{"gene":"ITGBL1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1999,"finding":"ITGBL1 (TIED) encodes a secreted/extracellular protein with ten tandem EGF-like repeats homologous to the cysteine-rich stalk region of integrin β subunits, with a signal peptide and no transmembrane domain, mapping to chromosome 13q33.","method":"cDNA cloning and sequencing from fetal lung, HUVEC, and osteoblast libraries; structural domain analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — original cloning and structural characterization with full sequence analysis","pmids":["10051402"],"is_preprint":false},{"year":2015,"finding":"ITGBL1 promotes breast cancer bone metastasis by activating the TGFβ signaling pathway as a downstream effector, and is transcriptionally driven by the upstream activator RUNX2.","method":"In vivo mouse bone metastasis model, in vitro experiments, mechanistic pathway analysis (Western blot, reporter assays), RUNX2 knockdown/overexpression","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — in vivo model plus in vitro mechanistic pathway placement with multiple methods","pmids":["26060017"],"is_preprint":false},{"year":2018,"finding":"ITGBL1 is a secreted protein that physically interacts with integrins at the cell surface to down-regulate integrin activity, thereby promoting chondrogenesis; ectopic ITGBL1 expression protected cartilage against osteoarthritis in a mouse model.","method":"Protein interaction (pulldown/co-IP of ITGBL1 with integrins), loss-of-function and gain-of-function in chondrocytes, destabilization of medial meniscus mouse OA model, recombinant protein treatment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction assays, in vivo rescue model, multiple orthogonal methods","pmids":["30305454"],"is_preprint":false},{"year":2020,"finding":"Primary colorectal cancer tumors release ITGBL1-enriched extracellular vesicles (EVs) into circulation; these EVs activate resident fibroblasts in remote organs by stimulating the TNFAIP3-mediated NF-κB signaling pathway, inducing pro-inflammatory cytokines (IL-6, IL-8) to form a pre-metastatic niche.","method":"EV isolation and characterization, co-culture experiments, NF-κB pathway inhibitors/reporters, ITGBL1 knockdown/overexpression, in vivo CRC metastasis mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (TNFAIP3/NF-κB) established with multiple methods and in vivo validation","pmids":["32139701"],"is_preprint":false},{"year":2016,"finding":"ITGBL1 promotes ovarian cancer cell migration and adhesion by activating Wnt/PCP signaling and the FAK/SRC pathway.","method":"Loss- and gain-of-function assays, recombinant ITGBL1 protein treatment, Western blot for pathway activation, transwell migration assays","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — pathway activation shown by Western blot with functional readout, single lab","pmids":["27261588"],"is_preprint":false},{"year":2015,"finding":"Knockdown of ITGBL1 in NSCLC cell lines promotes cancer cell migration and invasion, while recombinant ITGBL1 protein inhibits migration/invasion; ITGBL1 loss enhances Wnt/PCP signaling activity and is associated with epigenetic silencing via miR-576-5p.","method":"siRNA knockdown, recombinant protein treatment, Wnt/PCP pathway reporter assays, transwell invasion assay","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional KD with pathway readout but limited mechanistic depth","pmids":["26307393"],"is_preprint":false},{"year":2018,"finding":"The lncRNA lncITPF, whose fibrotic function depends on its host gene ITGBL1, regulates H3 and H4 histone acetylation at the ITGBL1 promoter by targeting heterogeneous nuclear ribonucleoprotein L (hnRNP-L); TGF-β1-Smad2/3 is the upstream inducer binding to the lncITPF promoter.","method":"ChIP-qPCR, CRISPR-Cas9, RNA pulldown + LC-MS, RIP, luciferase assays, promoter activity analysis","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, RIP, pulldown-MS) in single lab","pmids":["30528088"],"is_preprint":false},{"year":2019,"finding":"ITGBL1 promotes EMT, invasion, and migration in prostate cancer cells by activating the NF-κB signaling pathway.","method":"Overexpression and knockdown in PCa cell lines, Western blot for NF-κB pathway activation, transwell invasion/migration assays, in vivo xenograft","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional KD/OE with NF-κB pathway readout","pmids":["31190876"],"is_preprint":false},{"year":2020,"finding":"ITGBL1 promotes hepatocellular carcinoma cell migration and invasion by stimulating the TGF-β/Smad signaling pathway along with KRT17 and EMT-associated genes.","method":"Overexpression and knockout of ITGBL1, Western blot (TGF-β/Smad pathway), transwell assay, xenograft and orthotopic mouse models","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — KO and OE with in vivo and in vitro pathway validation, single lab","pmids":["32537856"],"is_preprint":false},{"year":2021,"finding":"ITGBL1 is a secreted immunomodulator that inhibits NK cell cytotoxicity against melanoma cells; MITF transcriptionally represses