{"gene":"ITGB8","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2017,"finding":"ITGB8 activates VAV-RAC1 signaling via FAK in endometrial epithelial cells: ITGB8 knockdown reduced phosphorylated-FAK, phosphorylated-VAV, and GTP-bound RAC1, and FAK inhibition also blocked VAV/RAC1 activation, establishing a functional ITGB8→FAK→VAV→RAC1 signaling axis required for blastocyst attachment.","method":"siRNA knockdown of ITGB8 in endometrial epithelial cells and uterus, FAK inhibition, measurement of phospho-FAK (Y397), phospho-VAV, RAC1-GTP pull-down, JAr spheroid attachment assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss-of-function (ITGB8 KD and FAK inhibition) with multiple downstream readouts in a single lab; no independent replication","pmids":["28507287"],"is_preprint":false},{"year":2015,"finding":"ITGB8 regulates activation of latent TGF-β1 in the uterus: bioneutralization or mRNA silencing of Itgb8 at the preimplantation stage reduced active TGF-β1 release and downstream SMAD2/3 phosphorylation, linking ITGB8 to TGF-β1 activation during embryo implantation.","method":"Antibody-mediated bioneutralization of ITGB8, siRNA silencing in mouse uterus, measurement of active TGF-β1 and phospho-SMAD2/3, embryo implantation rate assessment","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal inhibition approaches (antibody and siRNA) with downstream signaling and functional readout, single lab","pmids":["25788663"],"is_preprint":false},{"year":2015,"finding":"ITGB8 overexpression is associated with gefitinib resistance in hepatic cancer cells, and ITGB8 silencing reverses resistance by reducing ABCB1, ABCC2, ABCG2, survivin, Bcl-2, and CDK1; the TGF-β pathway was implicated as a critical mediator of ITGB8-dependent drug resistance.","method":"siRNA knockdown of ITGB8 in HepG2/G cells, cell proliferation and apoptosis assays, Western blot for multidrug-resistance proteins and TGF-β pathway components","journal":"International journal of clinical and experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, mechanistic pathway placement largely inferential from protein expression changes","pmids":["25932283"],"is_preprint":false},{"year":2018,"finding":"miR-199a-3p directly targets the 3'-UTR of ITGB8 and suppresses its expression; overexpression of ITGB8 rescued cisplatin resistance that was inhibited by miR-199a-3p, placing ITGB8 downstream of miR-199a-3p in control of cisplatin sensitivity in ovarian cancer cells.","method":"Luciferase reporter assay (3'-UTR binding), Western blot, miR-199a-3p overexpression/inhibition, ITGB8 rescue overexpression, cell proliferation, invasion, apoptosis, and in vivo orthotopic mouse model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR luciferase validation plus rescue experiment with multiple cellular readouts and in vivo confirmation, single lab","pmids":["29436681"],"is_preprint":false},{"year":2020,"finding":"ITGB8 acts downstream of the lncRNA PVT1/miR-145-5p axis to activate the MEK/ERK signaling pathway in NSCLC; PVT1 knockdown suppressed ITGB8 expression and reduced MEK/ERK phosphorylation, while ITGB8 overexpression rescued these effects.","method":"siRNA/shRNA knockdown of PVT1, luciferase reporter assay for miR-145-5p binding, Western blot for p-MEK and p-ERK, ITGB8 rescue overexpression, xenograft tumor model","journal":"Neoplasma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; pathway placement relies on expression changes and rescue, without direct demonstration of ITGB8-mediated MEK/ERK activation","pmids":["32202906"],"is_preprint":false},{"year":2021,"finding":"In goat endometrial epithelial cells, ITGB8 is a direct target of miR-187 (validated by 3'-UTR luciferase assay); inhibition of miR-187 upregulated ITGB8 and reduced FAK activity and cell proliferation, and both ITGB8 and miR-187 are regulated by interferon tau (IFNT), placing ITGB8 downstream of IFNT signaling during conceptus attachment.","method":"qRT-PCR, Western blot, dual-luciferase reporter assay in primary goat endometrial epithelial cells (EECs), miR-187 inhibition, FAK activity measurement","journal":"Theriogenology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct 3'-UTR validation present but functional follow-up limited to single cell-based assays in a single lab","pmids":["34973644"],"is_preprint":false},{"year":2023,"finding":"In bladder cancer, biomechanical stimuli from 3D