{"gene":"TGFBI","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2008,"finding":"TGFBI (betaig-h3) promotes cancer cell extravasation by inducing dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin αvβ5-Src signaling pathway, promoting colon cancer metastasis.","method":"Ectopic expression and shRNA knockdown in vivo metastasis models; mechanistic pathway delineation via integrin αvβ5-Src signaling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean KO/KD with defined cellular phenotype, in vivo metastasis model, signaling pathway identified; Moderate evidence","pmids":["18245446"],"is_preprint":false},{"year":2007,"finding":"Loss of TGFBI causes specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells; recombinant TGFBI restores paclitaxel sensitivity through integrin-dependent FAK- and Rho-dependent stabilization of microtubules.","method":"Loss-of-function (TGFBI-deficient cells), rescue with recombinant TGFBI protein, FAK/Rho pathway inhibition assays, in vitro microtubule stabilization assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with recombinant protein plus pathway mutagenesis/inhibition, multiple orthogonal methods","pmids":["18068629"],"is_preprint":false},{"year":2009,"finding":"TGFBI interacts with periostin via their N-terminal EMI domains; both proteins colocalize in the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation severely impairs TGFBI-periostin interaction and causes aberrant redistribution of mutant TGFBI to lysosomes.","method":"Co-immunoprecipitation, domain mapping (EMI domain constructs), confocal colocalization, subcellular fractionation, patient-derived corneal fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, domain-level binding mapping, subcellular localization with functional consequence, replicated in patient cells","pmids":["19478074"],"is_preprint":false},{"year":2012,"finding":"Mutant TGFBI (R124H; GCD2) is degraded by autophagy but not the ubiquitin/proteasome pathway; GCD2 corneal fibroblasts display defective autophagosome-lysosome fusion leading to impaired clearance of mutant TGFBIp and accumulation of autophagosomes containing mutant protein.","method":"Autophagy flux assays (bafilomycin A1 treatment), LC3-II/SQSTM1 western blot, confocal colocalization, rapamycin rescue experiments, caspase-3 activation assays in primary patient corneal fibroblasts","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in primary patient cells, pathway inhibitor/activator rescue","pmids":["22995918"],"is_preprint":false},{"year":2003,"finding":"Overexpression of mutant TGFBI (R124C, R555W, and others) induces apoptosis in corneal and HeLa cells through caspase-3 activation; apoptosis requires the C-terminal domain and specifically the PDI site (Pro-Asp-Ile, residues 616-618), a known site of interaction with α3β1 integrins.","method":"Transfection of mutant BIGH3-EGFP constructs, Hoechst/propidium iodide and annexin V staining, caspase-3 activation assay, truncation and site-specific mutagenesis of the PDI domain","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis + functional rescue, multiple mutants tested, defined molecular motif","pmids":["12824240"],"is_preprint":false},{"year":2013,"finding":"TGFBI binds αvβ3 integrin with high affinity (Kd ~3.8×10⁻⁸ M) through cooperative action of all four FAS1 domains and the RGD motif; this multi-domain cooperation confers ~2300-fold higher affinity than a single FAS1 domain alone and underlies potent anti-angiogenic and anti-tumor activities.","method":"Binding affinity assay (Kd measurement), recombinant domain constructs, in vitro anti-angiogenesis assays, in vivo tumor targeting experiments","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 — quantitative binding assay with domain mutants, functional validation in vitro and in vivo","pmids":["23792174"],"is_preprint":false},{"year":2011,"finding":"TGFBI suppresses mesothelioma progression via the PI3K/Akt/mTOR signaling pathway; loss of TGFBI elevates c-myc/cyclin D1/phospho-Rb and activates PI3K/Akt/mTOR signaling, while ectopic TGFBI expression reverses these changes.","method":"shRNA knockdown and ectopic overexpression, western blot for signaling pathway components, clonogenic and soft-agar growth assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — KD and OE with pathway readout, single lab","pmids":["21701776"],"is_preprint":false},{"year":2011,"finding":"Lithium (LiCl) reduces TGFBI expression by decreasing pSmad3 levels and enhancing interaction between GSK-3β and Smad3, and by inducing autophagy (elevated LC3-II/I ratio), thereby reducing normal and mutant TGFBIp accumulation in GCD2 corneal fibroblasts.","method":"Western blot (pSmad3, pGSK-3α/β, LC3-II), RT-PCR, co-immunoprecipitation of GSK-3β and Smad3, dose-response assays in primary corneal fibroblasts","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of signaling components, multiple pathway readouts; single lab","pmids":["21310903"],"is_preprint":false},{"year":2011,"finding":"Corneal deposits in GCD2 (R124H mutation) specifically accumulate TGFBIp along with serum amyloid P-component, clusterin, and type III collagen. In LCD amyloid (V624M), a C-terminal fragment of TGFBIp (residues Y571-R588 from FAS1-4 domain) accumulates with serine protease HtrA1, which shows proteolytic cleavage sites in FAS1-4, suggesting HtrA1 mediates proteolytic processing of amyloidogenic TGFBIp.","method":"Laser capture microdissection, tandem mass spectrometry, label-free quantitative proteomics of corneal deposits","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 — mass spectrometry-based identification of interacting proteins and cleavage sites in situ; single lab","pmids":["22155582"],"is_preprint":false},{"year":2017,"finding":"AR signaling stimulates SPDEF transcription factor activity, which represses TGFBI expression; androgen deprivation therapy (ADT) reduces nuclear SPDEF and increases TGFBI, and TGFBI promotes EMT and bone/brain metastasis of prostate cancer. TGFBI was identified as a type 1, 2, and 4 collagen-binding protein mediating this effect.","method":"KD/OE in prostate cancer cell lines, xenograft mouse models (bone/brain metastasis), patient tissue before/after ADT, SPDEF overexpression/knockdown","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (SPDEF→TGFBI pathway), in vivo xenograft models, patient tissue validation; Moderate-Strong evidence","pmids":["28811384"],"is_preprint":false},{"year":2014,"finding":"TGFBI activates the FAK/AKT/AKT1S1/RPS6/EIF4EBP1 signaling pathway in islets to promote cell survival and function; phosphoprotein array and siRNA knockdown of pathway components confirmed mechanistic relevance.","method":"Phosphoprotein array analysis in TGFBI KO islets, recombinant TGFBI stimulation, AKT chemical inhibitor, siRNA knockdown of AKT1S1/RPS6/EIF4EBP1, islet survival/function assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — phosphoproteomics plus siRNA pathway validation in KO model; single lab, Moderate evidence","pmids":["24728038"],"is_preprint":false},{"year":2009,"finding":"In zebrafish embryos, TGFBI localizes to myosepta (myotendinous junctions) and is required for myofibril bundling and muscle fibre growth; morpholino knockdown causes reduced fibre growth and disrupted myofibril bundles without affecting fibre attachment to myosepta.","method":"GFP-tagged TGFBI live imaging, antisense morpholino knockdown, muscle fibre phenotypic analysis in zebrafish embryos","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment (GFP-tagged protein) with functional consequence from morpholino KD; single lab","pmids":["19097068"],"is_preprint":false},{"year":2014,"finding":"Tgfbi deficiency in mice leads to reduced skeletal size and cartilage matrix degradation, with increased MMP13 and decreased type