{"gene":"ITGB7","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1991,"finding":"The complete amino acid sequence of integrin β7 was determined from overlapping cDNA clones obtained from leukocyte libraries. The β7 protein is predicted to contain a large extracellular portion, a transmembrane domain, and a cytoplasmic tail, with 32–46% identity to other human integrin β subunits and closest similarity to β2 (CD18). β7 mRNA was detected in T and B cell lines and macrophage-like cell lines but not in non-leukocyte cell lines, and phorbol ester stimulation markedly increased β7 mRNA levels in peripheral T cells.","method":"cDNA cloning and sequencing, Northern blot analysis, reverse transcription-PCR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete sequence determination with expression analysis; foundational characterization paper","pmids":["2040612"],"is_preprint":false},{"year":1992,"finding":"Integrin α4β7 (also called α4βP) was identified as the β7-containing heterodimer expressed in TK-1 T lymphoma cells and activated peripheral blood T cells. α4β7 functions as a fibronectin receptor that binds to the CS-1 region (not the RGD sequence) of fibronectin, and also supports adhesion to VCAM-1, both of which are markedly enhanced by PMA stimulation. Anti-α4 and anti-β7 antibodies induce homotypic cell clustering.","method":"Anti-peptide antiserum and mAb immunoprecipitation, affinity chromatography, cell adhesion assays, antibody blocking","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IP, affinity chromatography, adhesion assays, blocking) in a single rigorous study","pmids":["1372909"],"is_preprint":false},{"year":1992,"finding":"A family of β7 integrins on human mucosal lymphocytes was characterized: the HML-1 antigen (αEβ7) and α4β7 both use the β7 chain. The HML-1 α-subunit was designated αE (a novel integrin α chain). TGF-β1 reciprocally regulated HML-1 (αEβ7) and LFA-1 expression.","method":"N-terminal protein sequencing of purified HML-1 subunit, biochemical characterization, immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — protein sequencing and biochemical identification; foundational paper with multiple methods","pmids":["1542691"],"is_preprint":false},{"year":1992,"finding":"On the JY B lymphoblastoid cell line expressing α4β7 without α4β1, α4β7 makes little or no contribution to fibronectin or VCAM-1 binding under basal conditions; a minor contribution emerges only after PMA stimulation. α4β1 is the functionally dominant VCAM-1 and fibronectin receptor. This demonstrated that the β subunit partner determines the adhesive specificity of α4 integrins.","method":"Northern blotting, immunoprecipitation, cell adhesion assays with blocking antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal comparison of α4β7 vs. α4β1 with multiple assays and blocking antibodies","pmids":["1373725"],"is_preprint":false},{"year":1993,"finding":"α4β7 integrin was identified as the receptor for the mucosal vascular addressin MAdCAM-1. Antibodies to α4 and β7 (but not β2/LFA-1) inhibit lymphocyte binding to purified MAdCAM-1 and to MAdCAM-1 transfectants. Mn2+-induced integrin activation enhances binding. MAdCAM-1 is a preferential ligand for α4β7 over α4β1; α4β7 can also bind VCAM-1 but requires greater integrin activation.","method":"Antibody blocking assays, cell adhesion to purified MAdCAM-1 and transfectants, Mn2+ activation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal adhesion assays, transfectants, activation studies; highly replicated foundational finding","pmids":["7687523"],"is_preprint":false},{"year":1993,"finding":"α4β7 on human B lymphocytes mediates adhesion to fibronectin and VCAM-1 through distinct epitopes on the integrin. α4β7 expression is absent on resting lymphoid tissue B cells but induced upon activation. α4β7 also participates in homotypic B cell aggregation and co-clusters with α4β1 at fibronectin/VCAM-1-coated surfaces.","method":"Immunoprecipitation, cell adhesion assays, antibody blocking, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple adhesion assays with blocking antibodies and multiple cell populations","pmids":["7689608"],"is_preprint":false},{"year":1998,"finding":"The β7 integrin gene promoter contains TGF-β1 response regions at nucleotides -509 to -398 (TGFBRR1) and -122 to +32 (TGFBRR2) that drive TGF-β1-induced gene expression. TGF-β1 increases β7 and αE subunit mRNA and M290 (αEβ7) surface expression on T cells while decreasing α4 