{"gene":"ITGBL1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1999,"finding":"ITGBL1 (TIED) was cloned and characterized as a novel secreted protein comprising a signal peptide followed by 10 tandem EGF-like repeats strikingly similar to the cysteine-rich stalk-like structure of integrin beta subunits, with the EGF-like repeats containing 8 cysteines in positions distinct from laminin/fibrillin EGF domains. ITGBL1 mRNA (2.8 kb) was detected in aorta, thymus, and osteogenic sarcoma cells, and the gene was mapped to chromosome 13q33.","method":"cDNA cloning from fetal lung, HUVEC, and osteoblast libraries; Northern blot; chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original cloning with sequence characterization and expression analysis; single lab but multiple orthogonal methods (cDNA cloning, Northern blot, chromosomal mapping)","pmids":["10051402"],"is_preprint":false},{"year":2015,"finding":"ITGBL1 promotes breast cancer bone metastasis by activating the TGF-β signaling pathway as a downstream effector, and is transcriptionally activated upstream by the transcription factor Runx2. ITGBL1 expression facilitated recruitment, residence, and growth of cancer cells in bone microenvironment and osteoclast maturation to form osteolytic lesions in vivo and in vitro. ITGBL1 was identified as an essential mediator of Runx2-induced bone metastasis.","method":"In vivo mouse bone metastasis model, in vitro functional assays, Western blotting for TGF-β pathway, loss/gain-of-function experiments","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with pathway analysis; single lab with multiple orthogonal methods","pmids":["26060017"],"is_preprint":false},{"year":2018,"finding":"ITGBL1 is a secreted protein that physically interacts with integrins extracellularly to down-regulate integrin activity, thereby promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 acts from outside the cell. Itgbl1 expression was reduced in damaged articular cartilage of OA patients, and ectopic expression of Itgbl1 protected joint cartilage against OA development in a destabilization of the medial meniscus-induced mouse OA model.","method":"Co-immunoprecipitation/physical interaction assays, loss/gain-of-function in chondrocytes, Xenopus developmental model, mouse OA model (DMM), recombinant protein treatment","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — physical interaction with integrins demonstrated, in vivo mouse model with functional rescue, multiple orthogonal methods including recombinant protein treatment and genetic models","pmids":["30305454"],"is_preprint":false},{"year":2020,"finding":"Primary colorectal cancer tumors release ITGBL1-rich extracellular vesicles (EVs) into circulation, which activate resident fibroblasts in remote organs to form pre-metastatic niches. Mechanistically, ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-κB signaling pathway in fibroblasts, causing them to secrete pro-inflammatory cytokines IL-6 and IL-8 that promote metastatic cancer growth.","method":"EV isolation and characterization, in vitro fibroblast activation assays, cytokine measurement (ELISA), NF-κB pathway analysis (Western blot), in vivo mouse metastasis models, loss/gain-of-function","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EV isolation, in vitro signaling, in vivo models), clear mechanistic pathway established (ITGBL1-EV→TNFAIP3→NF-κB→IL-6/IL-8)","pmids":["32139701"],"is_preprint":false},{"year":2015,"finding":"ITGBL1 knockdown in NSCLC cell lines promotes cancer cell migration and invasion, while recombinant ITGBL1 protein treatment inhibits cell migration and invasion. ITGBL1 acts as a tumor suppressor in NSCLC, and its downregulation is associated with enhanced Wnt/PCP signaling activity. Downregulation of ITGBL1 may result from overexpressed miR-576-5p in NSCLC tissues.","method":"siRNA knockdown, recombinant protein treatment, transwell/migration assays, Wnt/PCP signaling pathway analysis","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with recombinant protein and knockdown, pathway analysis; single lab","pmids":["26307393"],"is_preprint":false},{"year":2016,"finding":"ITGBL1, as a secreted extracellular matrix protein, promotes ovarian cancer cell migration and adhesion in a concentration-dependent manner (using recombinant protein). ITGBL1 influences the activity of Wnt/PCP signaling and affects the FAK/Src pathway in vitro.","method":"Recombinant ITGBL1 protein treatment, transwell/wound healing assays, loss/gain-of-function, Wnt/PCP and FAK/Src pathway analysis","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with recombinant protein demonstrating dose-dependent effects; pathway analysis with single lab","pmids":["27261588"],"is_preprint":false},{"year":2019,"finding":"ITGBL1 promotes EMT, migration, and invasion in prostate cancer via activation of the NF-κB signaling pathway. Upregulation of ITGBL1 enhanced invasion and migration while downregulation showed opposite effects, both in vitro and in vivo.","method":"RT-qPCR, Western blot, in vitro migration/invasion assays, NF-κB pathway analysis, in vivo xenograft models","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional gain/loss-of-function with pathway placement via Western blot; single lab","pmids":["31190876"],"is_preprint":false},{"year":2020,"finding":"ITGBL1 promotes migration and invasion in hepatocellular carcinoma (HCC) cells by stimulating the TGF-β/Smads signaling pathway, along with upregulation of KRT17 and EMT-related genes. ITGBL1 overexpression activated the TGF-β/Smads pathway, while knockout inhibited it.","method":"Western blotting, RT-PCR, transwell/wound healing assays, xenograft and orthotopic mouse models, gain/loss-of-function","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro with defined TGF-β/Smads pathway placement; single lab with multiple methods","pmids":["32537856"],"is_preprint":false},{"year":2021,"finding":"ITGBL1 inhibited NK cell cytotoxicity against melanoma cells, counteracting beneficial effects of anti-PD1 treatment both in vitro and in vivo, functioning as an immunomodulator. Mechanistically, MITF inhibits RUNX2 (an activator of ITGBL1 transcription), and loss of MITF leads to increased RUNX2 activity and upregulation of ITGBL1, promoting immune evasion. Vitamin D3 (an inhibitor of RUNX2) improved melanoma cell killing by immune cells.","method":"In vitro NK cytotoxicity assays, anti-PD1 treatment models in vivo, gain/loss-of-function of MITF/RUNX2/ITGBL1, Vitamin D3 treatment","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo immune functional assays with defined MITF→RUNX2→ITGBL1 pathway; single lab","pmids":["33413419"],"is_preprint":false},{"year":2021,"finding":"ITGBL1 promotes gastric cancer cell proliferation, mobility, and invasion via activation of Akt signaling. Upregulation