF-1α directly binds to the LTBP2 promoter to transcriptionally activate LTBP2 expression. LTBP2 in turn interacts with LOXL1 (demonstrated by molecular docking and co-immunoprecipitation), and this interaction activates ERK signaling to promote hepatic stellate cell activation and EMT in liver fibrosis. AAV6-mediated knockdown of LTBP2 in HSCs markedly reduced CCl4-induced liver fibrosis. ChIP assay, dual-luciferase reporter assay, molecular docking, co-immunoprecipitation, AAV6-mediated in vivo knockdown, gain/loss-of-function in LX-2 cells, ERK pathway Western blotting Cellular and molecular life sciences Medium 40244455
2023 HIF-1α transcriptionally activates LTBP2 by binding its promoter. LTBP2 promotes oral mucosal fibrosis (OSF) by activating NF-κB signaling. Curcumin inhibits HIF-1α, thereby reducing LTBP2 expression and inactivating NF-κB to alleviate arecoline-induced OSF. This defines HIF-1α → LTBP2 → NF-κB as a fibrosis-promoting axis. Dual-luciferase reporter assay for HIF-1α/LTBP2 promoter interaction, siRNA knockdown, qRT-PCR, Western blotting, MTT/transwell/flow cytometry assays, ELISA Oral diseases Medium 37382472
2024 CAF-secreted LTBP2 interacts with integrin α6β4 on esophageal squamous cell carcinoma cells, activating Src signaling to promote metastasis and chemoresistance. Antagonistic antibodies targeting LTBP2 increased chemotherapy susceptibility. This identifies integrin α6β4 as a functional receptor for extracellular LTBP2. Co-immunoprecipitation (LTBP2/integrin α6β4), Src phosphorylation Western blotting, antagonistic antibody treatment, invasion/metastasis assays, chemoresistance assays Cancer research Medium 40245188
2025 LTBP2 deficiency reduces lung fibrosis in mice. Ltbp2−/− mice exposed to bleomycin or silica showed significantly reduced fibrosis versus wild-type, with reduced TGFβ signaling and impaired fibroblast migration in vitro. Transcriptomic analysis identified LTBP2-regulated genes including the antifibrotic lncRNA Airn. LTBP2 competes with the large latent TGFβ complex (LLC) for fibrillin N-terminus binding, and its loss promotes LLC sequestration and reduces active TGFβ release. However, Ltbp2−/− mice also showed impaired airway epithelial repair. Ltbp2 knockout mouse, bleomycin and silica fibrosis models, TGFβ signaling assays (pSmad), fibroblast wound closure assay, transcriptomics, naphthalene epithelial injury model bioRxivpreprint Medium 40654695
2025 LTBP2 knockout mice develop myxomatous mitral valve changes (histology and echocardiography). A human MVP-segregating LTBP2 mutation (V1506M knockin) reproduced the myxomatous valve phenotype. KO mice showed overexpression of TGFβ signaling targets RUNX2 and periostin in valve tissue, linking LTBP2 loss to dysregulated TGFβ signaling in valvular disease. LTBP2 knockout and knockin mouse generation, echocardiography, histology, qPCR for TGFβ target genes (periostin/POSTN, RUNX2, CTGF), exome sequencing with family segregation European heart journal open Medium 39882270

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 1451 20881960
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 Latent transforming growth factor-beta: structural features and mechanisms of activation. Kidney international 438 9150447
2016 Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins. Cold Spring Harbor perspectives in biology 329 27252363
2009 Null mutations in LTBP2 cause primary congenital glaucoma. American journal of human genetics 258 19361779
1999 Latent transforming growth factor-beta binding proteins (LTBPs)--structural extracellular matrix proteins for targeting TGF-beta action. Cytokine & growth factor reviews 241 10743502
2000 Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Molecular biology of the cell 234 10930463
2010 Proteomics characterization of extracellular space components in the human aorta. Molecular & cellular proteomics : MCP 231 20551380
2006 Elastic fibres in health and disease. Expert reviews in molecular medicine 183 16893474
1998 Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. Advances in cancer research 175 9709808
1994 Identification and characterization of LTBP-2, a novel latent transforming growth factor-beta-binding protein. The Journal of biological chemistry 143 7798248
2000 The latent transforming growth factor beta binding protein (LTBP) family. The Biochemical journal 139 11104663
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
2009 Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Human molecular genetics 132 19656777
2002 Bone abnormalities in latent TGF-[beta] binding protein (Ltbp)-3-null mice indicate a role for Ltbp-3 in modulating TGF-[beta] bioavailability. The Journal of cell biology 130 11790802
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