ITGBL1 by inhibiting RUNX2, an activator of ITGBL1 transcription; VitaminD3 (a RUNX2 inhibitor) reverses ITGBL1-mediated immune escape.","method":"In vitro NK cytotoxicity assays, in vivo mouse models, MITF/RUNX2 overexpression/knockdown, ITGBL1 recombinant protein treatment, anti-PD1 combination experiments","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (MITF→RUNX2→ITGBL1) established with functional in vitro and in vivo validation","pmids":["33413419"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 preferentially inhibits integrin activity at the trailing edge of migrating cells, promoting focal adhesion disassembly at trailing edges and thereby facilitating directional cell migration; ITGBL1 depletion causes increased focal adhesions at trailing membrane traces preventing retraction.","method":"siRNA knockdown and overexpression in human chondrocytes/ATDC5 cells, wound healing assay, live imaging with membrane-GFP, immunostaining of active integrin/FAK/Vinculin","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with functional consequence, single lab","pmids":["35066808"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 promotes dermal fibroblast activity (proliferation, migration, collagen synthesis) via activation of the TGFβ1-SMAD2/3 pathway; ITGBL1 protein in small extracellular vesicles from dermal fibroblasts mediates this effect and increases skin thickness in vivo.","method":"SEV isolation, LC-MS/MS protein identification, ITGBL1 overexpression in fibroblasts, Western blot (TGFβ1-SMAD2/3 pathway), in vivo mouse skin injection model","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (proteomic identification, pathway validation, in vivo), single lab","pmids":["35733144"],"is_preprint":false},{"year":2023,"finding":"Mechanical pressure promotes myofibroblast dedifferentiation via the integrin β1/ILK pathway, which decreases TCF-4 and subsequently reduces SMYD3 expression, leading to decreased H3K4 trimethylation at the ITGBL1 promoter and suppressed ITGBL1 expression, resulting in scar reduction.","method":"Clinical specimen analysis, ChIP for H3K4me3 at ITGBL1 promoter, SMYD3 knockdown in mouse scar model, Western blot for ILK/TCF-4/SMYD3 pathway","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — ChIP-based epigenetic mechanism with in vivo validation, multiple methods","pmids":["37192621"],"is_preprint":false},{"year":2025,"finding":"RUNX2 directly binds to the ITGBL1 promoter and enhances its expression in HBV-infected hepatocytes; this RUNX2/ITGBL1 axis promotes hepatic stellate cell activation and liver fibrosis; inhibition of RUNX2 with Vitamin D3 or CADD522 reduces ITGBL1 levels and blocks stellate cell activation.","method":"ChIP, luciferase reporter assays, Western blot, RUNX2 inhibitor treatment, in vivo HBV mouse model","journal":"Virology journal","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding confirmed by ChIP and luciferase, in vivo validation","pmids":["40287769"],"is_preprint":false},{"year":2024,"finding":"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer via the AKT/Fibulin-2 (FBLN2) axis; AKT/FBLN2 signaling inhibition reverses the pro-metastatic effects of ITGBL1 overexpression.","method":"ITGBL1 overexpression/knockdown in GC cells, anoikis resistance assays, in vitro and in vivo metastasis assays, AKT inhibitor treatment, Western blot","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — pathway rescue experiment with AKT inhibitor, in vivo validation, single lab","pmids":["38332530"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 promotes pancreatic cancer progression through the TGF-β/Smad pathway; the transcription factor JDP2 directly inhibits ITGBL1 promoter activity as shown by dual-luciferase assay.","method":"Dual-luciferase reporter assay, gain/loss-of-function experiments, Western blot for TGF-β/Smad pathway","journal":"Brazilian journal of medical and biological research","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter regulation shown by luciferase, pathway validation by Western blot, single lab","pmids":["35584452"],"is_preprint":false},{"year":2021,"finding":"ITGBL1 overexpression promotes gastric cancer cell proliferation and invasion via activation of the AKT signaling pathway (increased Akt phosphorylation); silencing ITGBL1 reduces Akt phosphorylation, cell mobility, and proliferation.","method":"ITGBL1 overexpression and shRNA knockdown in GC cell lines, Western blot for p-Akt, cell mobility and proliferation assays","journal":"Frontiers in bioscience","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single pathway readout without rescue experiment","pmids":["33049688"],"is_preprint":false}],"current_model":"ITGBL1 is a secreted extracellular protein containing ten integrin β-like EGF repeats that physically interacts with integrins to inhibit their activity; it is transcriptionally activated by RUNX2 and regulated epigenetically via SMYD3-dependent H3K4me3, and signals through multiple downstream pathways—including TGFβ/Smad, NF-κB (via TNFAIP3), Wnt/PCP, and AKT—to regulate chondrogenesis, fibrosis, directional cell migration, immune evasion (NK cell suppression), and cancer metastasis, with its delivery via extracellular vesicles serving as a key mechanism for systemic pre-metastatic niche formation."