{"gene":"LTBP2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1994,"finding":"LTBP-2 is synthesized as a 240-kDa protein by human foreskin fibroblasts and COS cells transfected with LTBP-2 cDNA. Co-transfection of LTBP-2 and TGF-β1 cDNAs revealed that LTBP-2 forms a high molecular weight complex with the TGF-β1 precursor, and a considerable part of LTBP-2 associates with extracellular matrix.","method":"Co-transfection, immunoprecipitation, metabolic labeling, ECM fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-transfection plus ECM fractionation in one lab, two orthogonal methods","pmids":["7798248"],"is_preprint":false},{"year":1998,"finding":"The second and third TGF-bp (8-cysteine) repeats of mouse LTBP-2 can covalently bind the small latent TGF-β1 complex, analogous to LTBP-3, indicating a disulfide-based interaction via the 8-cysteine structural motifs.","method":"Immunoprecipitation, SDS-PAGE, autoradiography","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, immunoprecipitation with SDS-PAGE and autoradiography, but only mouse LTBP-2 fragments tested","pmids":["9602168"],"is_preprint":false},{"year":2003,"finding":"LTBP-2 acts as an antiadhesive matrix component: fibroblasts do not adhere to full-length LTBP-2, and LTBP-2 disrupts fibroblast adhesion morphology and actin stress fibers on fibronectin substrata. The N-terminal proline-rich region of LTBP-2 mediates both weak adhesion and cytoskeleton-disrupting effects, and LTBP-2 binds fibronectin in vitro.","method":"Quantitative cell adhesion assay, actin staining, in vitro binding assay, recombinant fragment analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cell adhesion assay, cytoskeletal staining, in vitro binding), single lab, clear domain mapping","pmids":["14691143"],"is_preprint":false},{"year":2007,"finding":"LTBP-2 specifically binds the amino-terminal region of fibrillin-1 (but not fibrillin-2) with a Kd of ~9.4 nM. The major fibrillin-1 binding site resides near the C-terminus of LTBP-2. LTBP-2 competes with LTBP-1 for the same or overlapping binding site on fibrillin-1, suggesting LTBP-2 may act as an indirect negative modulator of large latent TGF-β complex storage on microfibrils.","method":"Solid-phase binding assay, overlay blotting, competitive binding assay with recombinant fragments, Ca2+ chelation experiments","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted binding with Kd determination, competitive inhibition, domain mapping using recombinant fragments, single lab with multiple orthogonal methods","pmids":["17293099"],"is_preprint":false},{"year":2009,"finding":"LTBP-2 matrix assembly depends on a pre-formed fibrillin-1 network: LTBP-2 associates with ECM only after confluency following deposition of fibronectin and fibrillin-1, colocalizes transiently with fibronectin, fails to assemble in fibronectin-deficient fibroblasts, and fibrillin-1 silencing via lentiviral shRNA profoundly disrupts LTBP-2 deposition.","method":"Metabolic labeling, immunoprecipitation, lentiviral shRNA knockdown of fibrillin-1, immunofluorescence colocalization","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (metabolic labeling, shRNA knockdown, immunofluorescence), single lab","pmids":["19681046"],"is_preprint":false},{"year":2010,"finding":"LTBP-2 has multiple heparin/heparan sulfate binding sites: full-length LTBP-2 binds heparin conjugated albumin with Kd ~0.9 nM, with the N-terminal fragment (Kd ~0.7 nM) and a central fragment (Kd ~80 nM) both contributing. Three major heparin-binding sequences were identified in the N-terminal region. LTBP-2 also interacts with cell-surface syndecan-4 and basement membrane perlecan (via heparan sulfate chains).","method":"Solid-phase binding assay, synthetic peptide inhibition, recombinant fragment analysis, Kd calculation","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with Kd determination, domain mapping, peptide inhibition, single lab with multiple orthogonal approaches","pmids":["20382221"],"is_preprint":false},{"year":2012,"finding":"Homozygous LTBP2 missense mutation (p.Val1177Met) causes Weill-Marchesani syndrome with disruptions of the microfibrillar network in the ECM of patient skin, as demonstrated by light, fluorescent, and electron microscopy.","method":"Homozygosity mapping, light/fluorescent/electron microscopy of patient skin ECM","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping plus direct ultrastructural ECM analysis in patient tissue using three microscopy modalities","pmids":["22539340"],"is_preprint":false},{"year":2013,"finding":"LTBP-2 competes with tropoelastin for binding to fibulin-5 (Kd for LTBP-2/fibulin-5 ~26.5 nM, comparable to tropoelastin/fibulin-5 ~24.7 nM) and inhibits tropoelastin-fibulin-5 interaction in a dose-dependent manner. LTBP-2 also significantly inhibits heparin binding to tropoelastin. Addition of exogenous LTBP-2 to chondrocyte cultures blocked elastinogenesis in a concentration-dependent manner, indicating a negative regulatory role in elastic fiber assembly.","method":"Solid-phase competitive binding assay, Kd calculation, confocal microscopy colocalization, chondrocyte elastinogenesis assay","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted competitive binding with Kd measurements plus functional cell-based elastinogenesis assay, single lab with multiple orthogonal methods","pmids":["24148803"],"is_preprint":false},{"year":2015,"finding":"LTBP-2 has a single high-affinity binding site for FGF-2 (Kd ~1.1 nM) located in a central region containing EGF-like motifs 9–14. LTBP-2 at 5-fold molar excess completely blocks FGF-2-stimulated fibroblast proliferation. LTBP-2 and FGF-2 co-localize in fibrotic keloid tissue in vivo.","method":"Solid-phase binding assay with recombinant LTBP-2 fragments, Kd calculation, cell proliferation assay, confocal microscopy","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with Kd determination, domain mapping, functional proliferation assay, in vivo co-localization, single lab with multiple orthogonal methods","pmids":["26263555"],"is_preprint":false},{"year":2015,"finding":"Re-expression of LTBP2 in nasopharyngeal carcinoma cells reduces phosphorylation of NF-κB p65 at Serine 536, inhibits nuclear localization of phosphorylated p65, and impairs p65 DNA-binding ability, leading to downregulation of p65-related gene expression.","method":"Loss- and gain-of-function (siRNA/overexpression), Western blot for p65 phosphorylation, nuclear fractionation, DNA-binding assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (phosphorylation, nuclear localization, DNA binding) with both KD and OE, single lab","pmids":["25974126"],"is_preprint":false},{"year":2017,"finding":"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 by activating both Akt and p38 MAPK signaling. Blocking either pathway individually abolished the TGF-β1 increase. Anti-αVβ3 integrin antibodies partially inhibited this effect, suggesting an indirect role for αVβ3 integrin.","method":"Recombinant LTBP-2 fragment treatment, kinase inhibitors, phosphorylation Western blot, ELISA for TGF-β1, blocking antibodies to integrins","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with recombinant fragments, multiple signaling readouts, functional antibody blocking, single lab","pmids":["28991210"],"is_preprint":false},{"year":2018,"finding":"LTBP2 knockdown in human trabecular meshwork cells affects canonical TGF-β and BMP signaling pathways, alters expression of ECM-related genes, and promotes apoptosis, with effects paralleling those of oxidative stress induction.","method":"siRNA knockdown, TGF-β/BMP signaling pathway assays, ECM gene expression analysis, apoptosis assay in primary human trabecular meshwork cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA KD with multiple pathway readouts, single lab, primary human cells","pmids":["29908281"],"is_preprint":false},{"year":2018,"finding":"LTBP2 is secreted from lung myofibroblasts and its expression is upregulated by TGF-β1 at mRNA and protein levels in human lung myofibroblasts; LTBP2 localizes broadly to fibrotic interstitium as an ECM protein and to