of ITGBL1 increased phosphorylation of Akt, while silencing ITGBL1 decreased Akt phosphorylation, cell mobility, and proliferation.","method":"Western blot for Akt phosphorylation, gain/loss-of-function assays, cell proliferation and migration assays","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Akt phosphorylation measured with gain/loss-of-function; single lab with multiple cell lines","pmids":["33049688"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 preferentially inhibits integrin activity at the trailing edge of migrating cells, promoting focal adhesion disassembly there and thus facilitating directional cell migration. ITGBL1-depleted cells showed increased focal adhesions at trailing edges preventing retraction, while ITGBL1 overexpression promoted directional migration by facilitating trailing-edge focal adhesion disassembly. Active forms of integrin, FAK, and Vinculin were specifically detected at trailing edges upon ITGBL1 modulation.","method":"siRNA knockdown, ITGBL1 overexpression, wound healing assays, live imaging of membrane-GFP labeled cells, immunostaining for active integrin/FAK/Vinculin","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with defined spatial mechanistic outcome at trailing edge; single lab with multiple orthogonal approaches","pmids":["35066808"],"is_preprint":false},{"year":2022,"finding":"Jianpi Jiedu Recipe inhibits CRC metastasis by reducing ITGBL1 levels in CRC-derived EVs, thereby inhibiting ITGBL1-rich EV-mediated activation of cancer-associated fibroblasts through the TNFAIP3-NF-κB signaling pathway, reducing IL-6, IL-8, and α-SMA expression.","method":"EV isolation/characterization, Western blot, ELISA, real-time PCR, flow cytometry, in vivo liver metastasis mouse model, immunohistochemistry, immunofluorescence","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — confirms ITGBL1-EV→TNFAIP3→NF-κB axis from prior work; in vivo and in vitro with multiple orthogonal methods; single lab","pmids":["35381565"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 in small extracellular vesicles derived from dermal fibroblasts promotes fibroblast proliferation, migration, collagen synthesis, and skin thickness in vivo. ITGBL1 protein within SEVs activates the downstream TGF-β1-SMAD2/3 signaling pathway, and overexpression of ITGBL1 increased skin thickness and collagen I content in mouse skin in vivo.","method":"LC-MS/MS proteomic analysis of SEVs, in vitro fibroblast functional assays, Western blot for TGF-β1-SMAD2/3, in vivo mouse skin injection model, overexpression assays","journal":"Journal of nanobiotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro with defined TGF-β1/SMAD2/3 pathway activation; single lab with multiple methods","pmids":["35733144"],"is_preprint":false},{"year":2022,"finding":"ITGBL1 transcription is suppressed by the transcription factor JDP2 via direct inhibition of the ITGBL1 promoter, as shown by dual-luciferase assay. ITGBL1 activates the TGF-β/Smad pathway to promote pancreatic cancer progression, and overexpression of ITGBL1 reverses the tumor-suppressive effects of JDP2 upregulation.","method":"Dual-luciferase reporter assay, gain/loss-of-function, Western blot for TGF-β/Smad pathway, proliferation/migration/invasion assays","journal":"Brazilian journal of medical and biological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay directly shows JDP2 inhibits ITGBL1 promoter; single lab with multiple assays","pmids":["35584452"],"is_preprint":false},{"year":2023,"finding":"Mechanical pressure therapy (PT) reduces scarring by inducing dedifferentiation of myofibroblasts into fibroblasts through the integrin β1/ILK pathway, which inhibits TCF-4, leading to reduced SMYD3 expression; decreased SMYD3 reduces H3K4me3 levels at the ITGBL1 promoter, suppressing ITGBL1 expression. Blocking SMYD3 in animal models reduces scarring, mimicking PT effects. ITGBL1 thus acts as a downstream sensor/mediator of mechanical pressure signals in fibrogenesis.","method":"Clinical specimen analysis, ChIP for H3K4me3 at ITGBL1 promoter, Western blot (integrin β1/ILK/TCF-4/SMYD3/ITGBL1 axis), animal scar model with SMYD3 blockade, siRNA knockdown","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating H3K4me3 regulation of ITGBL1 promoter by SMYD3; in vivo animal model validation; multiple orthogonal methods; clear mechanistic pathway","pmids":["37192621"],"is_preprint":false},{"year":2024,"finding":"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer through the AKT/Fibulin-2 (FBLN2) axis. ITGBL1 overexpression augments anoikis resistance and metastatic potential, while knockdown suppresses both. Inhibition of AKT/FBLN2 signaling reverses the impact of ITGBL1 on anoikis resistance and metastatic capability.","method":"Gain/loss-of-function (overexpression and knockdown), anoikis resistance assays, in vitro migration/invasion assays, in vivo metastasis models, AKT/FBLN2 pathway inhibition","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro with defined AKT/FBLN2 pathway; pathway inhibition rescue experiment; single lab","pmids":["38332530"],"is_preprint":false},{"year":2025,"finding":"RUNX2 directly binds to the ITGBL1 promoter and enhances its expression, promoting hepatic stellate cell activation and liver fibrosis in HBV infection. Inhibition of RUNX2 with Vitamin D3 or CADD522 significantly reduced ITGBL1 levels and blocked hepatic stellate cell activation. This RUNX2/ITGBL1 pathway is confirmed in both in vitro hepatocyte models and in vivo HBV mouse models.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assays, Western blotting, in vitro hepatocyte models, in vivo HBV mouse model, pharmacological inhibition of RUNX2","journal":"Virology journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP and luciferase assay directly demonstrate RUNX2 binding to ITGBL1 promoter; in vivo validation with pharmacological rescue; multiple orthogonal methods","pmids":["40287769"],"is_preprint":false},{"year":2025,"finding":"RBM15, an m6A methyltransferase, promotes ITGBL1 expression by increasing ITGBL1 mRNA stability through m6A methylation. RBM15-mediated upregulation of ITGBL1 promotes colon adenocarcinoma progression, M2-type macrophage polarization, and CD8+ T cell suppression. These mechanisms were validated by MeRIP and dual-luciferase reporter assay.","method":"MeRIP (methylated RNA immunoprecipitation), dual-luciferase reporter assay, RT-qPCR, Western blot, flow cytometry, CCK-8/colony formation/transwell assays, xenograft tumor model","journal":"The Turkish journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and luciferase assay demonstrate m6A-dependent mRNA stability mechanism; single lab with multiple orthogonal methods","pmids":["39840822"],"is_preprint":false},{"year":2026,"finding":"HSP90AB1 interacts with ITGBL1 protein and facilitates