{"gene":"ITGB7","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"TGF-β1 induces β7 integrin gene expression through two defined response regions in the promoter (TGFBRR1: nucleotides -509 to -398; TGFBRR2: -122 to +32). TGFBRR1 interacts with at least five protein complexes whose binding is induced by TGF-β1 stimulation and antagonized by TGFBRR2. TGFBRR2 interacts with at least two nuclear protein complexes in a phosphorylation-dependent manner. Genistein (a protein tyrosine kinase inhibitor) blocked induced β7 expression, implicating tyrosine phosphorylation in the signaling pathway.","method":"Promoter deletion analysis, reporter gene assays, DNase I hypersensitivity mapping, electrophoretic mobility shift assays (EMSA), pharmacological inhibition with genistein","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (deletion mapping, EMSA, reporter assays, pharmacological inhibition) in a single lab characterizing specific regulatory regions","pmids":["9683663"],"is_preprint":false},{"year":2020,"finding":"NRF2 directly binds to an antioxidant response element (ARE) in the ITGB7 promoter and transcriptionally activates ITGB7 expression downstream of ROS/TRIM2 signaling. NRF2 nuclear translocation rescues ITGB7 transcription, and ITGB7 in turn activates the FAK (focal adhesion kinase) pathway to promote pancreatic cancer progression.","method":"ChIP/promoter binding assays for NRF2 at ARE in ITGB7 promoter, N-acetyl-L-cysteine (ROS scavenger) treatment to modulate NRF2 and ITGB7 levels, siRNA knockdown, rescue experiments, in vivo tumorigenicity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding assay plus pharmacological/genetic manipulation in a single lab; functional link between NRF2→ITGB7→FAK established with multiple methods","pmids":["32929153"],"is_preprint":false},{"year":2019,"finding":"HPV16 capsid protein L2 (rVL2) suppresses ITGB7 expression, and this suppression inhibits the ITGB7/C/EBPβ signaling axis, leading to decreased expression of glycolytic enzymes GLUT1, LDHA, and ALDOA, reduced glucose uptake and lactate production, and inhibited cervical cancer cell proliferation.","method":"Gene-chip assay, RT-PCR, Western blot, glucose uptake and lactate production assay, in vivo animal model","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative molecular readouts linking rVL2 to ITGB7/C/EBPβ pathway without direct binding or reconstitution experiments for ITGB7 mechanistic role","pmids":["31819523"],"is_preprint":false},{"year":2008,"finding":"In the pregnant mouse uterus, ITGB7 is expressed on distinct dendritic cell (DC) subsets that reside in spatially distinct microdomains: ITGA4/ITGB7+ DCs are predominant in the vascular zone while ITGAE/ITGB7+ DCs localize to the lower central decidua basalis and myometrium. Confocal microscopy revealed direct contact between vascular zone DCs and uterine natural killer cells, suggesting a functional interaction.","method":"Multiparameter flow cytometry, confocal microscopy, tissue fractionation/localization","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by flow cytometry and confocal imaging identifying spatially distinct ITGB7+ DC subsets with functional implication from cell-cell contact observation","pmids":["18562709"],"is_preprint":false},{"year":2024,"finding":"Knockdown of ITGB7 in HaCaT cells significantly reduced HPV infection rate following Trichomonas vaginalis exposure, indicating that host ITGB7 is required for T. vaginalis-promoted HPV infection of epithelial cells.","method":"siRNA knockdown of ITGB7 in HaCaT cells, HPV infection rate quantification in vitro","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in a preprint; ITGB7 was one of 12 genes screened and its specific mechanism was not further characterized","pmids":[],"is_preprint":true}],"current_model":"ITGB7 (integrin β7) forms heterodimers with αE (ITGAE) or α4 (ITGA4) to mediate lymphocyte homing and retention at mucosal sites; its transcription is upregulated by TGF-β1 through defined promoter response regions in a tyrosine-phosphorylation-dependent manner, and also by NRF2 binding directly to an ARE element in its promoter downstream of ROS/TRIM2 signaling, with the resulting ITGB7 protein activating FAK-mediated adhesion signaling; distinct ITGB7-expressing dendritic cell subsets occupy spatially defined microdomains in the pregnant uterus, and host ITGB7 expression facilitates HPV infection of epithelial cells in the context of Trichomonas vaginalis co-infection."