αSMA-positive myofibroblasts in IPF lungs.","method":"FACS sorting, microarray, TGF-β1 stimulation, ELISA, immunohistochemistry","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TGF-β1 induction confirmed at mRNA and protein levels, localization by IHC, ELISA measurement, single lab","pmids":["30006483"],"is_preprint":false},{"year":2019,"finding":"LTBP-2 is a structural component required for tensile strength and longevity of ciliary zonular fibers: LTBP-2 knockout mice have ~50% reduced ultimate tensile strength and altered viscoelastic behavior of zonules, leading to fully penetrant ectopia lentis by 6 months, without affecting fiber number, diameter, or coaxial organization.","method":"LTBP-2 knockout mouse model, 3D zonule imaging, mechanical stress/strain testing, quasi-linear viscoelastic modeling, in vivo imaging","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — knockout mouse with quantitative biomechanical testing and in vivo phenotyping, multiple orthogonal methods, single lab","pmids":["33039488"],"is_preprint":false},{"year":2019,"finding":"LTBP2 knockdown in a rat DCM model reduces myocardial oxidative stress, fibrosis (collagen I and III), and remodeling, and these effects are reversed by NF-κB pathway activation, placing LTBP2 upstream of NF-κB signaling in cardiomyocyte pathology.","method":"siRNA knockdown in rat DCM model, NF-κB pathway activator rescue, Western blot, ROS/MDA measurements, histology","journal":"Acta physiologica (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD plus NF-κB activator epistasis, multiple readouts, single lab","pmids":["31512380"],"is_preprint":false},{"year":2023,"finding":"LTBP2 knockout mice show multi-organ phenotypes including altered body weight, fat mass, and defects in bone and skin development (with differentially affected tissue strength), whereas high-LTBP2-expressing tissues such as aorta and lung show no developmental phenotype, indicating complex tissue-specific effects on ECM or signaling.","method":"Knockout mouse phenotyping, body composition measurement, histology of bone and skin","journal":"Developmental dynamics : an official publication of the American Association of Anatomists","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO mouse with defined tissue phenotypes, single lab","pmids":["37688792"],"is_preprint":false},{"year":2024,"finding":"LTBP2 knockout mice show myxomatous mitral valve changes (7/9 KO vs 0/7 controls by histology; 7/9 vs 0/8 by echocardiography) and knockin of the human LTBP2 V1506M mutation also causes myxomatous valve phenotype. KO mice overexpress TGF-β signaling targets RUNX2 and periostin in valve tissue, indicating LTBP2 loss leads to dysregulated TGF-β signaling in valves.","method":"KO and knockin mouse generation, echocardiography, histology, qPCR for TGF-β signaling targets (periostin/POSTN, RUNX2, CTGF)","journal":"European heart journal open","confidence":"High","confidence_rationale":"Tier 2 / Moderate — both KO and knockin mouse models with echocardiography and histology, TGF-β pathway readouts, single lab with multiple orthogonal approaches","pmids":["39882270"],"is_preprint":false},{"year":2024,"finding":"In a feline PCG model caused by LTBP2 mutation, the earliest ultrastructural abnormalities occur at 2 weeks postnatally: elastic fibers in the trabecular meshwork are discontinuous and disorganized, followed by decreased intertrabecular space by 5 weeks and trabecular cell morphology changes, with intraocular pressure elevation coinciding with established ECM collapse by 12 weeks.","method":"Transmission electron microscopy of trabecular meshwork at multiple postnatal time points, quantitative assessment of intertrabecular space and cell morphology","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — longitudinal TEM with quantitative morphometry, single lab","pmids":["39432401"],"is_preprint":false},{"year":2025,"finding":"CAF-secreted LTBP2 interacts with integrin α6β4 as a functional receptor on ESCC cells and activates Src signaling, promoting metastasis and chemoresistance. Antagonistic anti-LTBP2 antibodies increase chemotherapy susceptibility of ESCC cells.","method":"Co-immunoprecipitation, signaling pathway analysis, antibody blocking experiments, cell migration/invasion assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP to identify receptor, functional antibody blocking, multiple cancer cell assays, single lab","pmids":["40245188"],"is_preprint":false},{"year":2025,"finding":"HIF-1α promotes LTBP2 expression by directly binding to the LTBP2 promoter region (confirmed by ChIP and dual-luciferase assay). LTBP2 interacts with LOXL1 (confirmed by molecular docking and Co-IP), and this interaction activates ERK signaling to promote hepatic stellate cell activation and EMT in liver fibrosis. AAV6-mediated LTBP2 knockdown in HSCs markedly reduces CCl4-induced liver fibrosis in mice.","method":"ChIP assay, dual-luciferase reporter assay, molecular docking, Co-IP, AAV6-mediated HSC-specific knockdown in vivo, gain/loss-of-function in LX-2 cells","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (ChIP, Co-IP, dual-luciferase, in vivo AAV knockdown) establishing transcriptional regulation, protein interaction, and downstream pathway, single lab","pmids":["40244455"],"is_preprint":false},{"year":2025,"finding":"LTBP2-deficient (Ltbp2-/-) mice exposed to bleomycin or silica show significantly reduced lung fibrosis compared to wild-type controls, with reduced TGFβ signaling in bleomycin-treated lungs. Isolated fibroblasts from Ltbp2-/- mice exhibit impaired migration in wound closure assays. Ltbp2-/- mice also show impaired airway epithelial repair after bleomycin and naphthalene injury.","method":"Ltbp2 knockout mouse with bleomycin/silica fibrosis models, TGFβ signaling assays, in vitro fibroblast wound closure assay, transcriptomic analysis, naphthalene injury model","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with two fibrosis models, in vitro fibroblast assay, transcriptomics, published as peer-reviewed journal article replicated from preprint","pmids":["42236262"],"is_preprint":false},{"year":2023,"finding":"HIF-1α binds to the LTBP2 promoter and transcriptionally activates LTBP2 expression. LTBP2 knockdown in oral mucosal fibroblasts relieves arecoline-induced OSF by inactivating NF-κB signaling, placing LTBP2 downstream of HIF-1α and upstream of NF-κB in the OSF fibrosis pathway.","method":"Dual-luciferase reporter assay, siRNA knockdown, Western blot for NF-κB pathway proteins, MTT/transwell/flow cytometry assays","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase for promoter binding plus functional KD, multiple readouts, single lab","pmids":["37382472"],"is_preprint":false},{"year":2022,"finding":"LTBP2 silencing in gastric cancer cells promotes ferroptosis by reducing GPX4 activity and cellular GSH levels, increasing ROS and MDA, and this is mediated through regulation of the p62-Keap1-Nrf2 pathway, downregulating GPX4 and xCT and upregulating PTGS2 and 4HNE.","method":"siRNA knockdown, cell viability assay, lipid peroxidation assay, ROS assay, GSH assay, Western blot, TEM","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple biochemical pathway readouts, single lab","pmids":["35968244"],"is_preprint":false},{"year":2020,"finding":"LTBP2 mutation in human pluripotent stem cells (hPSCs-LTBP2mu) delays cardiomyocyte development, with persistently upregulated pathways in cardiac development and congenital heart disease enriched in LTBP2-mutant cardiomyocytes compared to wild type.","method":"CRISPR/Cas9 mutation in hPSCs, differentiation to cardiomyocytes, transcriptomics at days 0, 9, and 13","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR/Cas9 mutation with transcriptomic analysis during differentiation, single lab","pmids":["33098376"],"is_preprint":false}],"current_model":"LTBP2 is a large extracellular matrix glycoprotein that associates with fibrillin-1-containing microfibrils (requiring a pre-formed fibrillin-1 network for its own ECM deposition), binds heparin/heparan sulfate proteoglycans (syndecan-4, perlecan) and FGF-2 at high affinity via distinct central EGF-like domains, competes with LTBP-1 and tropoelastin for fibrillin-1 and fibulin-5 binding respectively, acts as an antiadhesive component by disrupting fibronectin-mediated fibroblast adhesion via its N-terminal proline-rich region, provides structural tensile strength to ciliary zonular fibers, stimulates TGF-β1 expression via Akt and p38 MAPK signaling through a central 8-Cys/EGF-like bioactive region, modulates NF-κB p65 activity and nuclear localization, promotes TGF-β signaling in lung fibrosis (its absence reduces fibrosis in bleomycin and silica models), is transcriptionally activated by HIF-1α binding its promoter, and interacts with LOXL1 to activate ERK-driven hepatic stellate cell activation—collectively functioning as a multi-functional ECM scaffold and signaling modulator rather than a direct TGF-β chaperone."