its degradation through K63-linked ubiquitination (ubiquitin-proteasome pathway). Downregulation of ITGBL1 in osteosarcoma is partly attributed to abnormal HSP90AB1 upregulation. ITGBL1 activates ER stress by upregulating ROS, thereby triggering autophagy in osteosarcoma cells. Ivermectin was identified as a potent inhibitor of the HSP90AB1-ITGBL1 interaction and inhibited osteosarcoma progression in vivo.","method":"Co-immunoprecipitation (Co-IP), virtual drug screening, in vitro and in vivo functional assays, Western blot for ubiquitination and ER stress markers, ROS measurement, autophagy assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating HSP90AB1-ITGBL1 interaction and K63-ubiquitination; in vivo validation; single lab with multiple orthogonal methods","pmids":["41697125"],"is_preprint":false},{"year":2018,"finding":"lncITPF, a lncRNA whose fibrotic function depends on its host gene ITGBL1 (they do not share the same promoter and are not co-transcribed), regulates histone H3 and H4 acetylation at the ITGBL1 promoter by targeting heterogeneous nuclear ribonucleoprotein L (hnRNP-L). The upstream inducer of both lncITPF and ITGBL1 in pulmonary fibrosis is TGF-β1-Smad2/3 signaling (Smad2/3 binds to the lncITPF promoter). Note: this finding is primarily about lncITPF regulation OF ITGBL1 expression, not about ITGBL1 protein mechanism per se.","method":"RNA-protein pull-down, LC-MS, protein-RNA immunoprecipitation, ChIP-qPCR, CRISPR-Cas9, promoter activity analysis, Northern blot, RACE","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and RNA pulldown demonstrate hnRNP-L regulation of histone acetylation at ITGBL1 promoter; TGF-β1/Smad2/3 shown as upstream inducer; single lab with multiple methods","pmids":["30528088"],"is_preprint":false}],"current_model":"ITGBL1 (TIED) is a secreted extracellular protein containing 10 integrin-beta-like EGF repeats that physically interacts with integrins extracellularly to inhibit integrin-ECM binding, preferentially at the trailing edge of migrating cells to promote directional migration; it is transcriptionally activated by RUNX2, subject to epigenetic regulation via SMYD3-mediated H3K4me3, m6A-dependent mRNA stabilization by RBM15, and post-translational degradation by HSP90AB1-mediated K63-linked ubiquitination; it signals through TGF-β/Smad, NF-κB, AKT/FBLN2, and Wnt/PCP pathways to modulate cancer metastasis, fibrosis, chondrogenesis, and immune evasion, and when packaged into extracellular vesicles activates resident fibroblasts via the TNFAIP3–NF-κB axis to form pre-metastatic niches."},"narrative":{"mechanistic_narrative":"ITGBL1 (TIED) is a secreted extracellular protein built from a signal peptide and ten tandem integrin-beta-like EGF repeats that functions as an extracellular regulator of integrin activity in cell migration, tissue homeostasis, and cancer progression [PMID:10051402, PMID:30305454]. Unlike cytosolic integrin inhibitors, ITGBL1 physically engages integrins from outside the cell to down-regulate integrin-ECM binding, a mechanism that protects articular cartilage and promotes chondrogenesis [PMID:30305454], and that it deploys spatially by preferentially disassembling focal adhesions at the trailing edge of migrating cells to drive directional motility [PMID:35066808]. Its expression is governed by a multilayered regulatory network: transcriptional activation by RUNX2 (which itself is de-repressed upon loss of MITF) and suppression by JDP2 at the promoter [PMID:26060017, PMID:33413419, PMID:35584452, PMID:40287769]; epigenetic control via SMYD3-dependent H3K4me3 downstream of the integrin-beta1/ILK/TCF-4 mechanotransduction axis [PMID:37192621]; m6A-dependent mRNA stabilization by RBM15 [PMID:39840822]; and post-translational turnover through HSP90AB1-mediated K63-linked ubiquitination [PMID:41697125]. Functionally, ITGBL1 couples to multiple downstream signaling outputs depending on context — TGF-beta/Smad signaling in bone metastasis, hepatocellular and pancreatic cancer and fibrosis [PMID:26060017, PMID:32537856, PMID:35584452, PMID:30528088], NF-kappaB signaling in prostate cancer and in fibroblast activation [PMID:32139701, PMID:31190876], AKT/Fibulin-2 signaling in gastric cancer anoikis resistance and metastasis [PMID:33049688, PMID:38332530], and Wnt/PCP signaling [PMID:26307393, PMID:27261588]. When packaged into extracellular vesicles, ITGBL1 activates resident fibroblasts via a TNFAIP3-NF-kappaB axis to elicit IL-6/IL-8 secretion and establish pre-metastatic niches [PMID:32139701, PMID:35381565], while fibroblast-derived ITGBL1 vesicles drive collagen synthesis and skin fibrosis through TGF-beta1/SMAD2/3 [PMID:35733144]. ITGBL1 thus behaves context-dependently, acting as a metastasis- and fibrosis-promoting factor in most epithelial cancers and connective tissue settings yet as a Wnt/PCP-restraining tumor suppressor in NSCLC [PMID:26307393].","teleology":[{"year":1999,"claim":"Established the molecular identity of ITGBL1 as a secreted protein whose ten tandem EGF-like repeats mimic the cysteine-rich stalk of integrin beta subunits, framing the hypothesis that it acts in the integrin-ECM axis.","evidence":"cDNA cloning from fetal lung/HUVEC/osteoblast libraries with Northern blot and chromosomal mapping","pmids":["10051402"],"confidence":"Medium","gaps":["No functional or binding partner demonstrated at cloning","Tissue expression limited to aorta, thymus, osteosarcoma cells"]},{"year":2015,"claim":"Placed ITGBL1 in a defined oncogenic circuit as a RUNX2-induced effector activating TGF-beta signaling to drive breast cancer bone metastasis, while a parallel report cast it as a Wnt/PCP-restraining tumor suppressor in NSCLC — establishing context-dependent function.","evidence":"In vivo bone metastasis model with loss/gain-of-function and TGF-beta pathway analysis; siRNA/recombinant protein assays with Wnt/PCP analysis in NSCLC","pmids":["26060017","26307393"],"confidence":"Medium","gaps":["Opposite directionality across tissues not mechanistically reconciled","RUNX2-ITGBL1 promoter binding not yet demonstrated directly"]},{"year":2016,"claim":"Showed recombinant ITGBL1 promotes ovarian cancer migration/adhesion dose-dependently and modulates Wnt/PCP and FAK/Src signaling, linking the secreted protein to adhesion machinery.","evidence":"Recombinant protein treatment, transwell/wound healing, pathway analysis","pmids":["27261588"],"confidence":"Medium","gaps":["Direct integrin engagement not shown here","Single lab, no in vivo validation"]},{"year":2018,"claim":"Demonstrated the core molecular mechanism — ITGBL1 physically binds integrins extracellularly to down-regulate integrin activity, protecting cartilage and promoting chondrogenesis, distinguishing it from cytosolic integrin inhibitors.","evidence":"Co-IP physical interaction assays, chondrocyte