},"narrative":{"mechanistic_narrative":"ITGB7 (integrin β7) is a transcriptionally regulated adhesion molecule whose expression is controlled by distinct signaling inputs in immune and epithelial contexts [PMID:9683663, PMID:32929153]. TGF-β1 induces β7 integrin transcription through two defined promoter response regions (TGFBRR1 and TGFBRR2) that recruit inducible nuclear protein complexes in a tyrosine-phosphorylation-dependent manner [PMID:9683663]. In a separate regulatory axis, NRF2 binds directly to an antioxidant response element in the ITGB7 promoter downstream of ROS/TRIM2 signaling to activate ITGB7 transcription, and the resulting ITGB7 protein engages the focal adhesion kinase (FAK) pathway to promote pancreatic cancer progression [PMID:32929153]. ITGB7 marks spatially distinct dendritic cell subsets in the pregnant uterus, where ITGA4/ITGB7+ and ITGAE/ITGB7+ cells occupy separate microdomains and vascular-zone subsets make direct contact with uterine natural killer cells [PMID:18562709]. Beyond these transcriptional and adhesion-signaling roles, the structural details of its heterodimer-mediated function are not characterized in the available corpus.","teleology":[{"year":1998,"claim":"Established how β7 integrin transcription is induced, identifying the TGF-β1-responsive promoter architecture that links a cytokine signal to integrin expression.","evidence":"Promoter deletion analysis, reporter assays, DNase I hypersensitivity mapping, EMSA, and genistein inhibition in the β7 promoter","pmids":["9683663"],"confidence":"Medium","gaps":["Identity of the bound protein complexes not determined","The specific tyrosine kinase mediating the phosphorylation-dependent step not identified","Does not connect transcriptional induction to downstream adhesion function"]},{"year":2008,"claim":"Defined ITGB7 as a marker distinguishing functionally and spatially separate dendritic cell subsets at the maternal-fetal interface, implying distinct homing roles for its α4 and αE pairings.","evidence":"Multiparameter flow cytometry and confocal microscopy of pregnant mouse uterus","pmids":["18562709"],"confidence":"Medium","gaps":["The functional consequence of DC–uterine NK cell contact not demonstrated","Whether ITGB7 itself mediates the microdomain localization not tested","No loss-of-function validation"]},{"year":2020,"claim":"Connected a second transcriptional input (ROS/TRIM2/NRF2) to ITGB7 and established a downstream effector pathway (FAK) driving cancer progression, expanding ITGB7 beyond immune homing into tumor biology.","evidence":"NRF2 ChIP/promoter binding at ARE, ROS scavenger and siRNA manipulation, rescue and in vivo tumorigenicity assays in pancreatic cancer","pmids":["32929153"],"confidence":"Medium","gaps":["Mechanism by which ITGB7 activates FAK not resolved","Whether the αE/α4 partner is required for the oncogenic role not addressed","Generalizability beyond pancreatic cancer untested"]},{"year":2019,"claim":"Linked ITGB7 to a glycolytic/proliferative program in cervical cancer via a putative ITGB7/C/EBPβ axis modulated by HPV16 L2.","evidence":"Gene-chip, RT-PCR, Western blot, metabolic assays, and in vivo model in cervical cancer cells","pmids":["31819523"],"confidence":"Low","gaps":["Correlative readouts without direct ITGB7–C/EBPβ binding or reconstitution","No demonstration that ITGB7 directly regulates the glycolytic enzymes","Single lab, unconfirmed"]},{"year":2024,"claim":"Implicated host ITGB7 as a facilitator of HPV infection of epithelial cells in the context of Trichomonas vaginalis co-infection.","evidence":"siRNA knockdown of ITGB7 in HaCaT cells with HPV infection quantification (preprint)","pmids":[],"confidence":"Low","gaps":["Single knockdown among 12 screened genes; mechanism uncharacterized","Preprint, not peer-reviewed","No reciprocal or rescue validation"]},{"year":null,"claim":"How the ITGB7 heterodimer transduces adhesion signals at the molecular level, and whether its diverse transcriptional