},"narrative":{"mechanistic_narrative":"LTBP2 is a large secreted extracellular matrix glycoprotein that functions as a microfibril-associated structural scaffold and a modulator of matrix assembly and growth-factor signaling rather than a direct latent TGF-β chaperone [PMID:17293099, PMID:33039488]. Its own matrix incorporation is strictly dependent on a pre-formed fibronectin/fibrillin-1 network, and it binds the amino-terminal region of fibrillin-1 with high affinity (Kd ~9.4 nM) at a site near its own C-terminus, competing with LTBP-1 for this site [PMID:17293099, PMID:19681046]. Through distinct domains LTBP2 engages multiple matrix and cell-surface partners: a central EGF-like region binds FGF-2 (Kd ~1.1 nM) and blocks FGF-2-driven fibroblast proliferation, N-terminal sequences mediate high-affinity heparin/heparan-sulfate binding and interaction with syndecan-4 and perlecan, and it competes with tropoelastin for fibulin-5 to negatively regulate elastic fiber assembly [PMID:20382221, PMID:24148803, PMID:26263555]. Its N-terminal proline-rich region confers antiadhesive activity, disrupting fibronectin-mediated fibroblast adhesion and actin stress fibers [PMID:14691143]. As a structural element, LTBP2 provides tensile strength and viscoelastic integrity to ciliary zonular fibers, and its loss in knockout mice produces fully penetrant ectopia lentis [PMID:33039488]; consistent with this structural role, a homozygous LTBP2 missense mutation causes Weill-Marchesani syndrome with disruption of the dermal microfibrillar network [PMID:22539340]. Beyond structure, LTBP2 acts as a signaling modulator: a central 8-Cys/EGF-like bioactive region stimulates TGF-β1 expression via Akt and p38 MAPK [PMID:28991210], LTBP2 loss dysregulates TGF-β targets in cardiac valves [PMID:39882270], and it functions as an upstream regulator of NF-κB signaling [PMID:25974126, PMID:31512380]. In fibrosis, LTBP2 is induced downstream of HIF-1α, is upregulated by TGF-β1 in myofibroblasts, and drives profibrotic responses across lung, liver, and oral mucosa—its genetic loss reducing bleomycin- and silica-induced lung fibrosis and CCl4-induced liver fibrosis, the latter through a LOXL1–ERK axis in hepatic stellate cells [PMID:30006483, PMID:40244455, PMID:42236262, PMID:37382472]. In cancer, CAF-secreted LTBP2 engages integrin α6β4 to activate Src signaling and promote metastasis and chemoresistance [PMID:40245188].","teleology":[{"year":1994,"claim":"Established that LTBP-2 is a large secreted protein that can physically associate with the TGF-β1 precursor and partition into the extracellular matrix, framing it as an LTBP-family ECM component.","evidence":"Co-transfection, immunoprecipitation and ECM fractionation in fibroblasts and COS cells","pmids":["7798248"],"confidence":"Medium","gaps":["Did not establish whether the TGF-β1 association is functionally relevant in vivo","No domain mapping of the interaction","Single-lab biochemistry"]},{"year":1998,"claim":"Defined a structural basis for latent TGF-β1 binding by showing the second and third 8-cysteine repeats of mouse LTBP-2 covalently bind the small latent complex.","evidence":"Immunoprecipitation, SDS-PAGE and autoradiography of mouse LTBP-2 fragments","pmids":["9602168"],"confidence":"Medium","gaps":["Only mouse fragments tested","Functional consequence of disulfide binding unresolved","No reconstitution with full-length protein"]},{"year":2003,"claim":"Revealed an unexpected antiadhesive function, showing LTBP-2 disrupts fibroblast adhesion and cytoskeletal organization on fibronectin via its N-terminal proline-rich region.","evidence":"Quantitative cell adhesion assays, actin staining and in vitro binding with recombinant fragments","pmids":["14691143"],"confidence":"High","gaps":["Receptor mediating antiadhesion not identified","In vivo relevance of antiadhesion untested"]},{"year":2007,"claim":"Mapped LTBP-2 as a high-affinity fibrillin-1 ligand that competes with LTBP-1, positioning it as an indirect modulator of latent TGF-β storage on microfibrils.","evidence":"Solid-phase and competitive binding assays with Kd determination and recombinant domain fragments","pmids":["17293099"],"confidence":"High","gaps":["Functional consequence of LTBP-1 displacement on TGF-β release not measured","No fibrillin-2 binding"]},{"year":2009,"claim":"Showed LTBP-2 matrix deposition is hierarchically dependent on a pre-formed fibronectin/fibrillin-1 network, establishing it as a downstream microfibril-associated assembly component.","evidence":"Metabolic labeling, fibrillin-1 shRNA knockdown and immunofluorescence colocalization","pmids":["19681046"],"confidence":"High","gaps":["Sequence of assembly steps after fibrillin-1 binding not fully resolved","Tissue-specific assembly differences untested"]},{"year":2010,"claim":"Demonstrated multiple heparin/heparan-sulfate binding sites and interactions with syndecan-4 and perlecan, linking LTBP-2 to cell-surface and basement-membrane proteoglycans.","evidence":"Solid-phase binding with Kd determination, synthetic peptide inhibition and recombinant fragments","pmids":["20382221"],"confidence":"High","gaps":["Cellular signaling consequence of syndecan-4 engagement not defined","In vivo proteoglycan partnership unconfirmed"]},{"year":2012,"claim":"Provided human genetic evidence that LTBP2 is required for microfibrillar network integrity by linking a missense mutation to Weill-Marchesani syndrome.","evidence":"Homozygosity mapping plus multimodal microscopy of patient skin ECM","pmids":["22539340"],"confidence":"Medium","gaps":["Molecular mechanism by which the mutation disrupts assembly not shown","Single family"]},{"year":2013,"claim":"Established a negative regulatory role in elastic fiber assembly through competition with tropoelastin for fibulin-5 and inhibition of tropoelastin–heparin binding.","evidence":"Solid-phase competitive binding with Kd measurements and a chondrocyte elastinogenesis assay","pmids":["24148803"],"confidence":"High","gaps":["In vivo contribution to elastogenesis not tested","Stoichiometry of competition in tissue unknown"]},{"year":2015,"claim":"Identified LTBP-2 as a high-affinity FGF-2 sequestering protein whose central EGF-like region blocks FGF-2-driven proliferation, suggesting growth-factor reservoir/inhibitor activity.","evidence":"Solid-phase binding with Kd, recombinant fragment mapping, proliferation assay and tissue colocalization","pmids":["26263555"],"confidence":"High","gaps":["Whether FGF-2 sequestration occurs in vivo at physiological ratios unresolved"]},{"year":2015,"claim":"Connected LTBP2 to intracellular signaling by showing its re-expression suppresses NF-κB p65 phosphorylation, nuclear localization and DNA binding in carcinoma cells.","evidence":"Gain/loss-of-function with phospho-p65 Western blot, nuclear fractionation and DNA-binding assay","pmids":["25974126"],"confidence":"Medium","gaps":["Mechanism linking a secreted ECM protein to intracellular p65 unclear","No receptor intermediary identified"]},{"year":2017,"claim":"Defined a bioactive central 8-Cys/EGF region of LTBP-2 that drives TGF-β1 expression via Akt and p38 MAPK, with partial dependence on αVβ3 integrin.","evidence":"Recombinant fragment treatment, kinase inhibitors, phospho-Western, TGF-β1 ELISA