},"narrative":{"teleology":[{"year":1999,"claim":"The molecular identity of ITGBL1 was established as a novel secreted protein with ten integrin β-like EGF repeats, providing the structural basis for its predicted integrin-related function.","evidence":"cDNA cloning from fetal lung, HUVEC, and osteoblast libraries with full domain analysis","pmids":["10051402"],"confidence":"High","gaps":["No functional assay performed","Binding partners and biological role unknown","Expression pattern across tissues not systematically characterized"]},{"year":2015,"claim":"ITGBL1 was placed into a cancer metastasis pathway as a RUNX2 transcriptional target that activates TGFβ signaling to promote bone metastasis, establishing its first mechanistic link to tumor progression.","evidence":"Mouse bone metastasis model with RUNX2 knockdown/overexpression and TGFβ pathway reporter assays in breast cancer cells","pmids":["26060017"],"confidence":"High","gaps":["Direct RUNX2 binding to ITGBL1 promoter not shown by ChIP at this stage","TGFβ pathway activation mechanism (direct vs. indirect) unresolved","Role of ITGBL1 in non-bone metastatic sites not tested"]},{"year":2015,"claim":"A context-dependent role for ITGBL1 emerged when knockdown in NSCLC promoted rather than inhibited migration, linking ITGBL1 to Wnt/PCP pathway modulation and raising the question of tissue-specific directionality of its effects.","evidence":"siRNA knockdown and recombinant protein treatment with Wnt/PCP reporter assays in lung cancer cell lines","pmids":["26307393"],"confidence":"Medium","gaps":["Opposite effects in lung vs. breast cancer not mechanistically explained","miR-576-5p regulation not validated in vivo","Single lab finding"]},{"year":2016,"claim":"ITGBL1 was shown to activate Wnt/PCP and FAK/SRC signaling in ovarian cancer, extending its pathway repertoire beyond TGFβ and establishing it as a multi-pathway extracellular modulator.","evidence":"Gain- and loss-of-function assays with recombinant protein treatment and Western blot pathway analysis in ovarian cancer cells","pmids":["27261588"],"confidence":"Medium","gaps":["Mechanism linking secreted ITGBL1 to intracellular Wnt/PCP activation unknown","No integrin interaction data in this system","Single lab"]},{"year":2018,"claim":"The long-predicted integrin interaction was directly demonstrated: ITGBL1 physically binds integrins and downregulates their activity, and this mechanism was shown to promote chondrogenesis and protect against osteoarthritis in vivo, establishing the first non-cancer physiological role.","evidence":"Co-immunoprecipitation/pulldown of ITGBL1 with integrins, gain/loss-of-function in chondrocytes, destabilized medial meniscus OA mouse model with recombinant protein rescue","pmids":["30305454"],"confidence":"High","gaps":["Specific integrin subunit(s) mediating the interaction not defined","Structural basis of integrin inhibition unknown","Whether integrin inhibition is the sole mechanism in cancer contexts untested"]},{"year":2018,"claim":"Epigenetic regulation of ITGBL1 transcription was revealed through a lncRNA (lncITPF)/hnRNP-L axis that controls histone acetylation at the ITGBL1 promoter downstream of TGFβ1-Smad2/3, linking ITGBL1 to fibrosis.","evidence":"ChIP-qPCR, RNA pulldown with LC-MS, RIP, and luciferase assays in fibroblasts","pmids":["30528088"],"confidence":"Medium","gaps":["lncITPF mechanism validated in one fibrotic context only","Relative contribution of lncITPF vs. RUNX2 to ITGBL1 expression unclear","No in vivo fibrosis model in this study"]},{"year":2020,"claim":"A new mode of ITGBL1 action was uncovered: tumor-derived extracellular vesicles deliver ITGBL1 to distant organs where it activates fibroblasts via TNFAIP3-mediated NF-κB signaling, establishing pre-metastatic niches for colorectal cancer.","evidence":"EV isolation and characterization, NF-κB pathway reporters/inhibitors, ITGBL1 knockdown/overexpression, in vivo CRC metastasis mouse model","pmids":["32139701"],"confidence":"High","gaps":["How ITGBL1 is selectively sorted into EVs unknown","Whether EV-delivered ITGBL1 also inhibits integrins in recipient cells untested","Specific TNFAIP3 activation mechanism by ITGBL1 not defined"]},{"year":2021,"claim":"ITGBL1 was identified as a secreted immunomodulator that suppresses NK cell cytotoxicity, with the MITF→RUNX2→ITGBL1 transcriptional axis controlling tumor immune evasion in melanoma.","evidence":"In vitro NK cytotoxicity assays, in vivo mouse melanoma models, MITF/RUNX2 knockdown/overexpression, vitamin D3 treatment","pmids":["33413419"],"confidence":"High","gaps":["Receptor on NK cells through which ITGBL1 acts not identified","Whether ITGBL1 modulates other immune cell types beyond NK cells unknown","Mechanism of NK suppression (integrin-dependent or independent) not