II collagen in articular cartilage, indicating TGFBI is required for maintaining cartilage matrix homeostasis.","method":"Tgfbi knockout mice, skeletal preparation, safranin O/trichrome staining, IHC for type II collagen and MMP13","journal":"Calcified tissue international","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined tissue phenotype; single lab","pmids":["25450762"],"is_preprint":false},{"year":2021,"finding":"TGFBI promotes tumor angiogenesis in colorectal cancer metastasis; non-canonical TGFβ signaling positively regulates TGFBI expression, and TGFBI inhibition reduces liver metastasis in vivo.","method":"TGFBI knockdown, in vivo orthotopic CRC liver metastasis model, TGFβ pathway inhibition, radiolabeled antibody targeting in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD with defined metastasis phenotype; single lab","pmids":["33408771"],"is_preprint":false},{"year":2022,"finding":"TGFBI promotes glioblastoma stem cell maintenance and tumor growth through integrin αvβ5-Src-Stat3 signaling; recombinant TGFBI activates this pathway in GSCs in vitro and in orthotopic xenografts.","method":"Recombinant TGFBI treatment, integrin αvβ5-Src-Stat3 pathway inhibition, orthotopic xenograft models, Western blot, ELISA","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo xenograft with defined signaling pathway; single lab","pmids":["35673564"],"is_preprint":false},{"year":2013,"finding":"TGFBI inhibits CXCL12-induced migration of hematopoietic stem/progenitor cells (HSPCs) over fibronectin by inhibiting PMA-induced RAC1 activation and ERK phosphorylation, without altering integrin expression or actin polymerization.","method":"BIGH3 overexpression in primary HSPCs and HL60 cells, adhesion and ECIS assays, migration assays, RAC1 GTPase activity assay, ERK phosphorylation western blot","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 — OE with defined pathway readout (RAC1, ERK), multiple orthogonal assays; single lab","pmids":["24152593"],"is_preprint":false},{"year":2019,"finding":"TGFBI secreted by MSCs (present in both soluble and extracellular vesicle forms) acts as a chondroprotective factor; TGFBI silencing in MSCs abolishes their inductive effect on chondrocyte anabolic markers, and injection of TGFBI-silenced MSCs fails to protect mice from OA development.","method":"siRNA silencing, co-culture assays, in vivo OA mouse model, extracellular vesicle fractionation and TGFBI detection","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KD rescue model with EV fractionation; single lab","pmids":["31648137"],"is_preprint":false},{"year":2024,"finding":"Cathepsin D (Cat D) targets TGFBI to regulate macrophage polarization; Cat D KO elevates TGFBI expression in cancer cells, which reduces M2-like TAM polarization through CCL20 chemokine secretion. Double Cat D/TGFBI KO rescues the inhibitory effects of Cat D KO on metastasis.","method":"Cat D KO and TGFBI KO cancer cells, double KO rescue experiments, RNA-seq, secretome analysis, in vivo tumor metastasis models","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis (Cat D→TGFBI→CCL20), double KO rescue, in vivo validation; single lab","pmids":["38297161"],"is_preprint":false},{"year":2023,"finding":"TGFBI binds Notch-1 and stimulates its activation in adipocytes; TGFBI deficiency suppresses adipsin secretion via Notch-1-dependent signaling, leading to adipocyte browning and protection against obesity-induced metabolic dysfunction.","method":"TGFBI KO mice, co-immunoprecipitation of TGFBI and Notch-1, adipocyte browning assays, high-fat diet model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of TGFBI-Notch1 interaction, in vivo KO model; single lab","pmids":["36854775"],"is_preprint":false},{"year":2021,"finding":"TGFBI promotes angiogenesis in infantile hemangioma through OTUB1-mediated deubiquitination; OTUB1 interacts with TGFBI and deubiquitinates it at K22 and K25 residues in a catalytic-independent manner, stabilizing TGFBI and thereby promoting glycolysis-driven angiogenesis.","method":"Mass spectrometry, Co-IP, half-life assay, ubiquitination assay with site-specific mutants (K22, K25), OTUB1 KD/OE, in vitro angiogenesis assays, in vivo IH model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical identification of ubiquitination sites, reconstituted interaction, in vivo validation; single lab but multiple orthogonal methods","pmids":["36994729"],"is_preprint":false},{"year":2021,"finding":"Deletion of Tgfbi in MMTV-PyMT mammary tumor model dramatically reduces cancer stem cell (CSC) content and lung metastasis by normalizing tumor vasculature, improving perfusion, and decreasing tumor hypoxia.","method":"MMTV-PyMT × TgfbiΔ/Δ mouse cross, RNAseq, IHC and FACS of vasculature and immune compartment, bone marrow transplantation for source identification","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined vascular/hypoxia phenotype, in vivo model; single lab","pmids":["33080107"],"is_preprint":false},{"year":2022,"finding":"DKK3 interacts extracellularly with TGFBI; this interaction inhibits DKK3's functions supporting cell adhesion, motility, and invasion through focal adhesion kinase signaling in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation of secreted DKK3 and TGFBI, cell adhesion/motility/invasion assays, FAK signaling readout in HCC and HEK293 cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional assays; single lab","pmids":["35574828"],"is_preprint":false},{"year":2018,"finding":"TGFBI mediates cytokine-activated eosinophil adhesion via αMβ2 integrin; eosinophils on TGFBI substrate adopt distinct morphologies (acorn vs. pancake) depending on protein coating concentration, regulating their migratory behavior.","method":"Eosinophil adhesion and motility assays on TGFBI-coated substrates, αMβ2 blocking antibodies, video microscopy of cell morphology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct integrin blocking with functional readout; single lab, multiple conditions","pmids":["30048528"],"is_preprint":false},{"year":2016,"finding":"TGFβ induces BIGH3 expression in retinal pericytes and endothelial cells; BIGH3 protein acts in an autocrine loop to induce retinal pericyte apoptosis in a dose-dependent manner. Blocking antibodies against BIGH3 inhibit TGFβ-induced apoptosis.","method":"TUNEL assay, qPCR for BIGH3 mRNA, western blot, recombinant BIGH3 dose-response, neutralizing antibody inhibition, IHC in human post-mortem diabetic retina","journal":"Eye (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blocking of autocrine loop, dose-response with recombinant protein, human tissue validation; single lab","pmids":["27564721"],"is_preprint":false},{"year":2013,"finding":"TGFBI regulates melanoma cell proliferation through cyclins and cyclin-dependent kinases; TGFBI silencing increases melanoma cell motility/invasion but drastically reduces proliferation, identifying a role for TGFBI in cell cycle progression rather than dissemination.","method":"shRNA silencing, in vivo lung metastasis model (tail vein injection), cell cycle analysis, cyclin/CDK western blot","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — shRNA with defined cell cycle phenotype and in vivo metastasis model; single lab","pmids":["24499734"],"is_preprint":false},{"year":2017,"finding":"Proteomic profiling of TGFBI-null mouse corneas shows that TGFBIp interacts with type VI and XII collagens (among others); POSTN cannot compensate for loss of TGFBIp; and TGFBI mRNA is restricted to corneal epithelial cells.","method":"Quantitative proteomics of TGFBI-/- vs wild-type corneas, in situ hybridization for TGFBI mRNA, histology","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics-based identification of binding partners in KO context, confirmed by in situ hybridization; single