and integrin blocking antibodies","pmids":["28991210"],"confidence":"Medium","gaps":["Direct receptor for the bioactive fragment not identified","Partial integrin dependence leaves the main transducer unknown"]},{"year":2018,"claim":"Linked LTBP2 to TGF-β/BMP signaling and ECM gene regulation in ocular trabecular meshwork cells, tying its loss to apoptosis and oxidative-stress-like phenotypes.","evidence":"siRNA knockdown with pathway and apoptosis assays in primary trabecular meshwork cells","pmids":["29908281"],"confidence":"Medium","gaps":["Directionality of TGF-β/BMP effects not mechanistically dissected","In vivo relevance to glaucoma not established here"]},{"year":2018,"claim":"Positioned LTBP2 within a myofibroblast feed-forward loop in fibrotic lung, being TGF-β1-inducible and deposited in fibrotic interstitium.","evidence":"FACS sorting, microarray, TGF-β1 stimulation, ELISA and IHC of IPF lung","pmids":["30006483"],"confidence":"Medium","gaps":["Causal role in fibrosis not tested in this study","Functional consequence of myofibroblast deposition unresolved"]},{"year":2019,"claim":"Demonstrated a defined structural function: LTBP-2 confers tensile strength and viscoelastic integrity to ciliary zonules, with knockout producing fully penetrant ectopia lentis.","evidence":"LTBP-2 knockout mouse with 3D imaging, mechanical stress/strain testing and viscoelastic modeling","pmids":["33039488"],"confidence":"High","gaps":["Molecular basis of the mechanical contribution not resolved","Whether structural and signaling roles are separable untested"]},{"year":2019,"claim":"Placed LTBP2 upstream of NF-κB in cardiac pathology, showing its knockdown reduces oxidative stress and fibrosis in a manner reversed by NF-κB activation.","evidence":"siRNA knockdown in a rat DCM model with NF-κB activator epistasis and histology","pmids":["31512380"],"confidence":"Medium","gaps":["Direct molecular link from LTBP2 to NF-κB unidentified","Single in vivo model"]},{"year":2020,"claim":"Showed LTBP2 is required for normal cardiomyocyte development, with mutation delaying differentiation and dysregulating cardiac developmental programs.","evidence":"CRISPR/Cas9 mutation in hPSCs with transcriptomics across differentiation timepoints","pmids":["33098376"],"confidence":"Medium","gaps":["Mechanism of developmental delay not defined","Transcriptomic correlation only"]},{"year":2022,"claim":"Implicated LTBP2 in redox/ferroptosis control in cancer, where silencing promotes ferroptosis via the p62-Keap1-Nrf2/GPX4 axis.","evidence":"siRNA knockdown with lipid peroxidation, GSH, ROS assays and Western blot in gastric cancer cells","pmids":["35968244"],"confidence":"Medium","gaps":["How a secreted ECM protein regulates intracellular Nrf2/GPX4 unclear","No in vivo validation"]},{"year":2023,"claim":"Defined a HIF-1α → LTBP2 → NF-κB regulatory axis in oral submucous fibrosis, establishing transcriptional control of LTBP2 by hypoxia signaling.","evidence":"Dual-luciferase promoter assay, siRNA knockdown and NF-κB pathway Western blot in oral fibroblasts","pmids":["37382472"],"confidence":"Medium","gaps":["Direct HIF-1α promoter occupancy shown by reporter only here","Connection between secreted LTBP2 and NF-κB still indirect"]},{"year":2023,"claim":"Characterized multi-organ knockout phenotypes revealing tissue-specific requirements for LTBP2 in bone, skin and body composition despite no overt defect in high-expressing aorta/lung.","evidence":"Knockout mouse phenotyping with body composition and histology","pmids":["37688792"],"confidence":"Medium","gaps":["Basis for tissue-specific dependence unexplained","Compensation by paralogs not assessed"]},{"year":2024,"claim":"Provided causal evidence that LTBP2 loss dysregulates valvular TGF-β signaling, with both knockout and a human-mutation knockin causing myxomatous mitral valve disease.","evidence":"KO and knockin mice with echocardiography, histology and TGF-β target qPCR","pmids":["39882270"],"confidence":"High","gaps":["Direction of TGF-β dysregulation mechanistically incomplete","Cell type driving valve pathology not pinpointed"]},{"year":2024,"claim":"Established the temporal sequence of LTBP2-mutation pathology in glaucoma, with discontinuous trabecular elastic fibers preceding ECM collapse and intraocular pressure rise.","evidence":"Longitudinal transmission electron microscopy with quantitative morphometry in a feline PCG model","pmids":["39432401"],"confidence":"Medium","gaps":["Molecular cause of elastic fiber discontinuity not defined","Mutation-specific mechanism unresolved"]},{"year":2025,"claim":"Identified a paracrine cancer mechanism in which CAF-secreted LTBP2 signals through integrin α6β4 and Src to drive ESCC metastasis and chemoresistance, validated by neutralizing antibodies.","evidence":"Co-IP, signaling analysis, antibody blocking and migration/invasion assays","pmids":["40245188"],"confidence":"Medium","gaps":["Direct LTBP2-integrin binding interface not mapped","In vivo therapeutic efficacy of antibody limited data"]},{"year":2025,"claim":"Integrated transcriptional and effector mechanisms in liver fibrosis: HIF-1α directly activates LTBP2, which engages LOXL1 to drive ERK-dependent hepatic stellate cell activation, with HSC-specific knockdown reducing fibrosis.","evidence":"ChIP, dual-luciferase, molecular docking, Co-IP and AAV6-mediated HSC-specific knockdown in CCl4 mice","pmids":["40244455"],"confidence":"High","gaps":["LTBP2-LOXL1 binding interface not structurally resolved","Whether the LOXL1-ERK axis operates in other fibrotic tissues untested"]},{"year":2025,"claim":"Provided genetic causal evidence that LTBP2 promotes fibrosis and epithelial repair, with knockout reducing bleomycin/silica lung fibrosis and TGF-β signaling and impairing fibroblast migration.","evidence":"Ltbp2 knockout mice in two fibrosis and two injury models with TGF-β readouts, fibroblast wound assays and transcriptomics","pmids":["42236262"],"confidence":"High","gaps":["Molecular trigger linking LTBP2 to fibroblast migration not defined","Whether epithelial repair and fibrosis roles are separable unresolved"]},{"year":null,"claim":"How LTBP2's defined extracellular biochemistry (fibrillin-1, fibulin-5, FGF-2, proteoglycan, integrin binding) is mechanistically coupled to the recurrent intracellular TGF-β/NF-κB/ERK signaling outputs attributed to it remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single signaling receptor unifies the reported TGF-β, NF-κB and ERK effects","Structural model of LTBP2 domain architecture in matrix context lacking","Separability of structural scaffold versus signaling-modulator functions untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[13,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,8]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[18,10]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,2,4,12]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,12,18]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4,7]},{"term_id":"R-HSA-162582","term_label":"Signal 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synthesized as a 240-kDa protein by human foreskin fibroblasts and COS cells transfected with LTBP-2 cDNA. Co-transfection of LTBP-2 and TGF-β1 cDNAs revealed that LTBP-2 forms a high molecular weight complex with the TGF-β1 precursor, and a considerable part of LTBP-2 associates with extracellular matrix.\",\n      \"method\": \"Co-transfection, immunoprecipitation, metabolic labeling, ECM fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-transfection plus ECM fractionation in one lab, two orthogonal methods\",\n      \"pmids\": [\"7798248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The second and third TGF-bp (8-cysteine) repeats of mouse LTBP-2 can covalently bind the small latent TGF-β1 complex, analogous to LTBP-3, indicating a disulfide-based interaction via the 8-cysteine structural motifs.