regulators converge on a shared functional output, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ITGB7 heterodimers in the corpus","Ligand engagement and inside-out/outside-in signaling not characterized here","Mechanistic link between transcriptional induction and FAK activation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["ITGAE","ITGA4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26010","full_name":"Integrin beta-7","aliases":["Gut homing receptor beta subunit"],"length_aa":798,"mass_kda":86.9,"function":"Integrin ITGA4/ITGB7 (alpha-4/beta-7) (Peyer patches-specific homing receptor LPAM-1) is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT) (Probable). Integrin ITGA4/ITGB7 interacts with the cell surface adhesion molecules MADCAM1 which is normally expressed by the vascular endothelium of the gastrointestinal tract (PubMed:10837471, PubMed:14608374). Also interacts with VCAM1 and fibronectin, an extracellular matrix component (Probable). It recognizes one or more domains within the alternatively spliced CS-1 region of fibronectin (Probable). Interactions involve the tripeptide L-D-T in MADCAM1, and L-D-V in fibronectin (Probable). Integrin ITGAE/ITGB7 (alpha-E/beta-7, HML-1) is a receptor for E-cadherin (PubMed:10837471) (Microbial infection) Binds to HIV-1 gp120, thereby allowing the virus to enter GALT, which is thought to be the major trigger of AIDS disease. Interaction would involve a tripeptide L-D-I in HIV-1 gp120","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P26010/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB7","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGB7","total_profiled":1310},"omim":[{"mim_id":"618394","title":"IMMUNODEFICIENCY 60 AND AUTOIMMUNITY; IMD60","url":"https://www.omim.org/entry/618394"},{"mim_id":"605984","title":"EMBRYONIC ECTODERM DEVELOPMENT; EED","url":"https://www.omim.org/entry/605984"},{"mim_id":"605394","title":"BTB AND CNC HOMOLOGY 2; BACH2","url":"https://www.omim.org/entry/605394"},{"mim_id":"605163","title":"CHEMOKINE, CXC MOTIF, RECEPTOR 6; CXCR6","url":"https://www.omim.org/entry/605163"},{"mim_id":"604874","title":"KILLER CELL LECTIN-LIKE RECEPTOR, SUBFAMILY G, MEMBER 1; KLRG1","url":"https://www.omim.org/entry/604874"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":29.1}],"url":"https://www.proteinatlas.org/search/ITGB7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P26010","domains":[{"cath_id":"3.30.1680.10","chopping":"52-98","consensus_level":"high","plddt":89.2009,"start":52,"end":98},{"cath_id":"2.60.40.1510","chopping":"103-149_404-473","consensus_level":"high","plddt":87.2054,"start":103,"end":473},{"cath_id":"3.40.50.410","chopping":"178-187_196-238_251-341_349-376","consensus_level":"high","plddt":93.1477,"start":178,"end":376},{"cath_id":"2.10.25.10","chopping":"494-561","consensus_level":"medium","plddt":80.3971,"start":494,"end":561},{"cath_id":"-","chopping":"569-594","consensus_level":"high","plddt":86.5615,"start":569,"end":594},{"cath_id":"2.10.25.10","chopping":"602-642","consensus_level":"medium","plddt":83.7056,"start":602,"end":642},{"cath_id":"4.10.1240","chopping":"645-716","consensus_level":"high","plddt":80.9246,"start":645,"end":716}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26010","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26010-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26010-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB7","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB7"},"sequence":{"accession":"P26010","fasta_url":"https://rest.uniprot.org/uniprotkb/P26010.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26010/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26010"}},"corpus_meta":[{"pmid":"9683663","id":"PMC_9683663","title":"The beta7 integrin gene (Itgb-7) promoter is responsive to TGF-beta1: defining control regions.","date":"1998","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/9683663","citation_count":46,"is_preprint":false},{"pmid":"32929153","id":"PMC_32929153","title":"Oncogenic function of TRIM2 in pancreatic cancer by activating ROS-related NRF2/ITGB7/FAK axis.