2017 Comprehensive proteomic characterization of stem cell-derived extracellular matrices. Biomaterials 125 28327460
1995 Isolation of a novel latent transforming growth factor-beta binding protein gene (LTBP-3). The Journal of biological chemistry 123 7730318
2020 The circEPSTI1/mir-942-5p/LTBP2 axis regulates the progression of OSCC in the background of OSF via EMT and the PI3K/Akt/mTOR pathway. Cell death & disease 119 32826876
2007 LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein. Matrix biology : journal of the International Society for Matrix Biology 113 17293099
2012 LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Human mutation 107 22539340
2014 Activation of LTBP3 gene by a long noncoding RNA (lncRNA) MALAT1 transcript in mesenchymal stem cells from multiple myeloma. The Journal of biological chemistry 102 25187517
2007 Latent TGF-beta-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly. The EMBO journal 101 17581631
2010 LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. European journal of human genetics : EJHG 97 20179738
2011 Protein profile of exosomes from trabecular meshwork cells. Journal of proteomics 86 21362503
2014 Latent TGF-β binding protein-2 is essential for the development of ciliary zonule microfibrils. Human molecular genetics 80 24908666
2003 The DNA sequence and analysis of human chromosome 14. Nature 80 12508121
2014 Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci. Human molecular genetics 77 25429064
2017 HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma. American journal of cancer research 73 28469957
2011 Screening of CYP1B1 and LTBP2 genes in Saudi families with primary congenital glaucoma: genotype-phenotype correlation. Molecular vision 67 22128238
2007 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. Proteomics 66 17474147
2010 A homozygous mutation in LTBP2 causes isolated microspherophakia. Human genetics 65 20617341
1998 Recombinant latent transforming growth factor beta-binding protein 2 assembles to fibroblast extracellular matrix and is susceptible to proteolytic processing and release. The Journal of biological chemistry 63 9685426
2012 CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. American journal of ophthalmology 62 23218701
2009 Oligodontia is caused by mutation in LTBP3, the gene encoding latent TGF-beta binding protein 3. American journal of human genetics 62 19344874
2010 LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. European journal of human genetics : EJHG 61 21081970
2002 Bone defects in latent TGF-beta binding protein (Ltbp)-3 null mice; a role for Ltbp in TGF-beta presentation. The Journal of endocrinology 61 12379497
2011 Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations. Molecular vision 55 22025892
2016 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation. Circulation 54 27559042
2009 Exploring functional candidate genes for genetic association in german patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Investigative ophthalmology & visual science 52 19182256
2009 High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 52 19453261
2002 Secretion of human latent TGF-beta-binding protein-3 (LTBP-3) is dependent on co-expression of TGF-beta. Journal of cell science 52 12154076
2010 The identification of a novel locus for mandibular prognathism in the Han Chinese population. Journal of dental research 51 21041550
2022 Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension. Nature cardiovascular research 50 39196085
2018 LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis. Clinical science (London, England : 1979) 50 30006483
2014 Osteopontin and latent-TGF β binding-protein 2 as potential diagnostic markers for HBV-related hepatocellular carcinoma. International journal of cancer 50 24803312
2016 Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia. Journal of medical genetics 49 27068007
2016 Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins. Cardiovascular research 49 27068509
2016 Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production. Proceedings of the National Academy of Sciences of the United States of America 49 27911796
2018 LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. American journal of human genetics 48 29625025
2003 Latent transforming growth factor-beta-binding protein 2 is an adhesion protein for melanoma cells. The Journal of biological chemistry 48 12716902
2004 Genetic variations in humans associated with differences in the course of hepatitis C. Biochemical and biophysical research communications 47 15063762
2015 Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. Proceedings of the National Academy of Sciences of the United States of America 46 26494287
2002 Latent TGF-beta binding protein-3 (LTBP-3) requires binding to TGF-beta for secretion. FEBS letters 44 12062452