Matrigel activate an F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathway; Western blotting confirmed upregulation of ITGB8, TRIM59, and phospho-AKT in soft tumor cells, and this axis was associated with tumor softness, stemness, and recurrence.","method":"Atomic force microscopy, microfluidic isolation of soft cells, Western blot for ITGB8/TRIM59/p-AKT/mTOR, double immunostaining for F-actin/TRIM59, colony formation assay, xenograft tumor model","journal":"Chinese medical journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway ordering is correlative/Western-blot-based without direct functional manipulation of ITGB8 in this study; single lab","pmids":["37390491"],"is_preprint":false},{"year":2026,"finding":"Osteoblast-derived osteomodulin (OMD) engages integrin β8 on osteoclast precursors to suppress RhoA activity and enhance YAP phosphorylation, thereby reducing YAP/TEAD occupancy at the RRM2 promoter, repressing RRM2 transcription, decreasing mtDNA copy number and electron transport chain protein abundance, and reducing mitochondrial respiration and ATP production to restrain osteoclastogenesis.","method":"Osteoblast/MSC-specific and global Omd deletion mouse models, osteoclast precursor-specific deletion, recombinant OMD supplementation, pharmacologic RRM2 inhibition, ChIP (YAP/TEAD at RRM2 promoter), mitochondrial respiration assays, ITGB8-OMD interaction studies, ovariectomy and LPS bone-loss models","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple genetic models (global KO, cell-type-specific KO), reconstitution with recombinant protein, pharmacologic validation, ChIP, and functional bioenergetics assays in a single study establishing a multi-step mechanistic pathway","pmids":["41813908"],"is_preprint":false},{"year":2026,"finding":"Transcription factor EBF1 directly regulates ITGB8 expression in bone marrow mesenchymal stromal cells (MSCs); MSC-specific deletion of Itgb8 or ITGB8-neutralizing antibody treatment in myelofibrosis mice reduced BM fibrosis, decreased MPL-mutant cell frequencies, and reduced BM inflammation, establishing ITGB8 as a downstream effector of EBF1 in the fibrotic MSC gene program.","method":"MSC-specific conditional Itgb8 knockout mice (MPL W515L transplant MF model), ITGB8-neutralizing antibody treatment, EBF1 ChIP/gene regulation studies, histology and flow cytometry for fibrosis and myeloid expansion","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic deletion plus antibody neutralization in a disease model with multiple readouts, single lab, preprint not yet peer-reviewed","pmids":["41756923"],"is_preprint":true},{"year":2026,"finding":"miR-199a-3p directly targets ITGB8 (confirmed by dual-luciferase reporter assay) and suppresses FAK-ERK-RUNX2 signaling in bone marrow mesenchymal stem cells; silencing miR-199a-3p restored ITGB8 levels and reactivated FAK-ERK-RUNX2, correcting the osteogenic/adipogenic differentiation imbalance in steroid-induced osteonecrosis of the femoral head.","method":"Dual-luciferase reporter assay, mRNA-seq, miR-199a-3p overexpression/inhibition in BMSCs, Western blot for phospho-FAK, phospho-ERK, RUNX2, antagomiR-199a-3p in vivo in SONFH rat model","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR validation, rescue experiments, and in vivo pharmacologic intervention with multiple downstream pathway readouts; single lab","pmids":["41878635"],"is_preprint":false}],"current_model":"ITGB8 (integrin β8) is a transmembrane integrin subunit that functions as a receptor engaging extracellular ligands (including latent TGF-β1 and osteomodulin) to activate intracellular signaling cascades including FAK→VAV→RAC1 (endometrial receptivity), FAK→ERK→RUNX2 (osteogenic differentiation), and OMD→ITGB8→RhoA suppression→YAP phosphorylation→RRM2 repression→reduced mitochondrial respiration (osteoclastogenesis); it also links to MEK/ERK and AKT/mTOR pathways in cancer contexts, is transcriptionally regulated by EBF1 in mesenchymal stromal cells, and is post-transcriptionally suppressed by multiple miRNAs (miR-199a-3p, miR-145-5p, miR-187, miR-222, and others) targeting its 3'-UTR."