\",\n      \"method\": \"Immunoprecipitation, SDS-PAGE, autoradiography\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, immunoprecipitation with SDS-PAGE and autoradiography, but only mouse LTBP-2 fragments tested\",\n      \"pmids\": [\"9602168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LTBP-2 acts as an antiadhesive matrix component: fibroblasts do not adhere to full-length LTBP-2, and LTBP-2 disrupts fibroblast adhesion morphology and actin stress fibers on fibronectin substrata. The N-terminal proline-rich region of LTBP-2 mediates both weak adhesion and cytoskeleton-disrupting effects, and LTBP-2 binds fibronectin in vitro.\",\n      \"method\": \"Quantitative cell adhesion assay, actin staining, in vitro binding assay, recombinant fragment analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cell adhesion assay, cytoskeletal staining, in vitro binding), single lab, clear domain mapping\",\n      \"pmids\": [\"14691143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LTBP-2 specifically binds the amino-terminal region of fibrillin-1 (but not fibrillin-2) with a Kd of ~9.4 nM. The major fibrillin-1 binding site resides near the C-terminus of LTBP-2. LTBP-2 competes with LTBP-1 for the same or overlapping binding site on fibrillin-1, suggesting LTBP-2 may act as an indirect negative modulator of large latent TGF-β complex storage on microfibrils.\",\n      \"method\": \"Solid-phase binding assay, overlay blotting, competitive binding assay with recombinant fragments, Ca2+ chelation experiments\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted binding with Kd determination, competitive inhibition, domain mapping using recombinant fragments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17293099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LTBP-2 matrix assembly depends on a pre-formed fibrillin-1 network: LTBP-2 associates with ECM only after confluency following deposition of fibronectin and fibrillin-1, colocalizes transiently with fibronectin, fails to assemble in fibronectin-deficient fibroblasts, and fibrillin-1 silencing via lentiviral shRNA profoundly disrupts LTBP-2 deposition.\",\n      \"method\": \"Metabolic labeling, immunoprecipitation, lentiviral shRNA knockdown of fibrillin-1, immunofluorescence colocalization\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (metabolic labeling, shRNA knockdown, immunofluorescence), single lab\",\n      \"pmids\": [\"19681046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LTBP-2 has multiple heparin/heparan sulfate binding sites: full-length LTBP-2 binds heparin conjugated albumin with Kd ~0.9 nM, with the N-terminal fragment (Kd ~0.7 nM) and a central fragment (Kd ~80 nM) both contributing. Three major heparin-binding sequences were identified in the N-terminal region. LTBP-2 also interacts with cell-surface syndecan-4 and basement membrane perlecan (via heparan sulfate chains).\",\n      \"method\": \"Solid-phase binding assay, synthetic peptide inhibition, recombinant fragment analysis, Kd calculation\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with Kd determination, domain mapping, peptide inhibition, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"20382221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Homozygous LTBP2 missense mutation (p.Val1177Met) causes Weill-Marchesani syndrome with disruptions of the microfibrillar network in the ECM of patient skin, as demonstrated by light, fluorescent, and electron microscopy.\",\n      \"method\": \"Homozygosity mapping, light/fluorescent/electron microscopy of patient skin ECM\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mapping plus direct ultrastructural ECM analysis in patient tissue using three microscopy modalities\",\n      \"pmids\": [\"22539340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LTBP-2 competes with tropoelastin for binding to fibulin-5 (Kd for LTBP-2/fibulin-5 ~26.5 nM, comparable to tropoelastin/fibulin-5 ~24.7 nM) and inhibits tropoelastin-fibulin-5 interaction in a dose-dependent manner. LTBP-2 also significantly inhibits heparin binding to tropoelastin. Addition of exogenous LTBP-2 to chondrocyte cultures blocked elastinogenesis in a concentration-dependent manner, indicating a negative regulatory role in elastic fiber assembly.\",\n      \"method\": \"Solid-phase competitive binding assay, Kd calculation, confocal microscopy colocalization, chondrocyte elastinogenesis assay\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted competitive binding with Kd measurements plus functional cell-based elastinogenesis assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24148803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LTBP-2 has a single high-affinity binding site for FGF-2 (Kd ~1.1 nM) located in a central region containing EGF-like motifs 9–14. LTBP-2 at 5-fold molar excess completely blocks FGF-2-stimulated fibroblast proliferation. LTBP-2 and FGF-2 co-localize in fibrotic keloid tissue in vivo.\",\n      \"method\": \"Solid-phase binding assay with recombinant LTBP-2 fragments, Kd calculation, cell proliferation assay, confocal microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with Kd determination, domain mapping, functional proliferation assay, in vivo co-localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26263555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Re-expression of LTBP2 in nasopharyngeal carcinoma cells reduces phosphorylation of NF-κB p65 at Serine 536, inhibits nuclear localization of phosphorylated p65, and impairs p65 DNA-binding ability, leading to downregulation of p65-related gene expression.\",\n      \"method\": \"Loss- and gain-of-function (siRNA/overexpression), Western blot for p65 phosphorylation, nuclear fractionation, DNA-binding assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (phosphorylation, nuclear localization, DNA binding) with both KD and OE, single lab\",\n      \"pmids\": [\"25974126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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 by activating both Akt and p38 MAPK signaling. Blocking either pathway individually abolished the TGF-β1 increase. Anti-αVβ3 integrin antibodies partially inhibited this effect, suggesting an indirect role for αVβ3 integrin.\",\n      \"method\": \"Recombinant LTBP-2 fragment treatment, kinase inhibitors, phosphorylation Western blot, ELISA for TGF-β1, blocking antibodies to integrins\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with recombinant fragments, multiple signaling readouts, functional antibody blocking, single lab\",\n      \"pmids\": [\"28991210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LTBP2 knockdown in human trabecular meshwork cells affects canonical TGF-β and BMP signaling pathways, alters expression of ECM-related genes, and promotes apoptosis, with effects paralleling those of oxidative stress induction.\",\n      \"method\": \"siRNA knockdown, TGF-β/BMP signaling pathway assays, ECM gene expression analysis, apoptosis assay in primary human trabecular meshwork cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA KD with multiple pathway readouts, single lab, primary human cells\",\n      \"pmids\": [\"29908281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LTBP2 is secreted from lung myofibroblasts and its expression is upregulated by TGF-β1 at mRNA and protein levels in human lung myofibroblasts; LTBP2 localizes broadly to fibrotic interstitium as an ECM protein and to αSMA-positive myofibroblasts in IPF lungs.\",\n      \"method\": \"FACS sorting, microarray, TGF-β1 stimulation, ELISA, immunohistochemistry\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TGF-β1 induction confirmed at mRNA and protein levels, localization by IHC, ELISA measurement, single lab\",\n      \"pmids\": [\"30006483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LTBP-2 is a structural component required for tensile strength and longevity of ciliary zonular fibers: LTBP-2 knockout mice have ~50% reduced ultimate tensile strength and altered viscoelastic behavior of zonules, leading to fully penetrant ectopia lentis by 6 months, without affecting fiber number, diameter, or coaxial organization.