loss/gain-of-function, Xenopus and DMM mouse OA models, recombinant protein rescue","pmids":["30305454"],"confidence":"High","gaps":["Which integrin heterodimers are bound not fully resolved","Structural basis of the interaction not determined"]},{"year":2018,"claim":"Identified an upstream epigenetic regulatory layer in which the lncRNA lncITPF (dependent on its host gene ITGBL1) recruits hnRNP-L to control histone acetylation at the ITGBL1 promoter, downstream of TGF-beta1-Smad2/3 in pulmonary fibrosis.","evidence":"RNA pull-down, LC-MS, ChIP-qPCR, CRISPR-Cas9, RACE, promoter activity assays","pmids":["30528088"],"confidence":"Medium","gaps":["Finding concerns ITGBL1 expression regulation, not protein mechanism","Direct ITGBL1 protein output in fibrosis not assayed here"]},{"year":2019,"claim":"Extended ITGBL1's oncogenic output to NF-kappaB signaling driving EMT, migration, and invasion in prostate cancer.","evidence":"RT-qPCR, Western blot, migration/invasion assays, NF-kappaB analysis, xenografts","pmids":["31190876"],"confidence":"Medium","gaps":["How secreted ITGBL1 engages NF-kappaB upstream not defined","Single lab"]},{"year":2020,"claim":"Revealed a non-cell-autonomous metastatic mechanism: tumor-released ITGBL1-rich EVs activate remote fibroblasts via TNFAIP3-NF-kappaB to secrete IL-6/IL-8 and build pre-metastatic niches.","evidence":"EV isolation, fibroblast activation assays, ELISA, NF-kappaB Western blot, in vivo metastasis models","pmids":["32139701"],"confidence":"High","gaps":["Receptor on recipient fibroblasts not identified","How ITGBL1 is sorted into EVs unknown"]},{"year":2020,"claim":"Linked ITGBL1 to TGF-beta/Smads signaling and KRT17/EMT induction in hepatocellular carcinoma migration and invasion.","evidence":"Western blot, RT-PCR, transwell assays, xenograft and orthotopic mouse models","pmids":["32537856"],"confidence":"Medium","gaps":["Mechanism connecting secreted ITGBL1 to intracellular Smads not resolved"]},{"year":2021,"claim":"Defined ITGBL1 as an immune-evasion factor: loss of MITF de-represses RUNX2, upregulating ITGBL1 to inhibit NK cytotoxicity and counter anti-PD1 therapy in melanoma.","evidence":"NK cytotoxicity assays, in vivo anti-PD1 models, MITF/RUNX2/ITGBL1 manipulation, Vitamin D3 (RUNX2 inhibitor)","pmids":["33413419"],"confidence":"Medium","gaps":["Molecular target of ITGBL1 on NK cells unknown","Direct RUNX2 promoter binding not shown in this study"]},{"year":2021,"claim":"Added AKT signaling as an output of ITGBL1 driving gastric cancer proliferation and motility.","evidence":"Western blot for Akt phosphorylation, gain/loss-of-function, proliferation/migration assays","pmids":["33049688"],"confidence":"Medium","gaps":["Upstream coupling of secreted ITGBL1 to AKT not defined"]},{"year":2022,"claim":"Resolved the spatial logic of ITGBL1 in migration — it preferentially inhibits integrin and disassembles focal adhesions at the trailing edge to enable directional motility.","evidence":"siRNA/overexpression, wound healing, live imaging of membrane-GFP cells, active integrin/FAK/Vinculin immunostaining","pmids":["35066808"],"confidence":"Medium","gaps":["What spatially restricts ITGBL1 action to the trailing edge is unknown","Single lab"]},{"year":2022,"claim":"Mapped additional regulatory and effector arms: JDP2 directly represses the ITGBL1 promoter in pancreatic cancer; fibroblast-derived ITGBL1 EVs drive skin fibrosis via TGF-beta1/SMAD2/3; and a TCM recipe blunts CRC metastasis by lowering EV ITGBL1 and the TNFAIP3-NF-kappaB axis.","evidence":"Dual-luciferase promoter assays, LC-MS/MS EV proteomics, in vivo skin and liver metastasis models, Western blot/ELISA","pmids":["35584452","35733144","35381565"],"confidence":"Medium","gaps":["Whether TGF-beta/Smad activation is direct or secondary to integrin modulation unresolved"]},{"year":2024,"claim":"Identified the AKT/Fibulin-2 axis as the mechanism by which ITGBL1 confers anoikis resistance and metastatic capacity in gastric cancer.","evidence":"Gain/loss-of-function, anoikis assays, in vivo metastasis models, AKT/FBLN2 pathway inhibition rescue","pmids":["38332530"],"confidence":"Medium","gaps":["How ITGBL1 engages AKT/FBLN2 at the molecular level unclear"]},{"year":2025,"claim":"Established direct transcriptional and post-transcriptional control: RUNX2 directly binds the ITGBL1 promoter to drive hepatic stellate cell activation/liver fibrosis, and RBM15 stabilizes ITGBL1 mRNA via m6A to promote colon cancer immune suppression.","evidence":"ChIP and luciferase reporter assays (RUNX2), MeRIP and dual-luciferase (RBM15), in vivo HBV and xenograft models, pharmacological RUNX2 inhibition","pmids":["40287769","39840822"],"confidence":"High","gaps":["Reader proteins downstream of m6A marks not identified","Integration of the two regulatory layers not tested"]},{"year":2026,"claim":"Defined post-translational turnover and a cell-intrinsic stress role: HSP90AB1 binds ITGBL1 and targets it for K63-linked ubiquitin-proteasome degradation, while ITGBL1 itself triggers ROS-driven ER stress and autophagy in osteosarcoma.","evidence":"Co-IP, virtual drug screening (Ivermectin), ubiquitination/ER-stress Western blot, ROS and autophagy assays, in vivo osteosarcoma model","pmids":["41697125"],"confidence":"Medium","gaps":["Single Co-IP for HSP90AB1 interaction without reciprocal structural validation","Link between ER stress/autophagy and integrin function unexplored"]},{"year":null,"claim":"The identity of the specific integrin heterodimer(s) and any co-receptor through which secreted or EV-borne ITGBL1 transduces the diverse TGF-beta/Smad, NF-kappaB, AKT, and Wnt/PCP outputs remains unresolved, as does the structural basis for its integrin antagonism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ITGBL1-integrin complex","Receptor on recipient fibroblasts/immune cells unknown","Mechanism reconciling tumor-suppressor vs metastasis-promoting roles undefined"]}],"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":[0,2,5]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,12]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6,7,9,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,6,7,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,17]}],"complexes":[],"partners":["ITGB1","HSP90AB1"],"other_free_text":[]}},"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 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Global","url":"https://pubmed.ncbi.nlm.nih.gov/40677615","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41864,"output_tokens":5824,"usd":0.106476,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14432,"output_tokens":5147,"usd":0.100418,"stage2_stop_reason":"end_turn"},"total_usd":0.206894,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"ITGBL1 (TIED) was cloned and characterized as a novel secreted protein comprising a signal peptide followed by 10 tandem EGF-like repeats strikingly similar to the cysteine-rich stalk-like structure of integrin beta subunits, with the EGF-like repeats containing 8 cysteines in positions distinct from laminin/fibrillin EGF domains. ITGBL1 mRNA (2.8 kb) was detected in aorta, thymus, and osteogenic sarcoma cells, and the gene was mapped to chromosome 13q33.