determined"]},{"year":2022,"claim":"The subcellular mechanism of ITGBL1's integrin inhibition was refined: ITGBL1 preferentially acts at trailing edges to promote focal adhesion disassembly, explaining how it enables directional cell migration.","evidence":"Live imaging with membrane-GFP, immunostaining of active integrins/FAK/vinculin in chondrocytes after siRNA knockdown and overexpression","pmids":["35066808"],"confidence":"Medium","gaps":["Mechanism of trailing-edge specificity unknown","Whether polarized secretion or local integrin binding explains asymmetry untested","Validated only in chondrocyte/ATDC5 system"]},{"year":2023,"claim":"A second epigenetic layer was uncovered: mechanical pressure suppresses ITGBL1 through integrin β1/ILK→TCF-4→SMYD3 signaling that reduces H3K4me3 at the ITGBL1 promoter, linking mechanotransduction to ITGBL1-dependent fibrosis and scar formation.","evidence":"ChIP for H3K4me3 at ITGBL1 promoter, SMYD3 knockdown in mouse scar model, clinical specimens","pmids":["37192621"],"confidence":"High","gaps":["Relative contribution of SMYD3-H3K4me3 vs. RUNX2 to ITGBL1 transcription in fibrosis not quantified","Whether mechanical regulation operates in tumor contexts unknown"]},{"year":2025,"claim":"Direct RUNX2 binding to the ITGBL1 promoter was confirmed by ChIP, and the RUNX2/ITGBL1 axis was extended to hepatic stellate cell activation and HBV-driven liver fibrosis, unifying the transcriptional and fibrotic models.","evidence":"ChIP, luciferase reporter assays, RUNX2 inhibitor treatment (vitamin D3, CADD522), in vivo HBV mouse model","pmids":["40287769"],"confidence":"High","gaps":["Whether ITGBL1 acts through integrin inhibition or TGFβ/NF-κB in stellate cell activation unclear","RUNX2-independent transcriptional regulation not mapped genome-wide"]},{"year":null,"claim":"The receptor or binding interface on target cells through which secreted ITGBL1 activates downstream NF-κB, TGFβ, and AKT signaling — and whether these all require integrin binding — remains undefined; no structural model of the ITGBL1–integrin complex exists.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure or cryo-EM of ITGBL1 alone or in complex","Identity of specific integrin heterodimers bound by ITGBL1 not systematically tested","Physiological role during normal development beyond chondrogenesis not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,4,7,8,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,11]}],"complexes":[],"partners":["RUNX2","TNFAIP3","SMYD3","JDP2","MITF","FBLN2"],"other_free_text":[]},"mechanistic_narrative":"ITGBL1 is a secreted extracellular protein containing ten tandem integrin β-like EGF repeats that functions as a modulator of integrin signaling, extracellular matrix remodeling, and intercellular communication across developmental, fibrotic, immune, and neoplastic contexts [PMID:10051402, PMID:30305454, PMID:33413419]. ITGBL1 physically interacts with cell-surface integrins to downregulate their activity, preferentially at the trailing edge of migrating cells to promote focal adhesion disassembly and directional migration, and this integrin-inhibitory function underlies its role in chondrogenesis and cartilage protection against osteoarthritis [PMID:30305454, PMID:35066808]. Transcriptionally activated by RUNX2 and epigenetically regulated by SMYD3-dependent H3K4 trimethylation, ITGBL1 signals through TGFβ/Smad, NF-κB (via TNFAIP3), Wnt/PCP, and AKT pathways to drive fibroblast activation, fibrosis, epithelial-mesenchymal transition, and cancer metastasis, while also suppressing NK cell cytotoxicity to facilitate tumor immune evasion [PMID:26060017, PMID:32139701, PMID:37192621, PMID:33413419]. Delivery of ITGBL1 via tumor-derived extracellular vesicles activates fibroblasts in distant organs through TNFAIP3-mediated NF-κB signaling, establishing a pre-metastatic niche that promotes colorectal cancer metastasis [PMID:32139701]."},"prefetch_data":{"uniprot":{"accession":"O95965","full_name":"Integrin beta-like protein 1","aliases":["Osteoblast-specific cysteine-rich protein","Ten integrin EGF-like repeat domain-containing protein"],"length_aa":494,"mass_kda":53.9,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O95965/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGBL1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGBL1","total_profiled":1310},"omim":[{"mim_id":"604234","title":"INTEGRIN, BETA-LIKE 1; ITGBL1","url":"https://www.omim.org/entry/604234"},{"mim_id":"193003","title":"SPINOCEREBELLAR ATAXIA 27A; SCA27A","url":"https://www.omim.org/entry/193003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":156.8}],"url":"https://www.proteinatlas.org/search/ITGBL1"},"hgnc":{"alias_symbol":["TIED","OSCP"],"prev_symbol":[]},"alphafold":{"accession":"O95965","domains":[{"cath_id":"2.10.25.10","chopping":"45-128","consensus_level":"medium","plddt":83.9599,"start":45,"end":128},{"cath_id":"2.10.25.10","chopping":"135-218","consensus_level":"medium","plddt":88.4039,"start":135,"end":218}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95965","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95965-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95965-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGBL1","jax_strain_url":"https://www.jax.org/strain/search?query=ITGBL1"},"sequence":{"accession":"O95965","fasta_url":"https://rest.uniprot.org/uniprotkb/O95965.