},"narrative":{"mechanistic_narrative":"ITGB8 is a transmembrane integrin subunit that operates as a cell-surface receptor coupling extracellular ligand engagement to intracellular signaling that governs tissue remodeling, differentiation, and reproductive processes [PMID:41813908, PMID:25788663]. A core function is the activation of latent TGF-β1: during preimplantation, ITGB8 promotes release of active TGF-β1 and downstream SMAD2/3 phosphorylation, and parallel FAK-dependent signaling through ITGB8→FAK→VAV→RAC1 is required for blastocyst attachment in endometrial epithelium [PMID:25788663, PMID:28507287]. ITGB8 transduces FAK-anchored cascades in other contexts as well, supporting FAK→ERK→RUNX2 signaling that balances osteogenic versus adipogenic differentiation of mesenchymal stem cells [PMID:41878635]. In bone homeostasis, osteoblast-derived osteomodulin engages ITGB8 on osteoclast precursors to suppress RhoA, enhance YAP phosphorylation, and repress YAP/TEAD-driven RRM2 transcription, lowering mitochondrial respiration and restraining osteoclastogenesis [PMID:41813908]. ITGB8 expression is transcriptionally driven by EBF1 in fibrotic bone-marrow stromal cells [PMID:41756923] and is post-transcriptionally constrained by 3'-UTR-targeting miRNAs including miR-199a-3p and miR-187 [PMID:29436681, PMID:41878635, PMID:34973644]. Its expression is associated with chemoresistance and tumor signaling in cancer settings [PMID:29436681].","teleology":[{"year":2015,"claim":"Establishing that ITGB8 controls latent TGF-β1 activation in vivo defined its first concrete molecular role in tissue signaling during embryo implantation.","evidence":"Antibody bioneutralization and siRNA silencing of Itgb8 in mouse uterus, with active TGF-β1 and phospho-SMAD2/3 readouts","pmids":["25788663"],"confidence":"Medium","gaps":["Mechanism of how ITGB8 binds and presents latent TGF-β1 not structurally resolved","Single lab, no independent replication"]},{"year":2015,"claim":"Linking ITGB8 to TGF-β-dependent multidrug resistance extended its signaling role into cancer phenotypes.","evidence":"siRNA knockdown in HepG2/G hepatic cancer cells with drug-resistance protein and TGF-β component Western blots","pmids":["25932283"],"confidence":"Low","gaps":["Pathway placement inferred from expression changes only","No direct demonstration of ITGB8-driven TGF-β activation in this context"]},{"year":2017,"claim":"Defining the ITGB8→FAK→VAV→RAC1 axis showed ITGB8 transduces an intracellular cytoskeletal/GTPase signaling cascade required for blastocyst attachment.","evidence":"Reciprocal ITGB8 siRNA knockdown and FAK inhibition with phospho-FAK, phospho-VAV, RAC1-GTP, and spheroid attachment assays","pmids":["28507287"],"confidence":"Medium","gaps":["Ligand initiating the cascade not defined","No structural detail of receptor-effector coupling"]},{"year":2018,"claim":"Identifying ITGB8 as a direct miR-199a-3p target established post-transcriptional control of ITGB8 governing chemosensitivity.","evidence":"3'-UTR luciferase reporter, rescue overexpression, and orthotopic mouse model in ovarian cancer cells","pmids":["29436681"],"confidence":"Medium","gaps":["Downstream effector pathway of ITGB8 in cisplatin resistance not resolved","Single lab"]},{"year":2020,"claim":"Placing ITGB8 downstream of a PVT1/miR-145-5p axis tied it to MEK/ERK activation in lung cancer.","evidence":"PVT1 knockdown, miR-145-5p luciferase binding, p-MEK/p-ERK Western blot, and ITGB8 rescue in NSCLC xenografts","pmids":["32202906"],"confidence":"Low","gaps":["No direct demonstration of ITGB8-mediated MEK/ERK activation","Pathway relies on rescue and expression correlation"]},{"year":2021,"claim":"Validating miR-187 as a direct ITGB8 regulator linked to IFNT signaling extended miRNA control of ITGB8 to conceptus attachment.","evidence":"Dual-luciferase 3'-UTR assay, miR-187 inhibition, and FAK activity readout in goat endometrial epithelial cells","pmids":["34973644"],"confidence":"Low","gaps":["Functional follow-up limited to single cell-based assays","No in vivo validation"]},{"year":2023,"claim":"Embedding ITGB8 in a mechanosensitive F-actin/ITGB8/TRIM59/AKT/mTOR axis connected it to biomechanically driven tumor stemness.","evidence":"Atomic force microscopy, microfluidic soft-cell isolation, and Western blot for ITGB8/TRIM59/p-AKT in bladder cancer","pmids":["37390491"],"confidence":"Low","gaps":["Pathway ordering correlative without direct ITGB8 manipulation","Single lab"]},{"year":2026,"claim":"Resolving the OMD→ITGB8→RhoA→YAP→RRM2→mitochondrial respiration pathway gave ITGB8 a defined ligand and a multi-step mechanism controlling osteoclastogenesis.","evidence":"Global and cell-type-specific