2010 The ECM protein LTBP-2 is a suppressor of esophageal squamous cell carcinoma tumor formation but higher tumor expression associates with poor patient outcome. International journal of cancer 40 20878956
2009 Matrix association of latent TGF-beta binding protein-2 (LTBP-2) is dependent on fibrillin-1. Journal of cellular physiology 40 19681046
2016 A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus). PloS one 38 27149523
2015 Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta. Human molecular genetics 37 25669657
2003 Latent TGF-beta binding protein LTBP-2 decreases fibroblast adhesion to fibronectin. The Journal of cell biology 37 14691143
2020 Latent-transforming growth factor beta-binding protein-2 (LTBP-2) is required for longevity but not for development of zonular fibers. Matrix biology : journal of the International Society for Matrix Biology 33 33039488
2019 LTBP2 knockdown by siRNA reverses myocardial oxidative stress injury, fibrosis and remodelling during dilated cardiomyopathy. Acta physiologica (Oxford, England) 32 31512380
2015 NF-κB p65 Subunit Is Modulated by Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) in Nasopharyngeal Carcinoma HONE1 and HK1 Cells. PloS one 31 25974126
2010 LTBP-2 has multiple heparin/heparan sulfate binding sites. Matrix biology : journal of the International Society for Matrix Biology 31 20382221
2018 LTBP2 knockdown and oxidative stress affect glaucoma features including TGFβ pathways, ECM genes expression and apoptosis in trabecular meshwork cells. Gene 30 29908281
2015 Co-localization of LTBP-2 with FGF-2 in fibrotic human keloid and hypertrophic scar. Journal of molecular histology 29 26644005
2012 LTBP-2 confers pleiotropic suppression and promotes dormancy in a growth factor permissive microenvironment in nasopharyngeal carcinoma. Cancer letters 29 22743615
2008 Identification of LTBP2 on chromosome 14q as a novel candidate gene for bone mineral density variation and fracture risk association. The Journal of clinical endocrinology and metabolism 27 18697872
2019 Genotype-phenotype correlation and expansion of orodental anomalies in LTBP3-related disorders. Molecular genetics and genomics : MGG 26 30887145
2016 Identification of Novel Variants in LTBP2 and PXDN Using Whole-Exome Sequencing in Developmental and Congenital Glaucoma. PloS one 26 27409795
2013 LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis. Matrix biology : journal of the International Society for Matrix Biology 26 24148803
2023 Dengzhan Shengmai capsule attenuates cardiac fibrosis in post-myocardial infarction rats by regulating LTBP2 and TGF-β1/Smad3 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 24 37163903
2018 LTBP3 promotes early metastatic events during cancer cell dissemination. Oncogene 24 29348457
2016 Knockdown of Latent Transforming Growth Factor-β (TGF-β)-Binding Protein 2 (LTBP2) Inhibits Invasion and Tumorigenesis in Thyroid Carcinoma Cells. Oncology research 24 27712597
2012 LTBP-2 acts as a novel marker in human heart failure - a preliminary study. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 23 22515403
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2013 Screening of the LTBP2 gene in a north Indian population with primary congenital glaucoma. Molecular vision 20 23378721
2003 Growth retardation as well as spleen and thymus involution in latent TGF-beta binding protein (Ltbp)-3 null mice. Journal of cellular physiology 20 12811825
2018 Delineation of Novel Compound Heterozygous Variants in LTBP2 Associated with Juvenile Open Angle Glaucoma. Genes 19 30380740
2017 A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-β1 in Fibroblasts via Akt and p38 Signalling Pathways. International journal of molecular sciences 19 28991210
2012 LTBP2 gene analysis in the GLC3C-linked family and 94 CYP1B1-negative cases with primary congenital glaucoma. Ophthalmic genetics 19 22924778
2018 Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome. Biomechanics and modeling in mechanobiology 17 30306291
2015 LTBP-2 Has a Single High-Affinity Binding Site for FGF-2 and Blocks FGF-2-Induced Cell Proliferation. PloS one 17 26263555
2012 The novel marker LTBP2 predicts all-cause and pulmonary death in patients with acute dyspnoea. Clinical science (London, England : 1979) 17 22587491
2022 LTBP2 Knockdown Promotes Ferroptosis in Gastric Cancer Cells through p62-Keap1-Nrf2 Pathway. BioMed research international 16 35968244
2019 miR-421 promotes apoptosis and suppresses metastasis of osteosarcoma cells via targeting LTBP2. Journal of cellular biochemistry 16 30924175
2018 LTBP2-related "Marfan-like" phenotype in two Roma/Gypsy subjects with the LTBP2 homozygous p.R299X variant. American journal of medical genetics. Part A 15 30565850