lab","pmids":["29117645"],"is_preprint":false},{"year":2024,"finding":"HIF-2α (but not HIF-1α) directly binds to the TGFBI promoter under hypoxia to upregulate TGFBI transcription; TGFBI promotes cisplatin resistance in ovarian cancer by activating PI3K/Akt pathway to reduce apoptosis and enhance DNA damage repair (upregulating p-p95/NBS1, RAD51, p-DNA-PKcs, DNA Ligase IV, Artemis, BCL2).","method":"HIF-1α/HIF-2α plasmid transfection, ChIP/promoter binding assay, TGFBI siRNA KD, western blot for DNA repair and apoptosis markers, PI3K/Akt pathway analysis in cisplatin-resistant cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — transcription factor binding to promoter, KD with defined pathway readout; single lab","pmids":["38365849"],"is_preprint":false}],"current_model":"TGFBI encodes a secreted extracellular matrix protein (TGFBIp/keratoepithelin/βig-h3) that binds collagens and integrins (including αvβ3, αvβ5, α3β1, αMβ2) via its four FAS1 domains and RGD motif, and mediates diverse context-dependent cellular functions including: promoting cancer cell extravasation via integrin αvβ5-Src signaling; stabilizing microtubules and mediating paclitaxel sensitivity via integrin-FAK-Rho signaling; inducing apoptosis through its C-terminal PDI domain and caspase-3 activation; interacting with periostin via EMI domains in the trans-Golgi network prior to secretion (disrupted by corneal dystrophy mutations that also mislocalize TGFBIp to lysosomes); being degraded by autophagy (impaired in GCD2 due to defective autophagosome-lysosome fusion); activating AKT/mTOR/Notch-1 signaling pathways in various cell types; and being post-translationally regulated by OTUB1-mediated deubiquitination at K22/K25 and transcriptionally regulated by HIF-2α and TGFβ/Smad3 signaling."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that corneal dystrophy mutations in TGFBI are not merely loss-of-function but actively toxic: overexpression of R124C and R555W mutants induces caspase-3-dependent apoptosis through the C-terminal PDI motif, identifying a specific integrin-binding site as the effector domain for mutant cytotoxicity.","evidence":"Transfection of mutant BIGH3-EGFP constructs with truncation/site-directed mutagenesis of PDI domain, caspase-3 activation in corneal and HeLa cells","pmids":["12824240"],"confidence":"High","gaps":["Whether endogenous mutant protein levels are sufficient to trigger apoptosis in vivo","Whether PDI-mediated apoptosis is specific to corneal cell types or universal"]},{"year":2007,"claim":"Resolving how an ECM protein controls drug sensitivity: TGFBIp stabilizes microtubules through integrin-dependent FAK-Rho signaling, and its loss confers specific paclitaxel resistance in ovarian cancer, establishing TGFBIp as a functional link between extracellular matrix and cytoskeletal drug targets.","evidence":"TGFBI-deficient ovarian cancer cells rescued with recombinant protein; FAK/Rho inhibition and microtubule stabilization assays","pmids":["18068629"],"confidence":"High","gaps":["Whether TGFBIp-mediated microtubule stabilization operates through direct tubulin interaction or solely through integrin signaling","Generalizability to other microtubule-targeting agents"]},{"year":2008,"claim":"Defining TGFBIp's pro-metastatic mechanism: TGFBIp promotes cancer cell extravasation by disrupting endothelial VE-cadherin junctions via integrin αvβ5-Src signaling, identifying a paracrine ECM-to-endothelium axis in metastasis.","evidence":"Ectopic expression and shRNA knockdown in in vivo colon cancer metastasis models with integrin αvβ5-Src pathway delineation","pmids":["18245446"],"confidence":"High","gaps":["Whether endothelial cells or tumor cells are the primary source of TGFBIp in metastasis","Structural basis of αvβ5 selectivity over other integrins in this context"]},{"year":2009,"claim":"Identifying TGFBIp's pre-secretory partner and the molecular basis of corneal dystrophy protein mislocalization: TGFBIp interacts with periostin via EMI domains in the trans-Golgi network, and the R124H dystrophy mutation disrupts this interaction, causing aberrant redistribution to lysosomes.","evidence":"Reciprocal Co-IP, domain mapping with EMI constructs, confocal colocalization in patient-derived corneal fibroblasts","pmids":["19478074"],"confidence":"High","gaps":["Whether periostin interaction is required for normal TGFBIp secretion or only quality control","Whether other dystrophy mutations similarly disrupt periostin binding"]},{"year":2011,"claim":"Establishing how TGFBIp signals intracellularly and how its transcription is controlled: TGFBIp suppresses mesothelioma via PI3K/Akt/mTOR signaling, and TGFβ/Smad3 signaling drives TGFBI transcription, with GSK-3β modulating Smad3 activity.","evidence":"shRNA knockdown/overexpression with signaling readouts in mesothelioma; Co-IP of GSK-3β–Smad3, LiCl treatment in GCD2 fibroblasts","pmids":["21701776","21310903"],"confidence":"Medium","gaps":["Which integrin mediates PI3K/Akt/mTOR activation in mesothelioma","Direct Smad3 binding to TGFBI promoter not confirmed by ChIP in these studies"]},{"year":2012,"claim":"Revealing the proteostasis mechanism for mutant TGFBIp clearance: GCD2-mutant TGFBIp is degraded by autophagy rather than the proteasome, and the R124H mutation impairs autophagosome–lysosome fusion, causing accumulation of uncleared mutant protein—providing a mechanistic basis for corneal deposits.","evidence":"Autophagy flux assays with bafilomycin A1, LC3-II/SQSTM1 analysis, rapamycin rescue in primary GCD2 corneal fibroblasts","pmids":["22995918"],"confidence":"High","gaps":["Whether the fusion defect is specific to TGFBIp-containing autophagosomes or represents a general autophagy impairment","Identity of the autophagy receptor for TGFBIp"]},{"year":2013,"claim":"Quantifying the multi-domain integrin-binding mechanism: all four FAS1 domains plus the RGD motif cooperate to achieve ~2300-fold higher affinity for αvβ3 than a single FAS1 domain alone (Kd ~38 nM), explaining TGFBIp's potent biological activities.","evidence":"Quantitative binding assays with recombinant domain constructs, in vitro anti-angiogenesis and in vivo tumor targeting","pmids":["23792174"],"confidence":"High","gaps":["No crystal structure of the TGFBIp–integrin complex","Whether domain cooperativity differs across integrin subtypes"]},{"year":2014,"claim":"Extending TGFBIp's physiological roles beyond the cornea: Tgfbi-null mice show cartilage degradation with elevated MMP13, and TGFBIp activates FAK/AKT/mTOR in pancreatic islets to promote survival, establishing TGFBIp as a systemic matrix factor for tissue homeostasis.","evidence":"Tgfbi KO mice with skeletal phenotyping; phosphoprotein arrays and siRNA pathway validation in KO islets","pmids":["25450762","24728038"],"confidence":"Medium","gaps":["Whether cartilage phenotype is integrin-dependent","Human relevance of islet survival function"]},{"year":2017,"claim":"Establishing transcriptional control of TGFBI by AR-SPDEF axis in prostate cancer: androgen signaling through SPDEF represses TGFBI, and androgen deprivation therapy elevates TGFBIp to promote EMT and bone/brain metastasis, revealing an iatrogenic pro-metastatic mechanism.","evidence":"SPDEF KD/OE epistasis, xenograft bone/brain metastasis models, patient tissue before/after ADT","pmids":["28811384"],"confidence":"High","gaps":["Which integrin mediates TGFBI's metastatic function in prostate cancer","Whether TGFBI inhibition could mitigate ADT-induced metastasis"]},{"year":2021,"claim":"Identifying post-translational stabilization of TGFBIp: OTUB1 deubiquitinates TGFBIp at K22 and K25 in a catalytic-independent manner, stabilizing the protein and promoting glycolysis-driven angiogenesis in infantile hemangioma.","evidence":"Mass spectrometry, Co-IP, ubiquitination