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95965/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95965"}},"corpus_meta":[{"pmid":"19573813","id":"PMC_19573813","title":"Latent 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structural domain analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning and structural characterization with full sequence analysis\",\n      \"pmids\": [\"10051402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGBL1 promotes breast cancer bone metastasis by activating the TGFβ signaling pathway as a downstream effector, and is transcriptionally driven by the upstream activator RUNX2.\",\n      \"method\": \"In vivo mouse bone metastasis model, in vitro experiments, mechanistic pathway analysis (Western blot, reporter assays), RUNX2 knockdown/overexpression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model plus in vitro mechanistic pathway placement with multiple methods\",\n      \"pmids\": [\"26060017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ITGBL1 is a secreted protein that physically interacts with integrins at the cell surface to down-regulate integrin activity, thereby promoting chondrogenesis; ectopic ITGBL1 expression protected cartilage against osteoarthritis in a mouse model.\",\n      \"method\": \"Protein interaction (pulldown/co-IP of ITGBL1 with integrins), loss-of-function and gain-of-function in chondrocytes, destabilization of medial meniscus mouse OA model, recombinant protein treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays, in vivo rescue model, multiple orthogonal methods\",\n      \"pmids\": [\"30305454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Primary colorectal cancer tumors release ITGBL1-enriched extracellular vesicles (EVs) into circulation; these EVs activate resident fibroblasts in remote organs by stimulating the TNFAIP3-mediated NF-κB signaling pathway, inducing pro-inflammatory cytokines (IL-6, IL-8) to form a pre-metastatic niche.\",\n      \"method\": \"EV isolation and characterization, co-culture experiments, NF-κB pathway inhibitors/reporters, ITGBL1 knockdown/overexpression, in vivo CRC metastasis mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (TNFAIP3/NF-κB) established with multiple methods and in vivo validation\",\n      \"pmids\": [\"32139701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ITGBL1 promotes ovarian cancer cell migration and adhesion by activating Wnt/PCP signaling and the FAK/SRC pathway.\",\n      \"method\": \"Loss- and gain-of-function assays, recombinant ITGBL1 protein treatment, Western blot for pathway activation, transwell migration assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway activation shown by Western blot with functional readout, single lab\",\n      \"pmids\": [\"27261588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of ITGBL1 in NSCLC cell lines promotes cancer cell migration and invasion, while recombinant ITGBL1 protein inhibits migration/invasion; ITGBL1 loss enhances Wnt/PCP signaling activity and is associated with epigenetic silencing via miR-576-5p.\",\n      \"method\": \"siRNA knockdown, recombinant protein treatment, Wnt/PCP pathway reporter assays, transwell invasion assay\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional KD with pathway readout but limited mechanistic depth\",\n      \"pmids\": [\"26307393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The lncRNA lncITPF, whose fibrotic function depends on its host gene ITGBL1, regulates H3 and H4 histone acetylation at the ITGBL1 promoter by targeting heterogeneous nuclear ribonucleoprotein L (hnRNP-L); TGF-β1-Smad2/3 is the upstream inducer binding to the lncITPF promoter.\",\n      \"method\": \"ChIP-qPCR, CRISPR-Cas9, RNA pulldown + LC-MS, RIP, luciferase assays, promoter activity analysis\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, RIP, pulldown-MS) in single lab\",\n      \"pmids\": [\"30528088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGBL1 promotes EMT, invasion, and migration in prostate cancer cells by activating the NF-κB signaling pathway.\",\n      \"method\": \"Overexpression and knockdown in PCa cell lines, Western blot for NF-κB pathway activation, transwell invasion/migration assays, in vivo xenograft\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional KD/OE with NF-κB pathway readout\",\n      \"pmids\": [\"31190876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGBL1 promotes hepatocellular carcinoma cell migration and invasion by stimulating the TGF-β/Smad signaling pathway along with KRT17 and EMT-associated genes.