Omd/Itgb8 mouse models, recombinant OMD reconstitution, ChIP for YAP/TEAD at RRM2, and bioenergetics assays","pmids":["41813908"],"confidence":"High","gaps":["Structural basis of OMD-ITGB8 engagement not defined","Generalizability beyond bone not tested"]},{"year":2026,"claim":"Showing EBF1 directly drives ITGB8 in fibrotic stromal cells identified a transcriptional regulator and a disease role in myelofibrosis.","evidence":"MSC-specific Itgb8 knockout and neutralizing antibody in MPL W515L myelofibrosis mice, with EBF1 ChIP/regulation studies","pmids":["41756923"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","ITGB8 effector mechanism driving fibrosis not detailed"]},{"year":2026,"claim":"Demonstrating miR-199a-3p suppression of ITGB8→FAK→ERK→RUNX2 defined an ITGB8 differentiation-control axis relevant to osteonecrosis.","evidence":"Dual-luciferase assay, mRNA-seq, miR-199a-3p modulation, and antagomiR in a SONFH rat model with phospho-FAK/ERK/RUNX2 readouts","pmids":["41878635"],"confidence":"Medium","gaps":["Upstream ligand for FAK activation not identified","Single lab"]},{"year":null,"claim":"The structural basis and ligand-binding determinants by which ITGB8 selects among latent TGF-β1, osteomodulin, and other matrix ligands to direct distinct downstream cascades remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ITGB8 ligand engagement in corpus","Determinants of context-specific FAK vs RhoA/YAP output unknown","Heterodimer partner subunit not characterized in timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,7,9]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8]}],"complexes":[],"partners":["OMD","PTK2","VAV1","RAC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26012","full_name":"Integrin beta-8","aliases":[],"length_aa":769,"mass_kda":85.6,"function":"Integrin alpha-V:beta-8 (ITGAV:ITGB8) is a receptor for fibronectin (PubMed:1918072). It recognizes the sequence R-G-D in its ligands (PubMed:1918072). Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation on the surface of activated regulatory T-cells (Tregs) (Probable). Required during vasculogenesis (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P26012/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB8","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGB8","total_profiled":1310},"omim":[{"mim_id":"621353","title":"GLUTAMINE INSUFFICIENCY REGULATOR OF GLUTAMINASE LONG NONCODING RNA; GIRGL","url":"https://www.omim.org/entry/621353"},{"mim_id":"604318","title":"GTF2I REPEAT DOMAIN-CONTAINING PROTEIN 1; GTF2IRD1","url":"https://www.omim.org/entry/604318"},{"mim_id":"604160","title":"INTEGRIN, BETA-8; ITGB8","url":"https://www.omim.org/entry/604160"},{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGB8"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P26012","domains":[{"cath_id":"3.30.1680.10","chopping":"45-101","consensus_level":"high","plddt":80.4932,"start":45,"end":101},{"cath_id":"2.60.40.1510","chopping":"106-142_391-466","consensus_level":"high","plddt":85.1528,"start":106,"end":466},{"cath_id":"3.40.50.410","chopping":"148-388","consensus_level":"high","plddt":92.4812,"start":148,"end":388},{"cath_id":"2.10.25.10","chopping":"510-552","consensus_level":"medium","plddt":82.4721,"start":510,"end":552},{"cath_id":"2.10.25.10","chopping":"557-588","consensus_level":"medium","plddt":86.9619,"start":557,"end":588},{"cath_id":"2.10.25.10","chopping":"593-635","consensus_level":"medium","plddt":80.8905,"start":593,"end":635}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26012","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26012-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26012-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB8","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB8"},"sequence":{"accession":"P26012","fasta_url":"https://rest.uniprot.org/uniprotkb/P26012.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26012/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26012"}},"corpus_meta":[{"pmid":"34371180","id":"PMC_34371180","title":"lncRNA ITGB8-AS1 functions as a ceRNA to promote colorectal cancer growth and migration through integrin-mediated focal adhesion signaling.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34371180","citation_count":132,"is_preprint":false},{"pmid":"32196629","id":"PMC_32196629","title":"Circular RNA TTBK2 regulates cell proliferation, invasion and ferroptosis via miR-761/ITGB8 axis in glioma.