assays with K22/K25 mutants, OTUB1 KD/OE, in vivo hemangioma model","pmids":["36994729"],"confidence":"High","gaps":["E3 ligase responsible for TGFBIp ubiquitination at K22/K25 not identified","How intracellular ubiquitination regulates a secreted protein's stability"]},{"year":2022,"claim":"Defining TGFBIp's role in glioblastoma stem cell maintenance: TGFBIp activates an integrin αvβ5-Src-Stat3 signaling axis in glioblastoma stem cells, promoting self-renewal and tumor growth in orthotopic models.","evidence":"Recombinant TGFBIp treatment with pathway inhibition, orthotopic xenografts, Western blot/ELISA","pmids":["35673564"],"confidence":"Medium","gaps":["Whether TGFBIp is tumor- or stroma-derived in glioblastoma","Whether Stat3 activation is direct or secondary to Src"]},{"year":2023,"claim":"Revealing a non-integrin receptor for TGFBIp: TGFBIp directly binds Notch-1 to activate Notch signaling in adipocytes, controlling adipsin secretion and adipocyte browning, establishing a metabolic role for this ECM protein.","evidence":"Co-immunoprecipitation of TGFBIp–Notch-1, Tgfbi KO mice on high-fat diet, adipocyte browning assays","pmids":["36854775"],"confidence":"Medium","gaps":["Binding interface between TGFBIp and Notch-1 not mapped","Whether Notch activation is ligand-mimetic or modulatory"]},{"year":2024,"claim":"Establishing direct transcriptional regulation by HIF-2α: HIF-2α binds the TGFBI promoter under hypoxia to upregulate expression, and TGFBIp promotes cisplatin resistance via PI3K/Akt-dependent enhancement of DNA damage repair.","evidence":"ChIP/promoter binding assay for HIF-2α, TGFBI siRNA KD with DNA repair marker analysis in cisplatin-resistant ovarian cancer cells","pmids":["38365849"],"confidence":"Medium","gaps":["Whether HIF-2α regulation is conserved across tumor types","Direct mechanism linking extracellular TGFBIp to nuclear DNA repair machinery"]},{"year":null,"claim":"Despite extensive functional characterization, no structural model of the full-length TGFBIp–integrin complex exists, the E3 ubiquitin ligase targeting TGFBIp is unknown, the autophagy receptor for TGFBIp clearance has not been identified, and the mechanism by which an extracellular/secreted protein activates nuclear DNA repair pathways remains unexplained.","evidence":"Open questions from the literature","pmids":[],"confidence":"Low","gaps":["No full-length TGFBIp–integrin co-crystal structure","E3 ligase for K22/K25 ubiquitination unidentified","Autophagy receptor mediating TGFBIp degradation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,5,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,15,24]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,22,11]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5,9,11,25]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,16,21]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,9,12,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6,10,14,26]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,23]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,22]}],"complexes":[],"partners":["POSTN","ITGAV","ITGB5","ITGB3","OTUB1","NOTCH1","DKK3","ITGAM"],"other_free_text":[]},"mechanistic_narrative":"TGFBI encodes a secreted extracellular matrix protein (TGFBIp/βig-h3) that functions as a multivalent integrin ligand and collagen-binding matricellular factor, regulating cell adhesion, migration, survival, and tissue remodeling across diverse biological contexts. TGFBIp engages multiple integrins—including αvβ3, αvβ5, α3β1, and αMβ2—through cooperative action of its four FAS1 domains and a C-terminal RGD motif, achieving high-affinity binding (Kd ~38 nM for αvβ3) that underlies its anti-angiogenic, pro-metastatic, and microtubule-stabilizing activities depending on cellular context [PMID:23792174, PMID:18245446, PMID:18068629, PMID:30048528]. Downstream of integrin engagement, TGFBIp activates FAK, Src, PI3K/Akt/mTOR, Rho GTPase, and Stat3 signaling cascades to control cell survival, proliferation, and drug sensitivity, while also binding Notch-1 to regulate adipocyte browning and interacting with periostin via EMI domains prior to secretion [PMID:24728038, PMID:35673564, PMID:36854775, PMID:19478074]. Missense mutations in TGFBI (e.g., R124H, R124C) cause corneal dystrophies by impairing periostin interaction, mislocalizing TGFBIp to lysosomes, and disrupting autophagic clearance through defective autophagosome–lysosome fusion [PMID:19478074, PMID:22995918, PMID:12824240]. Transcriptionally, TGFBI is regulated by TGFβ/Smad3 signaling and HIF-2α under hypoxia, and its protein stability is controlled by OTUB1-mediated deubiquitination at K22/K25 [PMID:21310903, PMID:38365849, PMID:36994729]."},"prefetch_data":{"uniprot":{"accession":"Q15582","full_name":"Transforming growth factor-beta-induced protein ig-h3","aliases":["Kerato-epithelin","RGD-containing collagen-associated protein","RGD-CAP"],"length_aa":683,"mass_kda":74.7,"function":"Plays a role in cell adhesion (PubMed:8024701). 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pathway.","date":"2022","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/35357655","citation_count":20,"is_preprint":false},{"pmid":"20092310","id":"PMC_20092310","title":"Detection of the most common corneal dystrophies caused by BIGH3 gene point mutations using a multispot gold-capped nanoparticle array chip.","date":"2010","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20092310","citation_count":20,"is_preprint":false},{"pmid":"18357369","id":"PMC_18357369","title":"BIGH3 is overexpressed in clear cell renal cell carcinoma.","date":"2008","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/18357369","citation_count":19,"is_preprint":false},{"pmid":"25760614","id":"PMC_25760614","title":"Structure of Csd3 from Helicobacter pylori, a cell shape-determining metallopeptidase.","date":"2015","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/25760614","citation_count":19,"is_preprint":false},{"pmid":"18728790","id":"PMC_18728790","title":"A novel phenotype-genotype relationship with a TGFBI exon 14 mutation in a pedigree with a unique corneal dystrophy of Bowman's layer.","date":"2008","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/18728790","citation_count":19,"is_preprint":false},{"pmid":"29190493","id":"PMC_29190493","title":"BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation.","date":"2017","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29190493","citation_count":16,"is_preprint":false},{"pmid":"25932442","id":"PMC_25932442","title":"Mutation Analysis of the TGFBI Gene in Consecutive Korean Patients With Corneal Dystrophies.","date":"2015","source":"Annals of laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25932442","citation_count":15,"is_preprint":false},{"pmid":"30084753","id":"PMC_30084753","title":"TGFBI Expressed by Bone Marrow Niche Cells and Hematopoietic Stem and Progenitor Cells Regulates Hematopoiesis.","date":"2018","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/30084753","citation_count":13,"is_preprint":false},{"pmid":"37960829","id":"PMC_37960829","title":"FN1 and TGFBI are key biomarkers of macrophage immune injury in diabetic kidney disease.