\",\n      \"method\": \"LTBP-2 knockout mouse model, 3D zonule imaging, mechanical stress/strain testing, quasi-linear viscoelastic modeling, in vivo imaging\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — knockout mouse with quantitative biomechanical testing and in vivo phenotyping, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33039488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LTBP2 knockdown in a rat DCM model reduces myocardial oxidative stress, fibrosis (collagen I and III), and remodeling, and these effects are reversed by NF-κB pathway activation, placing LTBP2 upstream of NF-κB signaling in cardiomyocyte pathology.\",\n      \"method\": \"siRNA knockdown in rat DCM model, NF-κB pathway activator rescue, Western blot, ROS/MDA measurements, histology\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD plus NF-κB activator epistasis, multiple readouts, single lab\",\n      \"pmids\": [\"31512380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LTBP2 knockout mice show multi-organ phenotypes including altered body weight, fat mass, and defects in bone and skin development (with differentially affected tissue strength), whereas high-LTBP2-expressing tissues such as aorta and lung show no developmental phenotype, indicating complex tissue-specific effects on ECM or signaling.\",\n      \"method\": \"Knockout mouse phenotyping, body composition measurement, histology of bone and skin\",\n      \"journal\": \"Developmental dynamics : an official publication of the American Association of Anatomists\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO mouse with defined tissue phenotypes, single lab\",\n      \"pmids\": [\"37688792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LTBP2 knockout mice show myxomatous mitral valve changes (7/9 KO vs 0/7 controls by histology; 7/9 vs 0/8 by echocardiography) and knockin of the human LTBP2 V1506M mutation also causes myxomatous valve phenotype. KO mice overexpress TGF-β signaling targets RUNX2 and periostin in valve tissue, indicating LTBP2 loss leads to dysregulated TGF-β signaling in valves.\",\n      \"method\": \"KO and knockin mouse generation, echocardiography, histology, qPCR for TGF-β signaling targets (periostin/POSTN, RUNX2, CTGF)\",\n      \"journal\": \"European heart journal open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both KO and knockin mouse models with echocardiography and histology, TGF-β pathway readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"39882270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a feline PCG model caused by LTBP2 mutation, the earliest ultrastructural abnormalities occur at 2 weeks postnatally: elastic fibers in the trabecular meshwork are discontinuous and disorganized, followed by decreased intertrabecular space by 5 weeks and trabecular cell morphology changes, with intraocular pressure elevation coinciding with established ECM collapse by 12 weeks.\",\n      \"method\": \"Transmission electron microscopy of trabecular meshwork at multiple postnatal time points, quantitative assessment of intertrabecular space and cell morphology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — longitudinal TEM with quantitative morphometry, single lab\",\n      \"pmids\": [\"39432401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAF-secreted LTBP2 interacts with integrin α6β4 as a functional receptor on ESCC cells and activates Src signaling, promoting metastasis and chemoresistance. Antagonistic anti-LTBP2 antibodies increase chemotherapy susceptibility of ESCC cells.\",\n      \"method\": \"Co-immunoprecipitation, signaling pathway analysis, antibody blocking experiments, cell migration/invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP to identify receptor, functional antibody blocking, multiple cancer cell assays, single lab\",\n      \"pmids\": [\"40245188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF-1α promotes LTBP2 expression by directly binding to the LTBP2 promoter region (confirmed by ChIP and dual-luciferase assay). LTBP2 interacts with LOXL1 (confirmed by molecular docking and Co-IP), and this interaction activates ERK signaling to promote hepatic stellate cell activation and EMT in liver fibrosis. AAV6-mediated LTBP2 knockdown in HSCs markedly reduces CCl4-induced liver fibrosis in mice.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, molecular docking, Co-IP, AAV6-mediated HSC-specific knockdown in vivo, gain/loss-of-function in LX-2 cells\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (ChIP, Co-IP, dual-luciferase, in vivo AAV knockdown) establishing transcriptional regulation, protein interaction, and downstream pathway, single lab\",\n      \"pmids\": [\"40244455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LTBP2-deficient (Ltbp2-/-) mice exposed to bleomycin or silica show significantly reduced lung fibrosis compared to wild-type controls, with reduced TGFβ signaling in bleomycin-treated lungs. Isolated fibroblasts from Ltbp2-/- mice exhibit impaired migration in wound closure assays. Ltbp2-/- mice also show impaired airway epithelial repair after bleomycin and naphthalene injury.\",\n      \"method\": \"Ltbp2 knockout mouse with bleomycin/silica fibrosis models, TGFβ signaling assays, in vitro fibroblast wound closure assay, transcriptomic analysis, naphthalene injury model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with two fibrosis models, in vitro fibroblast assay, transcriptomics, published as peer-reviewed journal article replicated from preprint\",\n      \"pmids\": [\"42236262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF-1α binds to the LTBP2 promoter and transcriptionally activates LTBP2 expression. LTBP2 knockdown in oral mucosal fibroblasts relieves arecoline-induced OSF by inactivating NF-κB signaling, placing LTBP2 downstream of HIF-1α and upstream of NF-κB in the OSF fibrosis pathway.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, Western blot for NF-κB pathway proteins, MTT/transwell/flow cytometry assays\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase for promoter binding plus functional KD, multiple readouts, single lab\",\n      \"pmids\": [\"37382472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LTBP2 silencing in gastric cancer cells promotes ferroptosis by reducing GPX4 activity and cellular GSH levels, increasing ROS and MDA, and this is mediated through regulation of the p62-Keap1-Nrf2 pathway, downregulating GPX4 and xCT and upregulating PTGS2 and 4HNE.\",\n      \"method\": \"siRNA knockdown, cell viability assay, lipid peroxidation assay, ROS assay, GSH assay, Western blot, TEM\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple biochemical pathway readouts, single lab\",\n      \"pmids\": [\"35968244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LTBP2 mutation in human pluripotent stem cells (hPSCs-LTBP2mu) delays cardiomyocyte development, with persistently upregulated pathways in cardiac development and congenital heart disease enriched in LTBP2-mutant cardiomyocytes compared to wild type.\",\n      \"method\": \"CRISPR/Cas9 mutation in hPSCs, differentiation to cardiomyocytes, transcriptomics at days 0, 9, and 13\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/Cas9 mutation with transcriptomic analysis during differentiation, single lab\",\n      \"pmids\": [\"33098376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LTBP2 is a large extracellular matrix glycoprotein that associates with fibrillin-1-containing microfibrils (requiring a pre-formed fibrillin-1 network for its own ECM deposition), binds heparin/heparan sulfate proteoglycans (syndecan-4, perlecan) and FGF-2 at high affinity via distinct central EGF-like domains, competes with LTBP-1 and tropoelastin for fibrillin-1 and fibulin-5 binding respectively, acts as an antiadhesive component by disrupting fibronectin-mediated fibroblast adhesion via its N-terminal proline-rich region, provides structural tensile strength to ciliary zonular fibers, stimulates TGF-β1 expression via Akt and p38 MAPK signaling through a central 8-Cys/EGF-like bioactive region, modulates NF-κB p65 activity and nuclear localization, promotes TGF-β signaling in lung fibrosis (its absence reduces fibrosis in bleomycin and silica models), is transcriptionally activated by HIF-1α binding its promoter, and interacts with LOXL1 to activate ERK-driven hepatic stellate cell activation—collectively functioning as a multi-functional ECM scaffold and signaling modulator rather than a direct TGF-β chaperone.