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32196629","citation_count":87,"is_preprint":false},{"pmid":"29337055","id":"PMC_29337055","title":"A novel circular RNA, hsa_circ_0046701, promotes carcinogenesis by increasing the expression of miR-142-3p target ITGB8 in glioma.","date":"2018","source":"Biochemical and biophysical research 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Cross-Sectional Study.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41015604","citation_count":1,"is_preprint":false},{"pmid":"41813908","id":"PMC_41813908","title":"Osteoblast-derived osteomodulin restrains osteoclastogenesis via ITGB8/RRM2-mediated reduction of mitochondrial respiration and mitochondrial ATP production.","date":"2026","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41813908","citation_count":0,"is_preprint":false},{"pmid":"41878635","id":"PMC_41878635","title":"miR-199a-3p Promotes Adipogenic Differentiation to Aggravate Steroid-Induced Osteonecrosis of Femoral Head via the ITGB8/FAK-ERK/RUNX2 Pathway.","date":"2026","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/41878635","citation_count":0,"is_preprint":false},{"pmid":"41756923","id":"PMC_41756923","title":"Inhibition of the EBF1-ITGB8 Axis in Bone Marrow Niche Ameliorates Hallmarks of Myelofibrosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41756923","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.05.641539","title":"A cell atlas of human and mouse synovium from early and advanced stages of knee osteoarthritis: BHLHE40 regulates fibroblast activation","date":"2025-03-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.05.641539","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17944,"output_tokens":3105,"usd":0.050203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10458,"output_tokens":3317,"usd":0.067608,"stage2_stop_reason":"end_turn"},"total_usd":0.117811,"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\": 2017,\n      \"finding\": \"ITGB8 activates VAV-RAC1 signaling via FAK in endometrial epithelial cells: ITGB8 knockdown reduced phosphorylated-FAK, phosphorylated-VAV, and GTP-bound RAC1, and FAK inhibition also blocked VAV/RAC1 activation, establishing a functional ITGB8→FAK→VAV→RAC1 signaling axis required for blastocyst attachment.\",\n      \"method\": \"siRNA knockdown of ITGB8 in endometrial epithelial cells and uterus, FAK inhibition, measurement of phospho-FAK (Y397), phospho-VAV, RAC1-GTP pull-down, JAr spheroid attachment assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss-of-function (ITGB8 KD and FAK inhibition) with multiple downstream readouts in a single lab; no independent replication\",\n      \"pmids\": [\"28507287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGB8 regulates activation of latent TGF-β1 in the uterus: bioneutralization or mRNA silencing of Itgb8 at the preimplantation stage reduced active TGF-β1 release and downstream SMAD2/3 phosphorylation, linking ITGB8 to TGF-β1 activation during embryo implantation.\",\n      \"method\": \"Antibody-mediated bioneutralization of ITGB8, siRNA silencing in mouse uterus, measurement of active TGF-β1 and phospho-SMAD2/3, embryo implantation rate assessment\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal inhibition approaches (antibody and siRNA) with downstream signaling and functional readout, single lab\",\n      \"pmids\": [\"25788663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGB8 overexpression is associated with gefitinib resistance in hepatic cancer cells, and ITGB8 silencing reverses resistance by reducing ABCB1, ABCC2, ABCG2, survivin, Bcl-2, and CDK1; the TGF-β pathway was implicated as a critical mediator of ITGB8-dependent drug resistance.\",\n      \"method\": \"siRNA knockdown of ITGB8 in HepG2/G cells, cell proliferation and apoptosis assays, Western blot for multidrug-resistance proteins and TGF-β pathway components\",\n      \"journal\": \"International journal of clinical and experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, mechanistic pathway placement largely inferential from protein expression changes\",\n      \"pmids\": [\"25932283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-199a-3p directly targets the 3'-UTR of ITGB8 and suppresses its expression; overexpression of ITGB8 rescued cisplatin resistance that was inhibited by miR-199a-3p, placing ITGB8 downstream of miR-199a-3p in control of cisplatin sensitivity in ovarian cancer cells.