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32929153","citation_count":35,"is_preprint":false},{"pmid":"30552108","id":"PMC_30552108","title":"Genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in CSAD/lnc-ITGB7-1 on Chromosome 12q13.13 Associated With Susceptibility to Fulminant Type 1 Diabetes.","date":"2018","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30552108","citation_count":32,"is_preprint":false},{"pmid":"34134578","id":"PMC_34134578","title":"Integrated analysis reveals the participation of IL4I1, ITGB7, and FUT7 in reshaping the TNBC immune microenvironment by targeting glycolysis.","date":"2021","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34134578","citation_count":27,"is_preprint":false},{"pmid":"36660685","id":"PMC_36660685","title":"EccDNA-oriented ITGB7 expression in breast cancer.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36660685","citation_count":13,"is_preprint":false},{"pmid":"31819523","id":"PMC_31819523","title":"Recombinant Viral Capsid Protein L2 (rVL2) of HPV 16 Suppresses Cell Proliferation and Glucose Metabolism via ITGB7/C/EBPβ Signaling Pathway in Cervical Cancer Cell Lines.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31819523","citation_count":11,"is_preprint":false},{"pmid":"34827121","id":"PMC_34827121","title":"Circulating MAdCAM-1 and ITGB7 in Patients with Plaque Psoriasis and Eruptive Lichen Planus-Preliminary Data.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34827121","citation_count":10,"is_preprint":false},{"pmid":"18562709","id":"PMC_18562709","title":"Identification of ITGA4/ITGB7 and ITGAE/ITGB7 expressing subsets of decidual dendritic-like cells within distinct microdomains of the pregnant mouse uterus.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18562709","citation_count":10,"is_preprint":false},{"pmid":"41426254","id":"PMC_41426254","title":"ITGB7 Remodels Inflammation and Immune Microenvironment and Enhances Checkpoint Inhibitor-Based Immunotherapy in Pancreatic Cancer.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/41426254","citation_count":0,"is_preprint":false},{"pmid":"39814374","id":"PMC_39814374","title":"Retrospective detection of ITGB7 gene mutation in a holstein calf with chronic diarrhea that was suspected of hereditary cholesterol deficiency.","date":"2025","source":"The Journal of veterinary medical science","url":"https://pubmed.ncbi.nlm.nih.gov/39814374","citation_count":0,"is_preprint":false},{"pmid":"41509664","id":"PMC_41509664","title":"Epigenetic Regulation of ITGB7 Promotes Coronary Heart Disease via Immune and Metabolic Pathways: A Multimodal Mendelian Randomization Study.","date":"2026","source":"Cardiovascular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41509664","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.18.654695","title":"Clinical, Biological and Pathological Investigation of Bovine Lymphocyte Intestinal Retention Deficit (BLIRD): a new genetic disorder affecting life expectancy and immunity in Holstein dairy cattle","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.18.654695","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.27.615334","title":"TvAP65 in  <i>Trichomonas vaginalis</i>  Promotes HPV Infection by Interacting with Host Molecules","date":"2024-09-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.27.615334","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9114,"output_tokens":1577,"usd":0.025499,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8325,"output_tokens":2087,"usd":0.0469,"stage2_stop_reason":"end_turn"},"total_usd":0.072399,"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\": 1998,\n      \"finding\": \"TGF-β1 induces β7 integrin gene expression through two defined response regions in the promoter (TGFBRR1: nucleotides -509 to -398; TGFBRR2: -122 to +32). TGFBRR1 interacts with at least five protein complexes whose binding is induced by TGF-β1 stimulation and antagonized by TGFBRR2. TGFBRR2 interacts with at least two nuclear protein complexes in a phosphorylation-dependent manner. Genistein (a protein tyrosine kinase inhibitor) blocked induced β7 expression, implicating tyrosine phosphorylation in the signaling pathway.