\",\n      \"method\": \"cDNA cloning from fetal lung, HUVEC, and osteoblast libraries; Northern blot; chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original cloning with sequence characterization and expression analysis; single lab but multiple orthogonal methods (cDNA cloning, Northern blot, chromosomal mapping)\",\n      \"pmids\": [\"10051402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGBL1 promotes breast cancer bone metastasis by activating the TGF-β signaling pathway as a downstream effector, and is transcriptionally activated upstream by the transcription factor Runx2. ITGBL1 expression facilitated recruitment, residence, and growth of cancer cells in bone microenvironment and osteoclast maturation to form osteolytic lesions in vivo and in vitro. ITGBL1 was identified as an essential mediator of Runx2-induced bone metastasis.\",\n      \"method\": \"In vivo mouse bone metastasis model, in vitro functional assays, Western blotting for TGF-β pathway, loss/gain-of-function experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with pathway analysis; single lab with multiple orthogonal 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 extracellularly to down-regulate integrin activity, thereby promoting chondrogenesis. Unlike cytosolic integrin inhibitors, ITGBL1 acts from outside the cell. Itgbl1 expression was reduced in damaged articular cartilage of OA patients, and ectopic expression of Itgbl1 protected joint cartilage against OA development in a destabilization of the medial meniscus-induced mouse OA model.\",\n      \"method\": \"Co-immunoprecipitation/physical interaction assays, loss/gain-of-function in chondrocytes, Xenopus developmental model, mouse OA model (DMM), recombinant protein treatment\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — physical interaction with integrins demonstrated, in vivo mouse model with functional rescue, multiple orthogonal methods including recombinant protein treatment and genetic models\",\n      \"pmids\": [\"30305454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Primary colorectal cancer tumors release ITGBL1-rich extracellular vesicles (EVs) into circulation, which activate resident fibroblasts in remote organs to form pre-metastatic niches. Mechanistically, ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-κB signaling pathway in fibroblasts, causing them to secrete pro-inflammatory cytokines IL-6 and IL-8 that promote metastatic cancer growth.\",\n      \"method\": \"EV isolation and characterization, in vitro fibroblast activation assays, cytokine measurement (ELISA), NF-κB pathway analysis (Western blot), in vivo mouse metastasis models, loss/gain-of-function\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EV isolation, in vitro signaling, in vivo models), clear mechanistic pathway established (ITGBL1-EV→TNFAIP3→NF-κB→IL-6/IL-8)\",\n      \"pmids\": [\"32139701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGBL1 knockdown in NSCLC cell lines promotes cancer cell migration and invasion, while recombinant ITGBL1 protein treatment inhibits cell migration and invasion. ITGBL1 acts as a tumor suppressor in NSCLC, and its downregulation is associated with enhanced Wnt/PCP signaling activity. Downregulation of ITGBL1 may result from overexpressed miR-576-5p in NSCLC tissues.\",\n      \"method\": \"siRNA knockdown, recombinant protein treatment, transwell/migration assays, Wnt/PCP signaling pathway analysis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with recombinant protein and knockdown, pathway analysis; single lab\",\n      \"pmids\": [\"26307393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ITGBL1, as a secreted extracellular matrix protein, promotes ovarian cancer cell migration and adhesion in a concentration-dependent manner (using recombinant protein). ITGBL1 influences the activity of Wnt/PCP signaling and affects the FAK/Src pathway in vitro.\",\n      \"method\": \"Recombinant ITGBL1 protein treatment, transwell/wound healing assays, loss/gain-of-function, Wnt/PCP and FAK/Src pathway analysis\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with recombinant protein demonstrating dose-dependent effects; pathway analysis with single lab\",\n      \"pmids\": [\"27261588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGBL1 promotes EMT, migration, and invasion in prostate cancer via activation of the NF-κB signaling pathway. Upregulation of ITGBL1 enhanced invasion and migration while downregulation showed opposite effects, both in vitro and in vivo.\",\n      \"method\": \"RT-qPCR, Western blot, in vitro migration/invasion assays, NF-κB pathway analysis, in vivo xenograft models\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional gain/loss-of-function with pathway placement via Western blot; single lab\",\n      \"pmids\": [\"31190876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGBL1 promotes migration and invasion in hepatocellular carcinoma (HCC) cells by stimulating the TGF-β/Smads signaling pathway, along with upregulation of KRT17 and EMT-related genes. ITGBL1 overexpression activated the TGF-β/Smads pathway, while knockout inhibited it.\",\n      \"method\": \"Western blotting, RT-PCR, transwell/wound healing assays, xenograft and orthotopic mouse models, gain/loss-of-function\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro with defined TGF-β/Smads pathway placement; single lab with multiple methods\",\n      \"pmids\": [\"32537856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGBL1 inhibited NK cell cytotoxicity against melanoma cells, counteracting beneficial effects of anti-PD1 treatment both in vitro and in vivo, functioning as an immunomodulator. Mechanistically, MITF inhibits RUNX2 (an activator of ITGBL1 transcription), and loss of MITF leads to increased RUNX2 activity and upregulation of ITGBL1, promoting immune evasion. Vitamin D3 (an inhibitor of RUNX2) improved melanoma cell killing by immune cells.\",\n      \"method\": \"In vitro NK cytotoxicity assays, anti-PD1 treatment models in vivo, gain/loss-of-function of MITF/RUNX2/ITGBL1, Vitamin D3 treatment\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo immune functional assays with defined MITF→RUNX2→ITGBL1 pathway; single lab\",\n      \"pmids\": [\"33413419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGBL1 promotes gastric cancer cell proliferation, mobility, and invasion via activation of Akt signaling. Upregulation of ITGBL1 increased phosphorylation of Akt, while silencing ITGBL1 decreased Akt phosphorylation, cell mobility, and proliferation.