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LTBP2 is a large secreted extracellular matrix glycoprotein that functions as a microfibril-associated structural scaffold and a modulator of matrix assembly and growth-factor signaling rather than a direct latent TGF-\\u03b2 chaperone [#3, #13]. Its own matrix incorporation is strictly dependent on a pre-formed fibronectin/fibrillin-1 network, and it binds the amino-terminal region of fibrillin-1 with high affinity (Kd ~9.4 nM) at a site near its own C-terminus, competing with LTBP-1 for this site [#3, #4]. Through distinct domains LTBP2 engages multiple matrix and cell-surface partners: a central EGF-like region binds FGF-2 (Kd ~1.1 nM) and blocks FGF-2-driven fibroblast proliferation, N-terminal sequences mediate high-affinity heparin/heparan-sulfate binding and interaction with syndecan-4 and perlecan, and it competes with tropoelastin for fibulin-5 to negatively regulate elastic fiber assembly [#5, #7, #8]. Its N-terminal proline-rich region confers antiadhesive activity, disrupting fibronectin-mediated fibroblast adhesion and actin stress fibers [#2]. As a structural element, LTBP2 provides tensile strength and viscoelastic integrity to ciliary zonular fibers, and its loss in knockout mice produces fully penetrant ectopia lentis [#13]; consistent with this structural role, a homozygous LTBP2 missense mutation causes Weill-Marchesani syndrome with disruption of the dermal microfibrillar network [#6]. Beyond structure, LTBP2 acts as a signaling modulator: a central 8-Cys/EGF-like bioactive region stimulates TGF-\\u03b21 expression via Akt and p38 MAPK [#10], LTBP2 loss dysregulates TGF-\\u03b2 targets in cardiac valves [#16], and it functions as an upstream regulator of NF-\\u03baB signaling [#9, #14]. In fibrosis, LTBP2 is induced downstream of HIF-1\\u03b1, is upregulated by TGF-\\u03b21 in myofibroblasts, and drives profibrotic responses across lung, liver, and oral mucosa\\u2014its genetic loss reducing bleomycin- and silica-induced lung fibrosis and CCl4-induced liver fibrosis, the latter through a LOXL1\\u2013ERK axis in hepatic stellate cells [#12, #19, #20, #21]. In cancer, CAF-secreted LTBP2 engages integrin \\u03b16\\u03b24 to activate Src signaling and promote metastasis and chemoresistance [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that LTBP-2 is a large secreted protein that can physically associate with the TGF-\\u03b21 precursor and partition into the extracellular matrix, framing it as an LTBP-family ECM component.\",\n      \"evidence\": \"Co-transfection, immunoprecipitation and ECM fractionation in fibroblasts and COS cells\",\n      \"pmids\": [\"7798248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether the TGF-\\u03b21 association is functionally relevant in vivo\", \"No domain mapping of the interaction\", \"Single-lab biochemistry\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined a structural basis for latent TGF-\\u03b21 binding by showing the second and third 8-cysteine repeats of mouse LTBP-2 covalently bind the small latent complex.\",\n      \"evidence\": \"Immunoprecipitation, SDS-PAGE and autoradiography of mouse LTBP-2 fragments\",\n      \"pmids\": [\"9602168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only mouse fragments tested\", \"Functional consequence of disulfide binding unresolved\", \"No reconstitution with full-length protein\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed an unexpected antiadhesive function, showing LTBP-2 disrupts fibroblast adhesion and cytoskeletal organization on fibronectin via its N-terminal proline-rich region.\",\n      \"evidence\": \"Quantitative cell adhesion assays, actin staining and in vitro binding with recombinant fragments\",\n      \"pmids\": [\"14691143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating antiadhesion not identified\", \"In vivo relevance of antiadhesion untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped LTBP-2 as a high-affinity fibrillin-1 ligand that competes with LTBP-1, positioning it as an indirect modulator of latent TGF-\\u03b2 storage on microfibrils.\",\n      \"evidence\": \"Solid-phase and competitive binding assays with Kd determination and recombinant domain fragments\",\n      \"pmids\": [\"17293099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of LTBP-1 displacement on TGF-\\u03b2 release not measured\", \"No fibrillin-2 binding\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed LTBP-2 matrix deposition is hierarchically dependent on a pre-formed fibronectin/fibrillin-1 network, establishing it as a downstream microfibril-associated assembly component.\",\n      \"evidence\": \"Metabolic labeling, fibrillin-1 shRNA knockdown and immunofluorescence colocalization\",\n      \"pmids\": [\"19681046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence of assembly steps after fibrillin-1 binding not fully resolved\", \"Tissue-specific assembly differences untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated multiple heparin/heparan-sulfate binding sites and interactions with syndecan-4 and perlecan, linking LTBP-2 to cell-surface and basement-membrane proteoglycans.\",\n      \"evidence\": \"Solid-phase binding with Kd determination, synthetic peptide inhibition and recombinant fragments\",\n      \"pmids\": [\"20382221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular signaling consequence of syndecan-4 engagement not defined\", \"In vivo proteoglycan partnership unconfirmed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided human genetic evidence that LTBP2 is required for microfibrillar network integrity by linking a missense mutation to Weill-Marchesani syndrome.\",\n      \"evidence\": \"Homozygosity mapping plus multimodal microscopy of patient skin ECM\",\n      \"pmids\": [\"22539340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which the mutation disrupts assembly not shown\", \"Single family\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a negative regulatory role in elastic fiber assembly through competition with tropoelastin for fibulin-5 and inhibition of tropoelastin\\u2013heparin binding.\",\n      \"evidence\": \"Solid-phase competitive binding with Kd measurements and a chondrocyte elastinogenesis assay\",\n      \"pmids\": [\"24148803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution to elastogenesis not tested\", \"Stoichiometry of competition in tissue unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified LTBP-2 as a high-affinity FGF-2 sequestering protein whose central EGF-like region blocks FGF-2-driven proliferation, suggesting growth-factor reservoir/inhibitor activity.\",\n      \"evidence\": \"Solid-phase binding with Kd, recombinant fragment mapping, proliferation assay and tissue colocalization\",\n      \"pmids\": [\"26263555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FGF-2 sequestration occurs in vivo at physiological ratios unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected LTBP2 to intracellular signaling by showing its re-expression suppresses NF-\\u03baB p65 phosphorylation, nuclear localization and DNA binding in carcinoma cells.\",\n      \"evidence\": \"Gain/loss-of-function with phospho-p65 Western blot, nuclear fractionation and DNA-binding assay\",\n      \"pmids\": [\"25974126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking a secreted ECM protein to intracellular p65 unclear\", \"No receptor intermediary identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a bioactive central 8-Cys/EGF region of LTBP-2 that drives TGF-\\u03b21 expression via Akt and p38 MAPK, with partial dependence on \\u03b1V\\u03b23 integrin.