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR binding), Western blot, miR-199a-3p overexpression/inhibition, ITGB8 rescue overexpression, cell proliferation, invasion, apoptosis, and in vivo orthotopic mouse model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR luciferase validation plus rescue experiment with multiple cellular readouts and in vivo confirmation, single lab\",\n      \"pmids\": [\"29436681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGB8 acts downstream of the lncRNA PVT1/miR-145-5p axis to activate the MEK/ERK signaling pathway in NSCLC; PVT1 knockdown suppressed ITGB8 expression and reduced MEK/ERK phosphorylation, while ITGB8 overexpression rescued these effects.\",\n      \"method\": \"siRNA/shRNA knockdown of PVT1, luciferase reporter assay for miR-145-5p binding, Western blot for p-MEK and p-ERK, ITGB8 rescue overexpression, xenograft tumor model\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; pathway placement relies on expression changes and rescue, without direct demonstration of ITGB8-mediated MEK/ERK activation\",\n      \"pmids\": [\"32202906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In goat endometrial epithelial cells, ITGB8 is a direct target of miR-187 (validated by 3'-UTR luciferase assay); inhibition of miR-187 upregulated ITGB8 and reduced FAK activity and cell proliferation, and both ITGB8 and miR-187 are regulated by interferon tau (IFNT), placing ITGB8 downstream of IFNT signaling during conceptus attachment.\",\n      \"method\": \"qRT-PCR, Western blot, dual-luciferase reporter assay in primary goat endometrial epithelial cells (EECs), miR-187 inhibition, FAK activity measurement\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct 3'-UTR validation present but functional follow-up limited to single cell-based assays in a single lab\",\n      \"pmids\": [\"34973644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In bladder cancer, biomechanical stimuli from 3D Matrigel activate an F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathway; Western blotting confirmed upregulation of ITGB8, TRIM59, and phospho-AKT in soft tumor cells, and this axis was associated with tumor softness, stemness, and recurrence.\",\n      \"method\": \"Atomic force microscopy, microfluidic isolation of soft cells, Western blot for ITGB8/TRIM59/p-AKT/mTOR, double immunostaining for F-actin/TRIM59, colony formation assay, xenograft tumor model\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway ordering is correlative/Western-blot-based without direct functional manipulation of ITGB8 in this study; single lab\",\n      \"pmids\": [\"37390491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Osteoblast-derived osteomodulin (OMD) engages integrin β8 on osteoclast precursors to suppress RhoA activity and enhance YAP phosphorylation, thereby reducing YAP/TEAD occupancy at the RRM2 promoter, repressing RRM2 transcription, decreasing mtDNA copy number and electron transport chain protein abundance, and reducing mitochondrial respiration and ATP production to restrain osteoclastogenesis.\",\n      \"method\": \"Osteoblast/MSC-specific and global Omd deletion mouse models, osteoclast precursor-specific deletion, recombinant OMD supplementation, pharmacologic RRM2 inhibition, ChIP (YAP/TEAD at RRM2 promoter), mitochondrial respiration assays, ITGB8-OMD interaction studies, ovariectomy and LPS bone-loss models\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple genetic models (global KO, cell-type-specific KO), reconstitution with recombinant protein, pharmacologic validation, ChIP, and functional bioenergetics assays in a single study establishing a multi-step mechanistic pathway\",\n      \"pmids\": [\"41813908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Transcription factor EBF1 directly regulates ITGB8 expression in bone marrow mesenchymal stromal cells (MSCs); MSC-specific deletion of Itgb8 or ITGB8-neutralizing antibody treatment in myelofibrosis mice reduced BM fibrosis, decreased MPL-mutant cell frequencies, and reduced BM inflammation, establishing ITGB8 as a downstream effector of EBF1 in the fibrotic MSC gene program.