\",\n      \"method\": \"Western blot for Akt phosphorylation, gain/loss-of-function assays, cell proliferation and migration assays\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Akt phosphorylation measured with gain/loss-of-function; single lab with multiple cell lines\",\n      \"pmids\": [\"33049688\"],\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 there and thus facilitating directional cell migration. ITGBL1-depleted cells showed increased focal adhesions at trailing edges preventing retraction, while ITGBL1 overexpression promoted directional migration by facilitating trailing-edge focal adhesion disassembly. Active forms of integrin, FAK, and Vinculin were specifically detected at trailing edges upon ITGBL1 modulation.\",\n      \"method\": \"siRNA knockdown, ITGBL1 overexpression, wound healing assays, live imaging of membrane-GFP labeled cells, immunostaining for active integrin/FAK/Vinculin\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with defined spatial mechanistic outcome at trailing edge; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"35066808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Jianpi Jiedu Recipe inhibits CRC metastasis by reducing ITGBL1 levels in CRC-derived EVs, thereby inhibiting ITGBL1-rich EV-mediated activation of cancer-associated fibroblasts through the TNFAIP3-NF-κB signaling pathway, reducing IL-6, IL-8, and α-SMA expression.\",\n      \"method\": \"EV isolation/characterization, Western blot, ELISA, real-time PCR, flow cytometry, in vivo liver metastasis mouse model, immunohistochemistry, immunofluorescence\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — confirms ITGBL1-EV→TNFAIP3→NF-κB axis from prior work; in vivo and in vitro with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"35381565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGBL1 in small extracellular vesicles derived from dermal fibroblasts promotes fibroblast proliferation, migration, collagen synthesis, and skin thickness in vivo. ITGBL1 protein within SEVs activates the downstream TGF-β1-SMAD2/3 signaling pathway, and overexpression of ITGBL1 increased skin thickness and collagen I content in mouse skin in vivo.\",\n      \"method\": \"LC-MS/MS proteomic analysis of SEVs, in vitro fibroblast functional assays, Western blot for TGF-β1-SMAD2/3, in vivo mouse skin injection model, overexpression assays\",\n      \"journal\": \"Journal of nanobiotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro with defined TGF-β1/SMAD2/3 pathway activation; single lab with multiple methods\",\n      \"pmids\": [\"35733144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGBL1 transcription is suppressed by the transcription factor JDP2 via direct inhibition of the ITGBL1 promoter, as shown by dual-luciferase assay. ITGBL1 activates the TGF-β/Smad pathway to promote pancreatic cancer progression, and overexpression of ITGBL1 reverses the tumor-suppressive effects of JDP2 upregulation.\",\n      \"method\": \"Dual-luciferase reporter assay, gain/loss-of-function, Western blot for TGF-β/Smad pathway, proliferation/migration/invasion assays\",\n      \"journal\": \"Brazilian journal of medical and biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay directly shows JDP2 inhibits ITGBL1 promoter; single lab with multiple assays\",\n      \"pmids\": [\"35584452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mechanical pressure therapy (PT) reduces scarring by inducing dedifferentiation of myofibroblasts into fibroblasts through the integrin β1/ILK pathway, which inhibits TCF-4, leading to reduced SMYD3 expression; decreased SMYD3 reduces H3K4me3 levels at the ITGBL1 promoter, suppressing ITGBL1 expression. Blocking SMYD3 in animal models reduces scarring, mimicking PT effects. ITGBL1 thus acts as a downstream sensor/mediator of mechanical pressure signals in fibrogenesis.\",\n      \"method\": \"Clinical specimen analysis, ChIP for H3K4me3 at ITGBL1 promoter, Western blot (integrin β1/ILK/TCF-4/SMYD3/ITGBL1 axis), animal scar model with SMYD3 blockade, siRNA knockdown\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating H3K4me3 regulation of ITGBL1 promoter by SMYD3; in vivo animal model validation; multiple orthogonal methods; clear mechanistic pathway\",\n      \"pmids\": [\"37192621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGBL1 promotes anoikis resistance and metastasis in gastric cancer through the AKT/Fibulin-2 (FBLN2) axis. ITGBL1 overexpression augments anoikis resistance and metastatic potential, while knockdown suppresses both. Inhibition of AKT/FBLN2 signaling reverses the impact of ITGBL1 on anoikis resistance and metastatic capability.\",\n      \"method\": \"Gain/loss-of-function (overexpression and knockdown), anoikis resistance assays, in vitro migration/invasion assays, in vivo metastasis models, AKT/FBLN2 pathway inhibition\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro with defined AKT/FBLN2 pathway; pathway inhibition rescue experiment; single lab\",\n      \"pmids\": [\"38332530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RUNX2 directly binds to the ITGBL1 promoter and enhances its expression, promoting hepatic stellate cell activation and liver fibrosis in HBV infection. Inhibition of RUNX2 with Vitamin D3 or CADD522 significantly reduced ITGBL1 levels and blocked hepatic stellate cell activation. This RUNX2/ITGBL1 pathway is confirmed in both in vitro hepatocyte models and in vivo HBV mouse models.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assays, Western blotting, in vitro hepatocyte models, in vivo HBV mouse model, pharmacological inhibition of RUNX2\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP and luciferase assay directly demonstrate RUNX2 binding to ITGBL1 promoter; in vivo validation with pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"40287769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15, an m6A methyltransferase, promotes ITGBL1 expression by increasing ITGBL1 mRNA stability through m6A methylation. RBM15-mediated upregulation of ITGBL1 promotes colon adenocarcinoma progression, M2-type macrophage polarization, and CD8+ T cell suppression. These mechanisms were validated by MeRIP and dual-luciferase reporter assay.\",\n      \"method\": \"MeRIP (methylated RNA immunoprecipitation), dual-luciferase reporter assay, RT-qPCR, Western blot, flow cytometry, CCK-8/colony formation/transwell assays, xenograft tumor model\",\n      \"journal\": \"The Turkish journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and luciferase assay demonstrate m6A-dependent mRNA stability mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39840822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HSP90AB1 interacts with ITGBL1 protein and facilitates its degradation through K63-linked ubiquitination (ubiquitin-proteasome pathway). Downregulation of ITGBL1 in osteosarcoma is partly attributed to abnormal HSP90AB1 upregulation. ITGBL1 activates ER stress by upregulating ROS, thereby triggering autophagy in osteosarcoma cells. Ivermectin was identified as a potent inhibitor of the HSP90AB1-ITGBL1 interaction and inhibited osteosarcoma progression in vivo.