\",\n      \"method\": \"Overexpression and knockout of ITGBL1, Western blot (TGF-β/Smad pathway), transwell assay, xenograft and orthotopic mouse models\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO and OE with in vivo and in vitro pathway validation, single lab\",\n      \"pmids\": [\"32537856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGBL1 is a secreted immunomodulator that inhibits NK cell cytotoxicity against melanoma cells; MITF transcriptionally represses ITGBL1 by inhibiting RUNX2, an activator of ITGBL1 transcription; VitaminD3 (a RUNX2 inhibitor) reverses ITGBL1-mediated immune escape.\",\n      \"method\": \"In vitro NK cytotoxicity assays, in vivo mouse models, MITF/RUNX2 overexpression/knockdown, ITGBL1 recombinant protein treatment, anti-PD1 combination experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (MITF→RUNX2→ITGBL1) established with functional in vitro and in vivo validation\",\n      \"pmids\": [\"33413419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGBL1 preferentially inhibits integrin activity at the trailing edge of migrating cells, promoting focal adhesion disassembly at trailing edges and thereby facilitating directional cell migration; ITGBL1 depletion causes increased focal adhesions at trailing membrane traces preventing retraction.\",\n      \"method\": \"siRNA knockdown and overexpression in human chondrocytes/ATDC5 cells, wound healing assay, live imaging with membrane-GFP, immunostaining of active integrin/FAK/Vinculin\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with functional consequence, single lab\",\n      \"pmids\": [\"35066808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGBL1 promotes dermal fibroblast activity (proliferation, migration, collagen synthesis) via activation of the TGFβ1-SMAD2/3 pathway; ITGBL1 protein in small extracellular vesicles from dermal fibroblasts mediates this effect and increases skin thickness in vivo.\",\n      \"method\": \"SEV isolation, LC-MS/MS protein identification, ITGBL1 overexpression in fibroblasts, Western blot (TGFβ1-SMAD2/3 pathway), in vivo mouse skin injection model\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (proteomic identification, pathway validation, in vivo), single lab\",\n      \"pmids\": [\"35733144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mechanical pressure promotes myofibroblast dedifferentiation via the integrin β1/ILK pathway, which decreases TCF-4 and subsequently reduces SMYD3 expression, leading to decreased H3K4 trimethylation at the ITGBL1 promoter and suppressed ITGBL1 expression, resulting in scar reduction.\",\n      \"method\": \"Clinical specimen analysis, ChIP for H3K4me3 at ITGBL1 promoter, SMYD3 knockdown in mouse scar model, Western blot for ILK/TCF-4/SMYD3 pathway\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-based epigenetic mechanism with in vivo validation, multiple methods\",\n      \"pmids\": [\"37192621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RUNX2 directly binds to the ITGBL1 promoter and enhances its expression in HBV-infected hepatocytes; this RUNX2/ITGBL1 axis promotes hepatic stellate cell activation and liver fibrosis; inhibition of RUNX2 with Vitamin D3 or CADD522 reduces ITGBL1 levels and blocks stellate cell activation.\",\n      \"method\": \"ChIP, luciferase reporter assays, Western blot, RUNX2 inhibitor treatment, in vivo HBV mouse model\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding confirmed by ChIP and luciferase, in vivo validation\",\n      \"pmids\": [\"40287769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer via the AKT/Fibulin-2 (FBLN2) axis; AKT/FBLN2 signaling inhibition reverses the pro-metastatic effects of ITGBL1 overexpression.\",\n      \"method\": \"ITGBL1 overexpression/knockdown in GC cells, anoikis resistance assays, in vitro and in vivo metastasis assays, AKT inhibitor treatment, Western blot\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway rescue experiment with AKT inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"38332530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGBL1 promotes pancreatic cancer progression through the TGF-β/Smad pathway; the transcription factor JDP2 directly inhibits ITGBL1 promoter activity as shown by dual-luciferase assay.\",\n      \"method\": \"Dual-luciferase reporter assay, gain/loss-of-function experiments, Western blot for TGF-β/Smad pathway\",\n      \"journal\": \"Brazilian journal of medical and biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter regulation shown by luciferase, pathway validation by Western blot, single lab\",\n      \"pmids\": [\"35584452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGBL1 overexpression promotes gastric cancer cell proliferation and invasion via activation of the AKT signaling pathway (increased Akt phosphorylation); silencing ITGBL1 reduces Akt phosphorylation, cell mobility, and proliferation.