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37960829","citation_count":13,"is_preprint":false},{"pmid":"24801599","id":"PMC_24801599","title":"TGFBI, CHST6, and GSN gene analysis in Mexican patients with stromal corneal dystrophies.","date":"2014","source":"Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie","url":"https://pubmed.ncbi.nlm.nih.gov/24801599","citation_count":13,"is_preprint":false},{"pmid":"12225829","id":"PMC_12225829","title":"An analysis of BIGH3 mutations in patients with corneal dystrophies in the Kyushu district of Japan.","date":"2002","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/12225829","citation_count":13,"is_preprint":false},{"pmid":"25378215","id":"PMC_25378215","title":"BIGH3 protein and macrophages in retinal endothelial cell apoptosis.","date":"2015","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/25378215","citation_count":13,"is_preprint":false},{"pmid":"38365849","id":"PMC_38365849","title":"HIF-2α-dependent TGFBI promotes ovarian cancer chemoresistance by activating PI3K/Akt pathway to inhibit apoptosis and facilitate DNA repair process.","date":"2024","source":"Scientific 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mutation I522N within the TGFBI gene caused lattice corneal dystrophy I.","date":"2009","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/19956413","citation_count":12,"is_preprint":false},{"pmid":"36994729","id":"PMC_36994729","title":"OTUB1 Catalytic-Independently Deubiquitinates TGFBI and Mediates the Angiogenesis in Infantile Hemangioma by Regulating Glycolysis.","date":"2023","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36994729","citation_count":11,"is_preprint":false},{"pmid":"35083181","id":"PMC_35083181","title":"MiR-766-3p Suppresses Malignant Behaviors and Stimulates Apoptosis of Colon Cancer Cells via Targeting TGFBI.","date":"2022","source":"Canadian journal of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35083181","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53072,"output_tokens":6559,"usd":0.128801},"stage2":{"model":"claude-opus-4-6","input_tokens":10337,"output_tokens":3954,"usd":0.225802},"total_usd":0.354603,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"TGFBI (betaig-h3) promotes cancer cell extravasation by inducing dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin αvβ5-Src signaling pathway, promoting colon cancer metastasis.\",\n      \"method\": \"Ectopic expression and shRNA knockdown in vivo metastasis models; mechanistic pathway delineation via integrin αvβ5-Src signaling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/KD with defined cellular phenotype, in vivo metastasis model, signaling pathway identified; Moderate evidence\",\n      \"pmids\": [\"18245446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of TGFBI causes specific resistance to paclitaxel and mitotic spindle abnormalities in ovarian cancer cells; recombinant TGFBI restores paclitaxel sensitivity through integrin-dependent FAK- and Rho-dependent stabilization of microtubules.\",\n      \"method\": \"Loss-of-function (TGFBI-deficient cells), rescue with recombinant TGFBI protein, FAK/Rho pathway inhibition assays, in vitro microtubule stabilization assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with recombinant protein plus pathway mutagenesis/inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"18068629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TGFBI interacts with periostin via their N-terminal EMI domains; both proteins colocalize in the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation severely impairs TGFBI-periostin interaction and causes aberrant redistribution of mutant TGFBI to lysosomes.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (EMI domain constructs), confocal colocalization, subcellular fractionation, patient-derived corneal fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, domain-level binding mapping, subcellular localization with functional consequence, replicated in patient cells\",\n      \"pmids\": [\"19478074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mutant TGFBI (R124H; GCD2) is degraded by autophagy but not the ubiquitin/proteasome pathway; GCD2 corneal fibroblasts display defective autophagosome-lysosome fusion leading to impaired clearance of mutant TGFBIp and accumulation of autophagosomes containing mutant protein.\",\n      \"method\": \"Autophagy flux assays (bafilomycin A1 treatment), LC3-II/SQSTM1 western blot, confocal colocalization, rapamycin rescue experiments, caspase-3 activation assays in primary patient corneal fibroblasts\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in primary patient cells, pathway inhibitor/activator rescue\",\n      \"pmids\": [\"22995918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of mutant TGFBI (R124C, R555W, and others) induces apoptosis in corneal and HeLa cells through caspase-3 activation; apoptosis requires the C-terminal domain and specifically the PDI site (Pro-Asp-Ile, residues 616-618), a known site of interaction with α3β1 integrins.\",\n      \"method\": \"Transfection of mutant BIGH3-EGFP constructs, Hoechst/propidium iodide and annexin V staining, caspase-3 activation assay, truncation and site-specific mutagenesis of the PDI domain\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + functional rescue, multiple mutants tested, defined molecular motif\",\n      \"pmids\": [\"12824240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGFBI binds αvβ3 integrin with high affinity (Kd ~3.8×10⁻⁸ M) through cooperative action of all four FAS1 domains and the RGD motif; this multi-domain cooperation confers ~2300-fold higher affinity than a single FAS1 domain alone and underlies potent anti-angiogenic and anti-tumor activities.\",\n      \"method\": \"Binding affinity assay (Kd measurement), recombinant domain constructs, in vitro anti-angiogenesis assays, in vivo tumor targeting experiments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative binding assay with domain mutants, functional validation in vitro and in vivo\",\n      \"pmids\": [\"23792174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TGFBI suppresses mesothelioma progression via the PI3K/Akt/mTOR signaling pathway; loss of TGFBI elevates c-myc/cyclin D1/phospho-Rb and activates PI3K/Akt/mTOR signaling, while ectopic TGFBI expression reverses these changes.\",\n      \"method\": \"shRNA knockdown and ectopic overexpression, western blot for signaling pathway components, clonogenic and soft-agar growth assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD and OE with pathway readout, single lab\",\n      \"pmids\": [\"21701776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lithium (LiCl) reduces TGFBI expression by decreasing pSmad3 levels and enhancing interaction between GSK-3β and Smad3, and by inducing autophagy (elevated LC3-II/I ratio), thereby reducing normal and mutant TGFBIp accumulation in GCD2 corneal fibroblasts.\",\n      \"method\": \"Western blot (pSmad3, pGSK-3α/β, LC3-II), RT-PCR, co-immunoprecipitation of GSK-3β and Smad3, dose-response assays in primary corneal fibroblasts\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of signaling components, multiple pathway readouts; single lab\",\n      \"pmids\": [\"21310903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Corneal deposits in GCD2 (R124H mutation) specifically accumulate TGFBIp along with serum amyloid P-component, clusterin, and type III collagen. In LCD amyloid (V624M), a C-terminal fragment of TGFBIp (residues Y571-R588 from FAS1-4 domain) accumulates with serine protease HtrA1, which shows proteolytic cleavage sites in FAS1-4, suggesting HtrA1 mediates proteolytic processing of amyloidogenic TGFBIp.\",\n      \"method\": \"Laser capture microdissection, tandem mass spectrometry, label-free quantitative proteomics of corneal deposits\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry-based identification of interacting proteins and cleavage sites in situ; single lab\",\n      \"pmids\": [\"22155582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AR signaling stimulates SPDEF transcription factor activity, which represses TGFBI expression; androgen deprivation therapy (ADT) reduces nuclear SPDEF and increases TGFBI, and TGFBI promotes EMT and bone/brain metastasis of prostate cancer. TGFBI was identified as a type 1, 2, and 4 collagen-binding protein mediating this effect.