2011 The distribution of fibrillin-2 and LTBP-2, and their co-localisation with fibrillin-1 in adult bovine tail disc. Journal of anatomy 15 22098471
2017 Rapid Communication: High-resolution quantitative trait loci analysis identifies LTBP2 encoding latent transforming growth factor beta binding protein 2 associated with thoracic vertebrae number in a large F2 intercross between Landrace and Korean native pigs. Journal of animal science 14 28727023
2014 Confocal microscopy demonstrates association of LTBP-2 in fibrillin-1 microfibrils and colocalisation with perlecan in the disc cell pericellular matrix. Tissue & cell 14 24867584
2022 LTBP2 inhibits prostate cancer progression and metastasis via the PI3K/AKT signaling pathway. Experimental and therapeutic medicine 13 36034756
2020 Novel mutations in LTBP2 identified in familial cases of primary congenital glaucoma. Molecular vision 12 32165823
2020 Novel mutations of TCTN3/LTBP2 with cellular function changes in congenital heart disease associated with polydactyly. Journal of cellular and molecular medicine 11 33098376
2015 A Possible Role for LTBP2 in the Etiology of Primary Angle Closure Glaucoma. Journal of ophthalmic & vision research 11 26425313
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2022 Identification of LTBP2 gene polymorphisms and their association with thoracolumbar vertebrae number, body size, and carcass traits in Dezhou donkeys. Frontiers in genetics 9 36482906
2018 Next-generation sequencing reveals a new mutation in the LTBP2 gene associated with microspherophakia in a Spanish family. BMC medical genetics 9 29751740
2017 Candidate Gene Analysis Identifies Mutations in CYP1B1 and LTBP2 in Indian Families with Primary Congenital Glaucoma. Genetic testing and molecular biomarkers 9 28384041
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2024 SGLT2i improves kidney senescence by down-regulating the expression of LTBP2 in SAMP8 mice. Journal of cellular and molecular medicine 8 38454800
2020 Common variants in LTBP3 gene contributed to the risk of hip osteoarthritis in Han Chinese population. Bioscience reports 8 32452514
2024 Sodium Propionate Alleviates Atopic Dermatitis by Inhibiting Ferroptosis via Activation of LTBP2/FABP4 Signaling Pathway. Journal of inflammation research 7 39634285
2021 A Pedigree Report of a Rare Case of Weill-Marchesani Syndrome with New Compound Heterozygous LTBP2 Mutations. Risk management and healthcare policy 7 33958902
2015 Latent transforming growth factor-β binding proteins (LTBP-1 and LTBP-2) and gingiva keratinization. Oral diseases 6 25858550
2025 Lactate Promotes Collagen Expression, Proliferation, and Migration through H3K18 Lactylation-Dependent Stimulation of LTBP3/TGF-β1 Axis in Keloid Fibroblasts. The Journal of investigative dermatology 5 40633755
2023 Curcumin relieves arecoline-induced oral submucous fibrosis via inhibiting the LTBP2/NF-κB axis. Oral diseases 5 37382472
2021 Compound heterozygous mutations in the LTBP2 gene associated with microspherophakia in a Chinese patient: a case report and literature review. BMC medical genomics 5 34535142
2020 Bi-allelic loss-of-function novel variants in LTBP3-related skeletal dysplasia: Report of first patient from India. American journal of medical genetics. Part A 5 32432408
2025 Targeting LTBP2 Derived from Cancer-Associated Fibroblasts Sensitizes Esophageal Squamous Cell Carcinoma to Chemotherapy. Cancer research 4 40245188
2023 Plasma LTBP2 as a potential biomarker in differential diagnosis of connective tissue disease-associated interstitial lung disease and idiopathic pulmonary fibrosis: a pilot study. Clinical and experimental medicine 4 37864077
2022 CircWHSC1 expedites cervical cancer progression via miR-532-3p/LTBP2 axis. Molecular and cellular biochemistry 4 35235125
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2020 Genetic mapping of autosomal recessive microspherophakia to chromosome 14q24.3 in a consanguineous Pakistani family and screening of exon 36 of LTBP2 gene. JPMA. The Journal of the Pakistan Medical Association 4 32207437
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2025 Characterization of LTBP2 mutation causing mitral valve prolapse. European heart journal open 3 39882270
2025 HIF-1α/LTBP2 axis activate HSCs to promote liver fibrosis by interacting with LOXL1 via the ERK pathway. Cellular and molecular life sciences : CMLS 3 40244455
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2024 LTBP2 regulates cisplatin resistance in GC cells via activation of the NF-κB2/BCL3 pathway. Genetics and molecular biology 2 38577985
2024 Trabecular Meshwork Abnormalities in a Model of Congenital Glaucoma Due to LTBP2 Mutation. Investigative ophthalmology & visual science 2 39432401
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