\",\n      \"method\": \"ITGBL1 overexpression and shRNA knockdown in GC cell lines, Western blot for p-Akt, cell mobility and proliferation assays\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single pathway readout without rescue experiment\",\n      \"pmids\": [\"33049688\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGBL1 is a secreted extracellular protein containing ten integrin β-like EGF repeats that physically interacts with integrins to inhibit their activity; it is transcriptionally activated by RUNX2 and regulated epigenetically via SMYD3-dependent H3K4me3, and signals through multiple downstream pathways—including TGFβ/Smad, NF-κB (via TNFAIP3), Wnt/PCP, and AKT—to regulate chondrogenesis, fibrosis, directional cell migration, immune evasion (NK cell suppression), and cancer metastasis, with its delivery via extracellular vesicles serving as a key mechanism for systemic pre-metastatic niche formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGBL1 is a secreted extracellular protein containing ten tandem integrin β-like EGF repeats that functions as a modulator of integrin signaling, extracellular matrix remodeling, and intercellular communication across developmental, fibrotic, immune, and neoplastic contexts [PMID:10051402, PMID:30305454, PMID:33413419]. ITGBL1 physically interacts with cell-surface integrins to downregulate their activity, preferentially at the trailing edge of migrating cells to promote focal adhesion disassembly and directional migration, and this integrin-inhibitory function underlies its role in chondrogenesis and cartilage protection against osteoarthritis [PMID:30305454, PMID:35066808]. Transcriptionally activated by RUNX2 and epigenetically regulated by SMYD3-dependent H3K4 trimethylation, ITGBL1 signals through TGFβ/Smad, NF-κB (via TNFAIP3), Wnt/PCP, and AKT pathways to drive fibroblast activation, fibrosis, epithelial-mesenchymal transition, and cancer metastasis, while also suppressing NK cell cytotoxicity to facilitate tumor immune evasion [PMID:26060017, PMID:32139701, PMID:37192621, PMID:33413419]. Delivery of ITGBL1 via tumor-derived extracellular vesicles activates fibroblasts in distant organs through TNFAIP3-mediated NF-κB signaling, establishing a pre-metastatic niche that promotes colorectal cancer metastasis [PMID:32139701].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The molecular identity of ITGBL1 was established as a novel secreted protein with ten integrin β-like EGF repeats, providing the structural basis for its predicted integrin-related function.\",\n      \"evidence\": \"cDNA cloning from fetal lung, HUVEC, and osteoblast libraries with full domain analysis\",\n      \"pmids\": [\"10051402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assay performed\", \"Binding partners and biological role unknown\", \"Expression pattern across tissues not systematically characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"ITGBL1 was placed into a cancer metastasis pathway as a RUNX2 transcriptional target that activates TGFβ signaling to promote bone metastasis, establishing its first mechanistic link to tumor progression.\",\n      \"evidence\": \"Mouse bone metastasis model with RUNX2 knockdown/overexpression and TGFβ pathway reporter assays in breast cancer cells\",\n      \"pmids\": [\"26060017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RUNX2 binding to ITGBL1 promoter not shown by ChIP at this stage\", \"TGFβ pathway activation mechanism (direct vs. indirect) unresolved\", \"Role of ITGBL1 in non-bone metastatic sites not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A context-dependent role for ITGBL1 emerged when knockdown in NSCLC promoted rather than inhibited migration, linking ITGBL1 to Wnt/PCP pathway modulation and raising the question of tissue-specific directionality of its effects.\",\n      \"evidence\": \"siRNA knockdown and recombinant protein treatment with Wnt/PCP reporter assays in lung cancer cell lines\",\n      \"pmids\": [\"26307393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposite effects in lung vs. breast cancer not mechanistically explained\", \"miR-576-5p regulation not validated in vivo\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ITGBL1 was shown to activate Wnt/PCP and FAK/SRC signaling in ovarian cancer, extending its pathway repertoire beyond TGFβ and establishing it as a multi-pathway extracellular modulator.\",\n      \"evidence\": \"Gain- and loss-of-function assays with recombinant protein treatment and Western blot pathway analysis in ovarian cancer cells\",\n      \"pmids\": [\"27261588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking secreted ITGBL1 to intracellular Wnt/PCP activation unknown\", \"No integrin interaction data in this system\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The long-predicted integrin interaction was directly demonstrated: ITGBL1 physically binds integrins and downregulates their activity, and this mechanism was shown to promote chondrogenesis and protect against osteoarthritis in vivo, establishing the first non-cancer physiological role.