\",\n      \"method\": \"KD/OE in prostate cancer cell lines, xenograft mouse models (bone/brain metastasis), patient tissue before/after ADT, SPDEF overexpression/knockdown\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (SPDEF→TGFBI pathway), in vivo xenograft models, patient tissue validation; Moderate-Strong evidence\",\n      \"pmids\": [\"28811384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TGFBI activates the FAK/AKT/AKT1S1/RPS6/EIF4EBP1 signaling pathway in islets to promote cell survival and function; phosphoprotein array and siRNA knockdown of pathway components confirmed mechanistic relevance.\",\n      \"method\": \"Phosphoprotein array analysis in TGFBI KO islets, recombinant TGFBI stimulation, AKT chemical inhibitor, siRNA knockdown of AKT1S1/RPS6/EIF4EBP1, islet survival/function assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphoproteomics plus siRNA pathway validation in KO model; single lab, Moderate evidence\",\n      \"pmids\": [\"24728038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish embryos, TGFBI localizes to myosepta (myotendinous junctions) and is required for myofibril bundling and muscle fibre growth; morpholino knockdown causes reduced fibre growth and disrupted myofibril bundles without affecting fibre attachment to myosepta.\",\n      \"method\": \"GFP-tagged TGFBI live imaging, antisense morpholino knockdown, muscle fibre phenotypic analysis in zebrafish embryos\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment (GFP-tagged protein) with functional consequence from morpholino KD; single lab\",\n      \"pmids\": [\"19097068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Tgfbi deficiency in mice leads to reduced skeletal size and cartilage matrix degradation, with increased MMP13 and decreased type II collagen in articular cartilage, indicating TGFBI is required for maintaining cartilage matrix homeostasis.\",\n      \"method\": \"Tgfbi knockout mice, skeletal preparation, safranin O/trichrome staining, IHC for type II collagen and MMP13\",\n      \"journal\": \"Calcified tissue international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined tissue phenotype; single lab\",\n      \"pmids\": [\"25450762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGFBI promotes tumor angiogenesis in colorectal cancer metastasis; non-canonical TGFβ signaling positively regulates TGFBI expression, and TGFBI inhibition reduces liver metastasis in vivo.\",\n      \"method\": \"TGFBI knockdown, in vivo orthotopic CRC liver metastasis model, TGFβ pathway inhibition, radiolabeled antibody targeting in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with defined metastasis phenotype; single lab\",\n      \"pmids\": [\"33408771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGFBI promotes glioblastoma stem cell maintenance and tumor growth through integrin αvβ5-Src-Stat3 signaling; recombinant TGFBI activates this pathway in GSCs in vitro and in orthotopic xenografts.\",\n      \"method\": \"Recombinant TGFBI treatment, integrin αvβ5-Src-Stat3 pathway inhibition, orthotopic xenograft models, Western blot, ELISA\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft with defined signaling pathway; single lab\",\n      \"pmids\": [\"35673564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGFBI inhibits CXCL12-induced migration of hematopoietic stem/progenitor cells (HSPCs) over fibronectin by inhibiting PMA-induced RAC1 activation and ERK phosphorylation, without altering integrin expression or actin polymerization.\",\n      \"method\": \"BIGH3 overexpression in primary HSPCs and HL60 cells, adhesion and ECIS assays, migration assays, RAC1 GTPase activity assay, ERK phosphorylation western blot\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — OE with defined pathway readout (RAC1, ERK), multiple orthogonal assays; single lab\",\n      \"pmids\": [\"24152593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGFBI secreted by MSCs (present in both soluble and extracellular vesicle forms) acts as a chondroprotective factor; TGFBI silencing in MSCs abolishes their inductive effect on chondrocyte anabolic markers, and injection of TGFBI-silenced MSCs fails to protect mice from OA development.\",\n      \"method\": \"siRNA silencing, co-culture assays, in vivo OA mouse model, extracellular vesicle fractionation and TGFBI detection\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD rescue model with EV fractionation; single lab\",\n      \"pmids\": [\"31648137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cathepsin D (Cat D) targets TGFBI to regulate macrophage polarization; Cat D KO elevates TGFBI expression in cancer cells, which reduces M2-like TAM polarization through CCL20 chemokine secretion. Double Cat D/TGFBI KO rescues the inhibitory effects of Cat D KO on metastasis.\",\n      \"method\": \"Cat D KO and TGFBI KO cancer cells, double KO rescue experiments, RNA-seq, secretome analysis, in vivo tumor metastasis models\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (Cat D→TGFBI→CCL20), double KO rescue, in vivo validation; single lab\",\n      \"pmids\": [\"38297161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TGFBI binds Notch-1 and stimulates its activation in adipocytes; TGFBI deficiency suppresses adipsin secretion via Notch-1-dependent signaling, leading to adipocyte browning and protection against obesity-induced metabolic dysfunction.\",\n      \"method\": \"TGFBI KO mice, co-immunoprecipitation of TGFBI and Notch-1, adipocyte browning assays, high-fat diet model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of TGFBI-Notch1 interaction, in vivo KO model; single lab\",\n      \"pmids\": [\"36854775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGFBI promotes angiogenesis in infantile hemangioma through OTUB1-mediated deubiquitination; OTUB1 interacts with TGFBI and deubiquitinates it at K22 and K25 residues in a catalytic-independent manner, stabilizing TGFBI and thereby promoting glycolysis-driven angiogenesis.\",\n      \"method\": \"Mass spectrometry, Co-IP, half-life assay, ubiquitination assay with site-specific mutants (K22, K25), OTUB1 KD/OE, in vitro angiogenesis assays, in vivo IH model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical identification of ubiquitination sites, reconstituted interaction, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36994729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Deletion of Tgfbi in MMTV-PyMT mammary tumor model dramatically reduces cancer stem cell (CSC) content and lung metastasis by normalizing tumor vasculature, improving perfusion, and decreasing tumor hypoxia.\",\n      \"method\": \"MMTV-PyMT × TgfbiΔ/Δ mouse cross, RNAseq, IHC and FACS of vasculature and immune compartment, bone marrow transplantation for source identification\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined vascular/hypoxia phenotype, in vivo model; single lab\",\n      \"pmids\": [\"33080107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DKK3 interacts extracellularly with TGFBI; this interaction inhibits DKK3's functions supporting cell adhesion, motility, and invasion through focal adhesion kinase signaling in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation of secreted DKK3 and TGFBI, cell adhesion/motility/invasion assays, FAK signaling readout in HCC and HEK293 cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional assays; single lab\",\n      \"pmids\": [\"35574828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGFBI mediates cytokine-activated eosinophil adhesion via αMβ2 integrin; eosinophils on TGFBI substrate adopt distinct morphologies (acorn vs. pancake) depending on protein coating concentration, regulating their migratory behavior.