\",\n      \"method\": \"MSC-specific conditional Itgb8 knockout mice (MPL W515L transplant MF model), ITGB8-neutralizing antibody treatment, EBF1 ChIP/gene regulation studies, histology and flow cytometry for fibrosis and myeloid expansion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic deletion plus antibody neutralization in a disease model with multiple readouts, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41756923\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"miR-199a-3p directly targets ITGB8 (confirmed by dual-luciferase reporter assay) and suppresses FAK-ERK-RUNX2 signaling in bone marrow mesenchymal stem cells; silencing miR-199a-3p restored ITGB8 levels and reactivated FAK-ERK-RUNX2, correcting the osteogenic/adipogenic differentiation imbalance in steroid-induced osteonecrosis of the femoral head.\",\n      \"method\": \"Dual-luciferase reporter assay, mRNA-seq, miR-199a-3p overexpression/inhibition in BMSCs, Western blot for phospho-FAK, phospho-ERK, RUNX2, antagomiR-199a-3p in vivo in SONFH rat model\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR validation, rescue experiments, and in vivo pharmacologic intervention with multiple downstream pathway readouts; single lab\",\n      \"pmids\": [\"41878635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB8 (integrin β8) is a transmembrane integrin subunit that functions as a receptor engaging extracellular ligands (including latent TGF-β1 and osteomodulin) to activate intracellular signaling cascades including FAK→VAV→RAC1 (endometrial receptivity), FAK→ERK→RUNX2 (osteogenic differentiation), and OMD→ITGB8→RhoA suppression→YAP phosphorylation→RRM2 repression→reduced mitochondrial respiration (osteoclastogenesis); it also links to MEK/ERK and AKT/mTOR pathways in cancer contexts, is transcriptionally regulated by EBF1 in mesenchymal stromal cells, and is post-transcriptionally suppressed by multiple miRNAs (miR-199a-3p, miR-145-5p, miR-187, miR-222, and others) targeting its 3'-UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB8 is a transmembrane integrin subunit that operates as a cell-surface receptor coupling extracellular ligand engagement to intracellular signaling that governs tissue remodeling, differentiation, and reproductive processes [#7, #1]. A core function is the activation of latent TGF-\\u03b21: during preimplantation, ITGB8 promotes release of active TGF-\\u03b21 and downstream SMAD2/3 phosphorylation, and parallel FAK-dependent signaling through ITGB8\\u2192FAK\\u2192VAV\\u2192RAC1 is required for blastocyst attachment in endometrial epithelium [#1, #0]. ITGB8 transduces FAK-anchored cascades in other contexts as well, supporting FAK\\u2192ERK\\u2192RUNX2 signaling that balances osteogenic versus adipogenic differentiation of mesenchymal stem cells [#9]. In bone homeostasis, osteoblast-derived osteomodulin engages ITGB8 on osteoclast precursors to suppress RhoA, enhance YAP phosphorylation, and repress YAP/TEAD-driven RRM2 transcription, lowering mitochondrial respiration and restraining osteoclastogenesis [#7]. ITGB8 expression is transcriptionally driven by EBF1 in fibrotic bone-marrow stromal cells [#8] and is post-transcriptionally constrained by 3'-UTR-targeting miRNAs including miR-199a-3p and miR-187 [#3, #9, #5]. Its expression is associated with chemoresistance and tumor signaling in cancer settings [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that ITGB8 controls latent TGF-\\u03b21 activation in vivo defined its first concrete molecular role in tissue signaling during embryo implantation.\",\n      \"evidence\": \"Antibody bioneutralization and siRNA silencing of Itgb8 in mouse uterus, with active TGF-\\u03b21 and phospho-SMAD2/3 readouts\",\n      \"pmids\": [\"25788663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of how ITGB8 binds and presents latent TGF-\\u03b21 not structurally resolved\", \"Single lab, no independent replication\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linking ITGB8 to TGF-\\u03b2-dependent multidrug resistance extended its signaling role into cancer phenotypes.\",\n      \"evidence\": \"siRNA knockdown in HepG2/G hepatic cancer cells with drug-resistance protein and TGF-\\u03b2 component Western blots\",\n      \"pmids\": [\"25932283\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from expression changes only\", \"No direct demonstration of ITGB8-driven TGF-\\u03b2 activation in this context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the ITGB8\\u2192FAK\\u2192VAV\\u2192RAC1 axis showed ITGB8 transduces an intracellular cytoskeletal/GTPase signaling cascade required for blastocyst attachment.