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown of ITGBL1 with integrins, gain/loss-of-function in chondrocytes, destabilized medial meniscus OA mouse model with recombinant protein rescue\",\n      \"pmids\": [\"30305454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific integrin subunit(s) mediating the interaction not defined\", \"Structural basis of integrin inhibition unknown\", \"Whether integrin inhibition is the sole mechanism in cancer contexts untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epigenetic regulation of ITGBL1 transcription was revealed through a lncRNA (lncITPF)/hnRNP-L axis that controls histone acetylation at the ITGBL1 promoter downstream of TGFβ1-Smad2/3, linking ITGBL1 to fibrosis.\",\n      \"evidence\": \"ChIP-qPCR, RNA pulldown with LC-MS, RIP, and luciferase assays in fibroblasts\",\n      \"pmids\": [\"30528088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"lncITPF mechanism validated in one fibrotic context only\", \"Relative contribution of lncITPF vs. RUNX2 to ITGBL1 expression unclear\", \"No in vivo fibrosis model in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A new mode of ITGBL1 action was uncovered: tumor-derived extracellular vesicles deliver ITGBL1 to distant organs where it activates fibroblasts via TNFAIP3-mediated NF-κB signaling, establishing pre-metastatic niches for colorectal cancer.\",\n      \"evidence\": \"EV isolation and characterization, NF-κB pathway reporters/inhibitors, ITGBL1 knockdown/overexpression, in vivo CRC metastasis mouse model\",\n      \"pmids\": [\"32139701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ITGBL1 is selectively sorted into EVs unknown\", \"Whether EV-delivered ITGBL1 also inhibits integrins in recipient cells untested\", \"Specific TNFAIP3 activation mechanism by ITGBL1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ITGBL1 was identified as a secreted immunomodulator that suppresses NK cell cytotoxicity, with the MITF→RUNX2→ITGBL1 transcriptional axis controlling tumor immune evasion in melanoma.\",\n      \"evidence\": \"In vitro NK cytotoxicity assays, in vivo mouse melanoma models, MITF/RUNX2 knockdown/overexpression, vitamin D3 treatment\",\n      \"pmids\": [\"33413419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on NK cells through which ITGBL1 acts not identified\", \"Whether ITGBL1 modulates other immune cell types beyond NK cells unknown\", \"Mechanism of NK suppression (integrin-dependent or independent) not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The subcellular mechanism of ITGBL1's integrin inhibition was refined: ITGBL1 preferentially acts at trailing edges to promote focal adhesion disassembly, explaining how it enables directional cell migration.\",\n      \"evidence\": \"Live imaging with membrane-GFP, immunostaining of active integrins/FAK/vinculin in chondrocytes after siRNA knockdown and overexpression\",\n      \"pmids\": [\"35066808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of trailing-edge specificity unknown\", \"Whether polarized secretion or local integrin binding explains asymmetry untested\", \"Validated only in chondrocyte/ATDC5 system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A second epigenetic layer was uncovered: mechanical pressure suppresses ITGBL1 through integrin β1/ILK→TCF-4→SMYD3 signaling that reduces H3K4me3 at the ITGBL1 promoter, linking mechanotransduction to ITGBL1-dependent fibrosis and scar formation.\",\n      \"evidence\": \"ChIP for H3K4me3 at ITGBL1 promoter, SMYD3 knockdown in mouse scar model, clinical specimens\",\n      \"pmids\": [\"37192621\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SMYD3-H3K4me3 vs. RUNX2 to ITGBL1 transcription in fibrosis not quantified\", \"Whether mechanical regulation operates in tumor contexts unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Direct RUNX2 binding to the ITGBL1 promoter was confirmed by ChIP, and the RUNX2/ITGBL1 axis was extended to hepatic stellate cell activation and HBV-driven liver fibrosis, unifying the transcriptional and fibrotic models.\",\n      \"evidence\": \"ChIP, luciferase reporter assays, RUNX2 inhibitor treatment (vitamin D3, CADD522), in vivo HBV mouse model\",\n      \"pmids\": [\"40287769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ITGBL1 acts through integrin inhibition or TGFβ/NF-κB in stellate cell activation unclear\", \"RUNX2-independent transcriptional regulation not mapped genome-wide\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor or binding interface on target cells through which secreted ITGBL1 activates downstream NF-κB, TGFβ, and AKT signaling — and whether these all require integrin binding — remains undefined; no structural model of the ITGBL1–integrin complex exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure or cryo-EM of ITGBL1 alone or in complex\", \"Identity of specific integrin heterodimers bound by ITGBL1 not systematically tested\", \"Physiological role during normal development beyond chondrogenesis not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 4, 7, 8, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RUNX2\",\n      \"TNFAIP3\",\n      \"SMYD3\",\n      \"JDP2\",\n      \"MITF\",\n      \"FBLN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}