\",\n      \"method\": \"Promoter deletion analysis, reporter gene assays, DNase I hypersensitivity mapping, electrophoretic mobility shift assays (EMSA), pharmacological inhibition with genistein\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (deletion mapping, EMSA, reporter assays, pharmacological inhibition) in a single lab characterizing specific regulatory regions\",\n      \"pmids\": [\"9683663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NRF2 directly binds to an antioxidant response element (ARE) in the ITGB7 promoter and transcriptionally activates ITGB7 expression downstream of ROS/TRIM2 signaling. NRF2 nuclear translocation rescues ITGB7 transcription, and ITGB7 in turn activates the FAK (focal adhesion kinase) pathway to promote pancreatic cancer progression.\",\n      \"method\": \"ChIP/promoter binding assays for NRF2 at ARE in ITGB7 promoter, N-acetyl-L-cysteine (ROS scavenger) treatment to modulate NRF2 and ITGB7 levels, siRNA knockdown, rescue experiments, in vivo tumorigenicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding assay plus pharmacological/genetic manipulation in a single lab; functional link between NRF2→ITGB7→FAK established with multiple methods\",\n      \"pmids\": [\"32929153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HPV16 capsid protein L2 (rVL2) suppresses ITGB7 expression, and this suppression inhibits the ITGB7/C/EBPβ signaling axis, leading to decreased expression of glycolytic enzymes GLUT1, LDHA, and ALDOA, reduced glucose uptake and lactate production, and inhibited cervical cancer cell proliferation.\",\n      \"method\": \"Gene-chip assay, RT-PCR, Western blot, glucose uptake and lactate production assay, in vivo animal model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative molecular readouts linking rVL2 to ITGB7/C/EBPβ pathway without direct binding or reconstitution experiments for ITGB7 mechanistic role\",\n      \"pmids\": [\"31819523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In the pregnant mouse uterus, ITGB7 is expressed on distinct dendritic cell (DC) subsets that reside in spatially distinct microdomains: ITGA4/ITGB7+ DCs are predominant in the vascular zone while ITGAE/ITGB7+ DCs localize to the lower central decidua basalis and myometrium. Confocal microscopy revealed direct contact between vascular zone DCs and uterine natural killer cells, suggesting a functional interaction.\",\n      \"method\": \"Multiparameter flow cytometry, confocal microscopy, tissue fractionation/localization\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by flow cytometry and confocal imaging identifying spatially distinct ITGB7+ DC subsets with functional implication from cell-cell contact observation\",\n      \"pmids\": [\"18562709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of ITGB7 in HaCaT cells significantly reduced HPV infection rate following Trichomonas vaginalis exposure, indicating that host ITGB7 is required for T. vaginalis-promoted HPV infection of epithelial cells.\",\n      \"method\": \"siRNA knockdown of ITGB7 in HaCaT cells, HPV infection rate quantification in vitro\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in a preprint; ITGB7 was one of 12 genes screened and its specific mechanism was not further characterized\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ITGB7 (integrin β7) forms heterodimers with αE (ITGAE) or α4 (ITGA4) to mediate lymphocyte homing and retention at mucosal sites; its transcription is upregulated by TGF-β1 through defined promoter response regions in a tyrosine-phosphorylation-dependent manner, and also by NRF2 binding directly to an ARE element in its promoter downstream of ROS/TRIM2 signaling, with the resulting ITGB7 protein activating FAK-mediated adhesion signaling; distinct ITGB7-expressing dendritic cell subsets occupy spatially defined microdomains in the pregnant uterus, and host ITGB7 expression facilitates HPV infection of epithelial cells in the context of Trichomonas vaginalis co-infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB7 (integrin β7) is a transcriptionally regulated adhesion molecule whose expression is controlled by distinct signaling inputs in immune and epithelial contexts [#0, #1]. TGF-β1 induces β7 integrin transcription through two defined promoter response regions (TGFBRR1 and TGFBRR2) that recruit inducible nuclear protein