\",\n      \"evidence\": \"Reciprocal ITGB8 siRNA knockdown and FAK inhibition with phospho-FAK, phospho-VAV, RAC1-GTP, and spheroid attachment assays\",\n      \"pmids\": [\"28507287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand initiating the cascade not defined\", \"No structural detail of receptor-effector coupling\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying ITGB8 as a direct miR-199a-3p target established post-transcriptional control of ITGB8 governing chemosensitivity.\",\n      \"evidence\": \"3'-UTR luciferase reporter, rescue overexpression, and orthotopic mouse model in ovarian cancer cells\",\n      \"pmids\": [\"29436681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway of ITGB8 in cisplatin resistance not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placing ITGB8 downstream of a PVT1/miR-145-5p axis tied it to MEK/ERK activation in lung cancer.\",\n      \"evidence\": \"PVT1 knockdown, miR-145-5p luciferase binding, p-MEK/p-ERK Western blot, and ITGB8 rescue in NSCLC xenografts\",\n      \"pmids\": [\"32202906\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct demonstration of ITGB8-mediated MEK/ERK activation\", \"Pathway relies on rescue and expression correlation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validating miR-187 as a direct ITGB8 regulator linked to IFNT signaling extended miRNA control of ITGB8 to conceptus attachment.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR assay, miR-187 inhibition, and FAK activity readout in goat endometrial epithelial cells\",\n      \"pmids\": [\"34973644\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional follow-up limited to single cell-based assays\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Embedding ITGB8 in a mechanosensitive F-actin/ITGB8/TRIM59/AKT/mTOR axis connected it to biomechanically driven tumor stemness.\",\n      \"evidence\": \"Atomic force microscopy, microfluidic soft-cell isolation, and Western blot for ITGB8/TRIM59/p-AKT in bladder cancer\",\n      \"pmids\": [\"37390491\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway ordering correlative without direct ITGB8 manipulation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolving the OMD\\u2192ITGB8\\u2192RhoA\\u2192YAP\\u2192RRM2\\u2192mitochondrial respiration pathway gave ITGB8 a defined ligand and a multi-step mechanism controlling osteoclastogenesis.\",\n      \"evidence\": \"Global and cell-type-specific Omd/Itgb8 mouse models, recombinant OMD reconstitution, ChIP for YAP/TEAD at RRM2, and bioenergetics assays\",\n      \"pmids\": [\"41813908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of OMD-ITGB8 engagement not defined\", \"Generalizability beyond bone not tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing EBF1 directly drives ITGB8 in fibrotic stromal cells identified a transcriptional regulator and a disease role in myelofibrosis.\",\n      \"evidence\": \"MSC-specific Itgb8 knockout and neutralizing antibody in MPL W515L myelofibrosis mice, with EBF1 ChIP/regulation studies\",\n      \"pmids\": [\"41756923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"ITGB8 effector mechanism driving fibrosis not detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating miR-199a-3p suppression of ITGB8\\u2192FAK\\u2192ERK\\u2192RUNX2 defined an ITGB8 differentiation-control axis relevant to osteonecrosis.\",\n      \"evidence\": \"Dual-luciferase assay, mRNA-seq, miR-199a-3p modulation, and antagomiR in a SONFH rat model with phospho-FAK/ERK/RUNX2 readouts\",\n      \"pmids\": [\"41878635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream ligand for FAK activation not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis and ligand-binding determinants by which ITGB8 selects among latent TGF-\\u03b21, osteomodulin, and other matrix ligands to direct distinct downstream cascades remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ITGB8 ligand engagement in corpus\", \"Determinants of context-specific FAK vs RhoA/YAP output unknown\", \"Heterodimer partner subunit not characterized in timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 7, 9]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OMD\", \"PTK2\", \"VAV1\", \"RAC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}