\",\n      \"method\": \"Eosinophil adhesion and motility assays on TGFBI-coated substrates, αMβ2 blocking antibodies, video microscopy of cell morphology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct integrin blocking with functional readout; single lab, multiple conditions\",\n      \"pmids\": [\"30048528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGFβ induces BIGH3 expression in retinal pericytes and endothelial cells; BIGH3 protein acts in an autocrine loop to induce retinal pericyte apoptosis in a dose-dependent manner. Blocking antibodies against BIGH3 inhibit TGFβ-induced apoptosis.\",\n      \"method\": \"TUNEL assay, qPCR for BIGH3 mRNA, western blot, recombinant BIGH3 dose-response, neutralizing antibody inhibition, IHC in human post-mortem diabetic retina\",\n      \"journal\": \"Eye (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blocking of autocrine loop, dose-response with recombinant protein, human tissue validation; single lab\",\n      \"pmids\": [\"27564721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGFBI regulates melanoma cell proliferation through cyclins and cyclin-dependent kinases; TGFBI silencing increases melanoma cell motility/invasion but drastically reduces proliferation, identifying a role for TGFBI in cell cycle progression rather than dissemination.\",\n      \"method\": \"shRNA silencing, in vivo lung metastasis model (tail vein injection), cell cycle analysis, cyclin/CDK western blot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — shRNA with defined cell cycle phenotype and in vivo metastasis model; single lab\",\n      \"pmids\": [\"24499734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Proteomic profiling of TGFBI-null mouse corneas shows that TGFBIp interacts with type VI and XII collagens (among others); POSTN cannot compensate for loss of TGFBIp; and TGFBI mRNA is restricted to corneal epithelial cells.\",\n      \"method\": \"Quantitative proteomics of TGFBI-/- vs wild-type corneas, in situ hybridization for TGFBI mRNA, histology\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics-based identification of binding partners in KO context, confirmed by in situ hybridization; single lab\",\n      \"pmids\": [\"29117645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-2α (but not HIF-1α) directly binds to the TGFBI promoter under hypoxia to upregulate TGFBI transcription; TGFBI promotes cisplatin resistance in ovarian cancer by activating PI3K/Akt pathway to reduce apoptosis and enhance DNA damage repair (upregulating p-p95/NBS1, RAD51, p-DNA-PKcs, DNA Ligase IV, Artemis, BCL2).\",\n      \"method\": \"HIF-1α/HIF-2α plasmid transfection, ChIP/promoter binding assay, TGFBI siRNA KD, western blot for DNA repair and apoptosis markers, PI3K/Akt pathway analysis in cisplatin-resistant cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcription factor binding to promoter, KD with defined pathway readout; single lab\",\n      \"pmids\": [\"38365849\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TGFBI encodes a secreted extracellular matrix protein (TGFBIp/keratoepithelin/βig-h3) that binds collagens and integrins (including αvβ3, αvβ5, α3β1, αMβ2) via its four FAS1 domains and RGD motif, and mediates diverse context-dependent cellular functions including: promoting cancer cell extravasation via integrin αvβ5-Src signaling; stabilizing microtubules and mediating paclitaxel sensitivity via integrin-FAK-Rho signaling; inducing apoptosis through its C-terminal PDI domain and caspase-3 activation; interacting with periostin via EMI domains in the trans-Golgi network prior to secretion (disrupted by corneal dystrophy mutations that also mislocalize TGFBIp to lysosomes); being degraded by autophagy (impaired in GCD2 due to defective autophagosome-lysosome fusion); activating AKT/mTOR/Notch-1 signaling pathways in various cell types; and being post-translationally regulated by OTUB1-mediated deubiquitination at K22/K25 and transcriptionally regulated by HIF-2α and TGFβ/Smad3 signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TGFBI encodes a secreted extracellular matrix protein (TGFBIp/βig-h3) that functions as a multivalent integrin ligand and collagen-binding matricellular factor, regulating cell adhesion, migration, survival, and tissue remodeling across diverse biological contexts. TGFBIp engages multiple integrins—including αvβ3, αvβ5, α3β1, and αMβ2—through cooperative action of its four FAS1 domains and a C-terminal RGD motif, achieving high-affinity binding (Kd ~38 nM for αvβ3) that underlies its anti-angiogenic, pro-metastatic, and microtubule-stabilizing activities depending on cellular context [PMID:23792174, PMID:18245446, PMID:18068629, PMID:30048528]. Downstream of integrin engagement, TGFBIp activates FAK, Src, PI3K/Akt/mTOR, Rho GTPase, and Stat3 signaling cascades to control cell survival, proliferation, and drug sensitivity, while also binding Notch-1 to regulate adipocyte browning and interacting with periostin via EMI domains prior to secretion [PMID:24728038, PMID:35673564, PMID:36854775, PMID:19478074]. Missense mutations in TGFBI (e.g., R124H, R124C) cause corneal dystrophies by impairing periostin interaction, mislocalizing TGFBIp to lysosomes, and disrupting autophagic clearance through defective autophagosome–lysosome fusion [PMID:19478074, PMID:22995918, PMID:12824240]. Transcriptionally, TGFBI is regulated by TGFβ/Smad3 signaling and HIF-2α under hypoxia, and its protein stability is controlled by OTUB1-mediated deubiquitination at K22/K25 [PMID:21310903, PMID:38365849, PMID:36994729].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that corneal dystrophy mutations in TGFBI are not merely loss-of-function but actively toxic: overexpression of R124C and R555W mutants induces caspase-3-dependent apoptosis through the C-terminal PDI motif, identifying a specific integrin-binding site as the effector domain for mutant cytotoxicity.\",\n      \"evidence\": \"Transfection of mutant BIGH3-EGFP constructs with truncation/site-directed mutagenesis of PDI domain, caspase-3 activation in corneal and HeLa cells\",\n      \"pmids\": [\"12824240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous mutant protein levels are sufficient to trigger apoptosis in vivo\", \"Whether PDI-mediated apoptosis is specific to corneal cell types or universal\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolving how an ECM protein controls drug sensitivity: TGFBIp stabilizes microtubules through integrin-dependent FAK-Rho signaling, and its loss confers specific paclitaxel resistance in ovarian cancer, establishing TGFBIp as a functional link between extracellular matrix and cytoskeletal drug targets.\",\n      \"evidence\": \"TGFBI-deficient ovarian cancer cells rescued with recombinant protein; FAK/Rho inhibition and microtubule stabilization assays\",\n      \"pmids\": [\"18068629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TGFBIp-mediated microtubule stabilization operates through direct tubulin interaction or solely through integrin signaling\", \"Generalizability to other microtubule-targeting agents\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining TGFBIp's pro-metastatic mechanism: TGFBIp promotes cancer cell extravasation by disrupting endothelial VE-cadherin junctions via integrin αvβ5-Src signaling, identifying a paracrine ECM-to-endothelium axis in metastasis.\",\n      \"evidence\": \"Ectopic expression and shRNA knockdown in in vivo colon cancer metastasis models with integrin αvβ5-Src pathway delineation\",\n      \"pmids\": [\"18245446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endothelial cells or tumor cells are the primary source of TGFBIp in metastasis\", \"Structural basis of αvβ5 selectivity over other integrins in this context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying TGFBIp's pre-secretory partner and the molecular basis of corneal dystrophy protein mislocalization: TGFBIp interacts with periostin via EMI domains in the trans-Golgi network, and the R124H dystrophy mutation disrupts this interaction, causing aberrant redistribution to lysosomes.