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), virtual drug screening, in vitro and in vivo functional assays, Western blot for ubiquitination and ER stress markers, ROS measurement, autophagy assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating HSP90AB1-ITGBL1 interaction and K63-ubiquitination; in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41697125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"lncITPF, a lncRNA whose fibrotic function depends on its host gene ITGBL1 (they do not share the same promoter and are not co-transcribed), regulates histone H3 and H4 acetylation at the ITGBL1 promoter by targeting heterogeneous nuclear ribonucleoprotein L (hnRNP-L). The upstream inducer of both lncITPF and ITGBL1 in pulmonary fibrosis is TGF-β1-Smad2/3 signaling (Smad2/3 binds to the lncITPF promoter). Note: this finding is primarily about lncITPF regulation OF ITGBL1 expression, not about ITGBL1 protein mechanism per se.\",\n      \"method\": \"RNA-protein pull-down, LC-MS, protein-RNA immunoprecipitation, ChIP-qPCR, CRISPR-Cas9, promoter activity analysis, Northern blot, RACE\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and RNA pulldown demonstrate hnRNP-L regulation of histone acetylation at ITGBL1 promoter; TGF-β1/Smad2/3 shown as upstream inducer; single lab with multiple methods\",\n      \"pmids\": [\"30528088\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGBL1 (TIED) is a secreted extracellular protein containing 10 integrin-beta-like EGF repeats that physically interacts with integrins extracellularly to inhibit integrin-ECM binding, preferentially at the trailing edge of migrating cells to promote directional migration; it is transcriptionally activated by RUNX2, subject to epigenetic regulation via SMYD3-mediated H3K4me3, m6A-dependent mRNA stabilization by RBM15, and post-translational degradation by HSP90AB1-mediated K63-linked ubiquitination; it signals through TGF-β/Smad, NF-κB, AKT/FBLN2, and Wnt/PCP pathways to modulate cancer metastasis, fibrosis, chondrogenesis, and immune evasion, and when packaged into extracellular vesicles activates resident fibroblasts via the TNFAIP3–NF-κB axis to form pre-metastatic niches.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGBL1 (TIED) is a secreted extracellular protein built from a signal peptide and ten tandem integrin-beta-like EGF repeats that functions as an extracellular regulator of integrin activity in cell migration, tissue homeostasis, and cancer progression [#0, #2]. Unlike cytosolic integrin inhibitors, ITGBL1 physically engages integrins from outside the cell to down-regulate integrin-ECM binding, a mechanism that protects articular cartilage and promotes chondrogenesis [#2], and that it deploys spatially by preferentially disassembling focal adhesions at the trailing edge of migrating cells to drive directional motility [#10]. Its expression is governed by a multilayered regulatory network: transcriptional activation by RUNX2 (which itself is de-repressed upon loss of MITF) and suppression by JDP2 at the promoter [#1, #8, #13, #16]; epigenetic control via SMYD3-dependent H3K4me3 downstream of the integrin-beta1/ILK/TCF-4 mechanotransduction axis [#14]; m6A-dependent mRNA stabilization by RBM15 [#17]; and post-translational turnover through HSP90AB1-mediated K63-linked ubiquitination [#18]. Functionally, ITGBL1 couples to multiple downstream signaling outputs depending on context — TGF-beta/Smad signaling in bone metastasis, hepatocellular and pancreatic cancer and fibrosis [#1, #7, #13, #19], NF-kappaB signaling in prostate cancer and in fibroblast activation [#3, #6], AKT/Fibulin-2 signaling in gastric cancer anoikis resistance and metastasis [#9, #15], and Wnt/PCP signaling [#4, #5]. When packaged into extracellular vesicles, ITGBL1 activates resident fibroblasts via a TNFAIP3-NF-kappaB axis to elicit IL-6/IL-8 secretion and establish pre-metastatic niches [#3, #11], while fibroblast-derived ITGBL1 vesicles drive collagen synthesis and skin fibrosis through TGF-beta1/SMAD2/3 [#12]. ITGBL1 thus behaves context-dependently, acting as a metastasis- and fibrosis-promoting factor in most epithelial cancers and connective tissue settings yet as a Wnt/PCP-restraining tumor suppressor in NSCLC [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the molecular identity of ITGBL1 as a secreted protein whose ten tandem EGF-like repeats mimic the cysteine-rich stalk of integrin beta subunits, framing the hypothesis that it acts in the integrin-ECM axis.\",\n      \"evidence\": \"cDNA cloning from fetal lung/HUVEC/osteoblast libraries with Northern blot and chromosomal mapping\",\n      \"pmids\": [\"10051402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or binding partner demonstrated at cloning\", \"Tissue expression limited to aorta, thymus, osteosarcoma cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed ITGBL1 in a defined oncogenic circuit as a RUNX2-induced effector activating TGF-beta signaling to drive breast cancer bone metastasis, while a parallel report cast it as a Wnt/PCP-restraining tumor suppressor in NSCLC — establishing context-dependent function.\",\n      \"evidence\": \"In vivo bone metastasis model with loss/gain-of-function and TGF-beta pathway analysis; siRNA/recombinant protein assays with Wnt/PCP analysis in NSCLC\",\n      \"pmids\": [\"26060017\", \"26307393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposite directionality across tissues not mechanistically reconciled\", \"RUNX2-ITGBL1 promoter binding not yet demonstrated directly\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed recombinant ITGBL1 promotes ovarian cancer migration/adhesion dose-dependently and modulates Wnt/PCP and FAK/Src signaling, linking the secreted protein to adhesion machinery.\",\n      \"evidence\": \"Recombinant protein treatment, transwell/wound healing, pathway analysis\",\n      \"pmids\": [\"27261588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integrin engagement not shown here\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated the core molecular mechanism — ITGBL1 physically binds integrins extracellularly to down-regulate integrin activity, protecting cartilage and promoting chondrogenesis, distinguishing it from cytosolic integrin inhibitors.