\",\n      \"evidence\": \"Recombinant fragment treatment, kinase inhibitors, phospho-Western, TGF-\\u03b21 ELISA and integrin blocking antibodies\",\n      \"pmids\": [\"28991210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor for the bioactive fragment not identified\", \"Partial integrin dependence leaves the main transducer unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked LTBP2 to TGF-\\u03b2/BMP signaling and ECM gene regulation in ocular trabecular meshwork cells, tying its loss to apoptosis and oxidative-stress-like phenotypes.\",\n      \"evidence\": \"siRNA knockdown with pathway and apoptosis assays in primary trabecular meshwork cells\",\n      \"pmids\": [\"29908281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of TGF-\\u03b2/BMP effects not mechanistically dissected\", \"In vivo relevance to glaucoma not established here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned LTBP2 within a myofibroblast feed-forward loop in fibrotic lung, being TGF-\\u03b21-inducible and deposited in fibrotic interstitium.\",\n      \"evidence\": \"FACS sorting, microarray, TGF-\\u03b21 stimulation, ELISA and IHC of IPF lung\",\n      \"pmids\": [\"30006483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role in fibrosis not tested in this study\", \"Functional consequence of myofibroblast deposition unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a defined structural function: LTBP-2 confers tensile strength and viscoelastic integrity to ciliary zonules, with knockout producing fully penetrant ectopia lentis.\",\n      \"evidence\": \"LTBP-2 knockout mouse with 3D imaging, mechanical stress/strain testing and viscoelastic modeling\",\n      \"pmids\": [\"33039488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the mechanical contribution not resolved\", \"Whether structural and signaling roles are separable untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed LTBP2 upstream of NF-\\u03baB in cardiac pathology, showing its knockdown reduces oxidative stress and fibrosis in a manner reversed by NF-\\u03baB activation.\",\n      \"evidence\": \"siRNA knockdown in a rat DCM model with NF-\\u03baB activator epistasis and histology\",\n      \"pmids\": [\"31512380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from LTBP2 to NF-\\u03baB unidentified\", \"Single in vivo model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed LTBP2 is required for normal cardiomyocyte development, with mutation delaying differentiation and dysregulating cardiac developmental programs.\",\n      \"evidence\": \"CRISPR/Cas9 mutation in hPSCs with transcriptomics across differentiation timepoints\",\n      \"pmids\": [\"33098376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of developmental delay not defined\", \"Transcriptomic correlation only\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated LTBP2 in redox/ferroptosis control in cancer, where silencing promotes ferroptosis via the p62-Keap1-Nrf2/GPX4 axis.\",\n      \"evidence\": \"siRNA knockdown with lipid peroxidation, GSH, ROS assays and Western blot in gastric cancer cells\",\n      \"pmids\": [\"35968244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a secreted ECM protein regulates intracellular Nrf2/GPX4 unclear\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a HIF-1\\u03b1 \\u2192 LTBP2 \\u2192 NF-\\u03baB regulatory axis in oral submucous fibrosis, establishing transcriptional control of LTBP2 by hypoxia signaling.\",\n      \"evidence\": \"Dual-luciferase promoter assay, siRNA knockdown and NF-\\u03baB pathway Western blot in oral fibroblasts\",\n      \"pmids\": [\"37382472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1\\u03b1 promoter occupancy shown by reporter only here\", \"Connection between secreted LTBP2 and NF-\\u03baB still indirect\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Characterized multi-organ knockout phenotypes revealing tissue-specific requirements for LTBP2 in bone, skin and body composition despite no overt defect in high-expressing aorta/lung.\",\n      \"evidence\": \"Knockout mouse phenotyping with body composition and histology\",\n      \"pmids\": [\"37688792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for tissue-specific dependence unexplained\", \"Compensation by paralogs not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided causal evidence that LTBP2 loss dysregulates valvular TGF-\\u03b2 signaling, with both knockout and a human-mutation knockin causing myxomatous mitral valve disease.\",\n      \"evidence\": \"KO and knockin mice with echocardiography, histology and TGF-\\u03b2 target qPCR\",\n      \"pmids\": [\"39882270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direction of TGF-\\u03b2 dysregulation mechanistically incomplete\", \"Cell type driving valve pathology not pinpointed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the temporal sequence of LTBP2-mutation pathology in glaucoma, with discontinuous trabecular elastic fibers preceding ECM collapse and intraocular pressure rise.\",\n      \"evidence\": \"Longitudinal transmission electron microscopy with quantitative morphometry in a feline PCG model\",\n      \"pmids\": [\"39432401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cause of elastic fiber discontinuity not defined\", \"Mutation-specific mechanism unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a paracrine cancer mechanism in which CAF-secreted LTBP2 signals through integrin \\u03b16\\u03b24 and Src to drive ESCC metastasis and chemoresistance, validated by neutralizing antibodies.\",\n      \"evidence\": \"Co-IP, signaling analysis, antibody blocking and migration/invasion assays\",\n      \"pmids\": [\"40245188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LTBP2-integrin binding interface not mapped\", \"In vivo therapeutic efficacy of antibody limited data\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Integrated transcriptional and effector mechanisms in liver fibrosis: HIF-1\\u03b1 directly activates LTBP2, which engages LOXL1 to drive ERK-dependent hepatic stellate cell activation, with HSC-specific knockdown reducing fibrosis.\",\n      \"evidence\": \"ChIP, dual-luciferase, molecular docking, Co-IP and AAV6-mediated HSC-specific knockdown in CCl4 mice\",\n      \"pmids\": [\"40244455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LTBP2-LOXL1 binding interface not structurally resolved\", \"Whether the LOXL1-ERK axis operates in other fibrotic tissues untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided genetic causal evidence that LTBP2 promotes fibrosis and epithelial repair, with knockout reducing bleomycin/silica lung fibrosis and TGF-\\u03b2 signaling and impairing fibroblast migration.\",\n      \"evidence\": \"Ltbp2 knockout mice in two fibrosis and two injury models with TGF-\\u03b2 readouts, fibroblast wound assays and transcriptomics\",\n      \"pmids\": [\"42236262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger linking LTBP2 to fibroblast migration not defined\", \"Whether epithelial repair and fibrosis roles are separable unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LTBP2's defined extracellular biochemistry (fibrillin-1, fibulin-5, FGF-2, proteoglycan, integrin binding) is mechanistically coupled to the recurrent intracellular TGF-\\u03b2/NF-\\u03baB/ERK signaling outputs attributed to it remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No single signaling receptor unifies the reported TGF-\\u03b2, NF-\\u03baB and ERK effects\", \"Structural model of LTBP2 domain architecture in matrix context lacking\", \"Separability of structural scaffold versus signaling-modulator functions untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [13, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [18, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 2, 4, 12]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 12, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 18, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 16, 20, 19]}\n    ],\n    \"complexes\": [\n      \"fibrillin-1 microfibril\",\n      \"ciliary zonule\"\n    ],\n    \"partners\": [\n      \"FBN1\",\n      \"FBLN5\",\n      \"FGF2\",\n      \"SDC4\",\n      \"HSPG2\",\n      \"FN1\",\n      \"ITGB4\",\n      \"LOXL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}