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping with EMI constructs, confocal colocalization in patient-derived corneal fibroblasts\",\n      \"pmids\": [\"19478074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether periostin interaction is required for normal TGFBIp secretion or only quality control\", \"Whether other dystrophy mutations similarly disrupt periostin binding\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing how TGFBIp signals intracellularly and how its transcription is controlled: TGFBIp suppresses mesothelioma via PI3K/Akt/mTOR signaling, and TGFβ/Smad3 signaling drives TGFBI transcription, with GSK-3β modulating Smad3 activity.\",\n      \"evidence\": \"shRNA knockdown/overexpression with signaling readouts in mesothelioma; Co-IP of GSK-3β–Smad3, LiCl treatment in GCD2 fibroblasts\",\n      \"pmids\": [\"21701776\", \"21310903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which integrin mediates PI3K/Akt/mTOR activation in mesothelioma\", \"Direct Smad3 binding to TGFBI promoter not confirmed by ChIP in these studies\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealing the proteostasis mechanism for mutant TGFBIp clearance: GCD2-mutant TGFBIp is degraded by autophagy rather than the proteasome, and the R124H mutation impairs autophagosome–lysosome fusion, causing accumulation of uncleared mutant protein—providing a mechanistic basis for corneal deposits.\",\n      \"evidence\": \"Autophagy flux assays with bafilomycin A1, LC3-II/SQSTM1 analysis, rapamycin rescue in primary GCD2 corneal fibroblasts\",\n      \"pmids\": [\"22995918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the fusion defect is specific to TGFBIp-containing autophagosomes or represents a general autophagy impairment\", \"Identity of the autophagy receptor for TGFBIp\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Quantifying the multi-domain integrin-binding mechanism: all four FAS1 domains plus the RGD motif cooperate to achieve ~2300-fold higher affinity for αvβ3 than a single FAS1 domain alone (Kd ~38 nM), explaining TGFBIp's potent biological activities.\",\n      \"evidence\": \"Quantitative binding assays with recombinant domain constructs, in vitro anti-angiogenesis and in vivo tumor targeting\",\n      \"pmids\": [\"23792174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the TGFBIp–integrin complex\", \"Whether domain cooperativity differs across integrin subtypes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending TGFBIp's physiological roles beyond the cornea: Tgfbi-null mice show cartilage degradation with elevated MMP13, and TGFBIp activates FAK/AKT/mTOR in pancreatic islets to promote survival, establishing TGFBIp as a systemic matrix factor for tissue homeostasis.\",\n      \"evidence\": \"Tgfbi KO mice with skeletal phenotyping; phosphoprotein arrays and siRNA pathway validation in KO islets\",\n      \"pmids\": [\"25450762\", \"24728038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cartilage phenotype is integrin-dependent\", \"Human relevance of islet survival function\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing transcriptional control of TGFBI by AR-SPDEF axis in prostate cancer: androgen signaling through SPDEF represses TGFBI, and androgen deprivation therapy elevates TGFBIp to promote EMT and bone/brain metastasis, revealing an iatrogenic pro-metastatic mechanism.\",\n      \"evidence\": \"SPDEF KD/OE epistasis, xenograft bone/brain metastasis models, patient tissue before/after ADT\",\n      \"pmids\": [\"28811384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which integrin mediates TGFBI's metastatic function in prostate cancer\", \"Whether TGFBI inhibition could mitigate ADT-induced metastasis\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying post-translational stabilization of TGFBIp: OTUB1 deubiquitinates TGFBIp at K22 and K25 in a catalytic-independent manner, stabilizing the protein and promoting glycolysis-driven angiogenesis in infantile hemangioma.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, ubiquitination assays with K22/K25 mutants, OTUB1 KD/OE, in vivo hemangioma model\",\n      \"pmids\": [\"36994729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for TGFBIp ubiquitination at K22/K25 not identified\", \"How intracellular ubiquitination regulates a secreted protein's stability\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining TGFBIp's role in glioblastoma stem cell maintenance: TGFBIp activates an integrin αvβ5-Src-Stat3 signaling axis in glioblastoma stem cells, promoting self-renewal and tumor growth in orthotopic models.\",\n      \"evidence\": \"Recombinant TGFBIp treatment with pathway inhibition, orthotopic xenografts, Western blot/ELISA\",\n      \"pmids\": [\"35673564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TGFBIp is tumor- or stroma-derived in glioblastoma\", \"Whether Stat3 activation is direct or secondary to Src\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing a non-integrin receptor for TGFBIp: TGFBIp directly binds Notch-1 to activate Notch signaling in adipocytes, controlling adipsin secretion and adipocyte browning, establishing a metabolic role for this ECM protein.\",\n      \"evidence\": \"Co-immunoprecipitation of TGFBIp–Notch-1, Tgfbi KO mice on high-fat diet, adipocyte browning assays\",\n      \"pmids\": [\"36854775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between TGFBIp and Notch-1 not mapped\", \"Whether Notch activation is ligand-mimetic or modulatory\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing direct transcriptional regulation by HIF-2α: HIF-2α binds the TGFBI promoter under hypoxia to upregulate expression, and TGFBIp promotes cisplatin resistance via PI3K/Akt-dependent enhancement of DNA damage repair.\",\n      \"evidence\": \"ChIP/promoter binding assay for HIF-2α, TGFBI siRNA KD with DNA repair marker analysis in cisplatin-resistant ovarian cancer cells\",\n      \"pmids\": [\"38365849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HIF-2α regulation is conserved across tumor types\", \"Direct mechanism linking extracellular TGFBIp to nuclear DNA repair machinery\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive functional characterization, no structural model of the full-length TGFBIp–integrin complex exists, the E3 ubiquitin ligase targeting TGFBIp is unknown, the autophagy receptor for TGFBIp clearance has not been identified, and the mechanism by which an extracellular/secreted protein activates nuclear DNA repair pathways remains unexplained.\",\n      \"evidence\": \"Open questions from the literature\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length TGFBIp–integrin co-crystal structure\", \"E3 ligase for K22/K25 ubiquitination unidentified\", \"Autophagy receptor mediating TGFBIp degradation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 5, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 15, 24]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 22, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5, 9, 11, 25]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 16, 21]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 9, 12, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6, 10, 14, 26]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"POSTN\",\n      \"ITGAV\",\n      \"ITGB5\",\n      \"ITGB3\",\n      \"OTUB1\",\n      \"NOTCH1\",\n      \"DKK3\",\n      \"ITGAM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}