complexes in a tyrosine-phosphorylation-dependent manner [#0]. In a separate regulatory axis, NRF2 binds directly to an antioxidant response element in the ITGB7 promoter downstream of ROS/TRIM2 signaling to activate ITGB7 transcription, and the resulting ITGB7 protein engages the focal adhesion kinase (FAK) pathway to promote pancreatic cancer progression [#1]. ITGB7 marks spatially distinct dendritic cell subsets in the pregnant uterus, where ITGA4/ITGB7+ and ITGAE/ITGB7+ cells occupy separate microdomains and vascular-zone subsets make direct contact with uterine natural killer cells [#3]. Beyond these transcriptional and adhesion-signaling roles, the structural details of its heterodimer-mediated function are not characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established how β7 integrin transcription is induced, identifying the TGF-β1-responsive promoter architecture that links a cytokine signal to integrin expression.\",\n      \"evidence\": \"Promoter deletion analysis, reporter assays, DNase I hypersensitivity mapping, EMSA, and genistein inhibition in the β7 promoter\",\n      \"pmids\": [\"9683663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the bound protein complexes not determined\", \"The specific tyrosine kinase mediating the phosphorylation-dependent step not identified\", \"Does not connect transcriptional induction to downstream adhesion function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined ITGB7 as a marker distinguishing functionally and spatially separate dendritic cell subsets at the maternal-fetal interface, implying distinct homing roles for its α4 and αE pairings.\",\n      \"evidence\": \"Multiparameter flow cytometry and confocal microscopy of pregnant mouse uterus\",\n      \"pmids\": [\"18562709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional consequence of DC–uterine NK cell contact not demonstrated\", \"Whether ITGB7 itself mediates the microdomain localization not tested\", \"No loss-of-function validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected a second transcriptional input (ROS/TRIM2/NRF2) to ITGB7 and established a downstream effector pathway (FAK) driving cancer progression, expanding ITGB7 beyond immune homing into tumor biology.\",\n      \"evidence\": \"NRF2 ChIP/promoter binding at ARE, ROS scavenger and siRNA manipulation, rescue and in vivo tumorigenicity assays in pancreatic cancer\",\n      \"pmids\": [\"32929153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ITGB7 activates FAK not resolved\", \"Whether the αE/α4 partner is required for the oncogenic role not addressed\", \"Generalizability beyond pancreatic cancer untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked ITGB7 to a glycolytic/proliferative program in cervical cancer via a putative ITGB7/C/EBPβ axis modulated by HPV16 L2.\",\n      \"evidence\": \"Gene-chip, RT-PCR, Western blot, metabolic assays, and in vivo model in cervical cancer cells\",\n      \"pmids\": [\"31819523\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative readouts without direct ITGB7–C/EBPβ binding or reconstitution\", \"No demonstration that ITGB7 directly regulates the glycolytic enzymes\", \"Single lab, unconfirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated host ITGB7 as a facilitator of HPV infection of epithelial cells in the context of Trichomonas vaginalis co-infection.\",\n      \"evidence\": \"siRNA knockdown of ITGB7 in HaCaT cells with HPV infection quantification (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown among 12 screened genes; mechanism uncharacterized\", \"Preprint, not peer-reviewed\", \"No reciprocal or rescue validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the ITGB7 heterodimer transduces adhesion signals at the molecular level, and whether its diverse transcriptional regulators converge on a shared functional output, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ITGB7 heterodimers in the corpus\", \"Ligand engagement and inside-out/outside-in signaling not characterized here\", \"Mechanistic link between transcriptional induction and FAK activation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGAE\", \"ITGA4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}