\",\n      \"evidence\": \"Co-IP physical interaction assays, chondrocyte loss/gain-of-function, Xenopus and DMM mouse OA models, recombinant protein rescue\",\n      \"pmids\": [\"30305454\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which integrin heterodimers are bound not fully resolved\", \"Structural basis of the interaction not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified an upstream epigenetic regulatory layer in which the lncRNA lncITPF (dependent on its host gene ITGBL1) recruits hnRNP-L to control histone acetylation at the ITGBL1 promoter, downstream of TGF-beta1-Smad2/3 in pulmonary fibrosis.\",\n      \"evidence\": \"RNA pull-down, LC-MS, ChIP-qPCR, CRISPR-Cas9, RACE, promoter activity assays\",\n      \"pmids\": [\"30528088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Finding concerns ITGBL1 expression regulation, not protein mechanism\", \"Direct ITGBL1 protein output in fibrosis not assayed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended ITGBL1's oncogenic output to NF-kappaB signaling driving EMT, migration, and invasion in prostate cancer.\",\n      \"evidence\": \"RT-qPCR, Western blot, migration/invasion assays, NF-kappaB analysis, xenografts\",\n      \"pmids\": [\"31190876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How secreted ITGBL1 engages NF-kappaB upstream not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-cell-autonomous metastatic mechanism: tumor-released ITGBL1-rich EVs activate remote fibroblasts via TNFAIP3-NF-kappaB to secrete IL-6/IL-8 and build pre-metastatic niches.\",\n      \"evidence\": \"EV isolation, fibroblast activation assays, ELISA, NF-kappaB Western blot, in vivo metastasis models\",\n      \"pmids\": [\"32139701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on recipient fibroblasts not identified\", \"How ITGBL1 is sorted into EVs unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked ITGBL1 to TGF-beta/Smads signaling and KRT17/EMT induction in hepatocellular carcinoma migration and invasion.\",\n      \"evidence\": \"Western blot, RT-PCR, transwell assays, xenograft and orthotopic mouse models\",\n      \"pmids\": [\"32537856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting secreted ITGBL1 to intracellular Smads not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ITGBL1 as an immune-evasion factor: loss of MITF de-represses RUNX2, upregulating ITGBL1 to inhibit NK cytotoxicity and counter anti-PD1 therapy in melanoma.\",\n      \"evidence\": \"NK cytotoxicity assays, in vivo anti-PD1 models, MITF/RUNX2/ITGBL1 manipulation, Vitamin D3 (RUNX2 inhibitor)\",\n      \"pmids\": [\"33413419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of ITGBL1 on NK cells unknown\", \"Direct RUNX2 promoter binding not shown in this study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Added AKT signaling as an output of ITGBL1 driving gastric cancer proliferation and motility.\",\n      \"evidence\": \"Western blot for Akt phosphorylation, gain/loss-of-function, proliferation/migration assays\",\n      \"pmids\": [\"33049688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream coupling of secreted ITGBL1 to AKT not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the spatial logic of ITGBL1 in migration — it preferentially inhibits integrin and disassembles focal adhesions at the trailing edge to enable directional motility.\",\n      \"evidence\": \"siRNA/overexpression, wound healing, live imaging of membrane-GFP cells, active integrin/FAK/Vinculin immunostaining\",\n      \"pmids\": [\"35066808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What spatially restricts ITGBL1 action to the trailing edge is unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped additional regulatory and effector arms: JDP2 directly represses the ITGBL1 promoter in pancreatic cancer; fibroblast-derived ITGBL1 EVs drive skin fibrosis via TGF-beta1/SMAD2/3; and a TCM recipe blunts CRC metastasis by lowering EV ITGBL1 and the TNFAIP3-NF-kappaB axis.\",\n      \"evidence\": \"Dual-luciferase promoter assays, LC-MS/MS EV proteomics, in vivo skin and liver metastasis models, Western blot/ELISA\",\n      \"pmids\": [\"35584452\", \"35733144\", \"35381565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TGF-beta/Smad activation is direct or secondary to integrin modulation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the AKT/Fibulin-2 axis as the mechanism by which ITGBL1 confers anoikis resistance and metastatic capacity in gastric cancer.\",\n      \"evidence\": \"Gain/loss-of-function, anoikis assays, in vivo metastasis models, AKT/FBLN2 pathway inhibition rescue\",\n      \"pmids\": [\"38332530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ITGBL1 engages AKT/FBLN2 at the molecular level unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established direct transcriptional and post-transcriptional control: RUNX2 directly binds the ITGBL1 promoter to drive hepatic stellate cell activation/liver fibrosis, and RBM15 stabilizes ITGBL1 mRNA via m6A to promote colon cancer immune suppression.\",\n      \"evidence\": \"ChIP and luciferase reporter assays (RUNX2), MeRIP and dual-luciferase (RBM15), in vivo HBV and xenograft models, pharmacological RUNX2 inhibition\",\n      \"pmids\": [\"40287769\", \"39840822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reader proteins downstream of m6A marks not identified\", \"Integration of the two regulatory layers not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined post-translational turnover and a cell-intrinsic stress role: HSP90AB1 binds ITGBL1 and targets it for K63-linked ubiquitin-proteasome degradation, while ITGBL1 itself triggers ROS-driven ER stress and autophagy in osteosarcoma.\",\n      \"evidence\": \"Co-IP, virtual drug screening (Ivermectin), ubiquitination/ER-stress Western blot, ROS and autophagy assays, in vivo osteosarcoma model\",\n      \"pmids\": [\"41697125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for HSP90AB1 interaction without reciprocal structural validation\", \"Link between ER stress/autophagy and integrin function unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the specific integrin heterodimer(s) and any co-receptor through which secreted or EV-borne ITGBL1 transduces the diverse TGF-beta/Smad, NF-kappaB, AKT, and Wnt/PCP outputs remains unresolved, as does the structural basis for its integrin antagonism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the ITGBL1-integrin complex\", \"Receptor on recipient fibroblasts/immune cells unknown\", \"Mechanism reconciling tumor-suppressor vs metastasis-promoting roles undefined\"]\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, 5]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6, 7, 9, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 6, 7, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGB1\", \"HSP90AB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}