transcripts. Induced β7 expression is inhibited by the tyrosine kinase inhibitor genistein. TGFBRR1 and TGFBRR2 interact with distinct nuclear protein complexes in a phosphorylation-dependent manner.","method":"Promoter-reporter deletion analysis, DNase I hypersensitivity mapping, gel-shift assays, RT-PCR, genistein inhibition","journal":"Immunogenetics","confidence":"High","confidence_rationale":"Tier 2 — deletion analysis with reporter assays, protein-DNA binding, pharmacological inhibition","pmids":["9683663"],"is_preprint":false},{"year":2001,"finding":"The β7 integrin cytoplasmic tail binds strongly to filamin A, and this tight filamin binding inhibits integrin-dependent cell migration by suppressing transient membrane protrusion and cell polarization. Amino acid substitutions that selectively ablate filamin binding from the β7 tail (or confer it onto β1A) confirm this mechanistic link: increased filamin binding correlates with reduced migration without affecting fibronectin matrix assembly or focal adhesion formation.","method":"Mutagenesis mapping of filamin-binding site, cell migration assays, membrane protrusion analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function mutagenesis with defined phenotypic readouts; replicated mechanistic conclusion","pmids":["11781567"],"is_preprint":false},{"year":2003,"finding":"Integrin α4β7 adhesiveness is bistably regulated by a linear array of three divalent cation-binding sites in the β7 I-like domain: MIDAS is required for both rolling and firm adhesion; ADMIDAS (adjacent to MIDAS) negatively regulates via Ca2+ to permit rolling; LIMBS positively responds to low Ca2+ to promote firm adhesion. ADMIDAS mutation converts rolling to firm adhesion; LIMBS mutation converts firm adhesion to rolling.","method":"Site-directed mutagenesis of metal-binding sites, adhesion assays under defined ionic conditions (Ca2+, Mg2+, Mn2+)","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of defined structural sites with quantitative adhesion phenotypes","pmids":["14608374"],"is_preprint":false},{"year":2003,"finding":"Multiple PTB domain-containing proteins (talin, ICAP1-α, Numb, Dok-1) bind to the NPXY motifs in integrin β cytoplasmic tails via a conserved PTB domain–NPXY ligand interaction. β7 and β3 tail mutations of the NPXY motif block these interactions. Gain- and loss-of-function mutations in the β7 tail confirmed class-specific interactions with particular PTB domains (e.g., Dab, EPS8, tensin show integrin class-specific binding).","method":"Recombinant PTB domain binding to integrin tails, mutagenesis, molecular modeling, Co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted binding with mutagenesis across multiple integrin tails and PTB domains","pmids":["12606711"],"is_preprint":false},{"year":2003,"finding":"Peyer's patch dendritic cells selectively imprint gut-homing specificity on T cells by inducing high levels of α4β7 (ITGB7-containing integrin) and CCR9, enabling small intestinal homing. This imprinting is specific to Peyer's patch DCs: peripheral lymph node and spleen DCs induced equivalent activation but did not upregulate α4β7 or gut-homing ability.","method":"T cell stimulation with DCs from different anatomical sites, flow cytometry for α4β7 expression, in vivo homing assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — defined cellular assay with in vivo validation and controlled comparisons across DC populations","pmids":["12840763"],"is_preprint":false},{"year":2007,"finding":"αEβ7 (CD103/ITGB7) interaction with E-cadherin on tumor cells promotes antitumor CTL activity by recruiting αEβ7 to the immunological synapse and driving lytic granule polarization and exocytosis. Blocking anti-CD103 antibody or siRNA knockdown of E-cadherin abrogates tumor cell killing. TGF-β1 treatment of CD103- CTL clones upregulates αEβ7 and potentiates cytotoxicity.","method":"Antibody blocking, RNA interference, confocal microscopy of immunological synapse, cytotoxicity assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (antibody blocking, RNAi, confocal imaging) with defined mechanistic readout","pmids":["17325197"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of filamin A domains IgFLNa19-21 at 2.5 Å reveals auto-inhibition: the N-terminus of IgFLNa20 forms a β-strand that occupies the integrin β-tail binding site on IgFLNa21. Disrupting this auto-inhibitory IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin β-tails including β7.","method":"X-ray crystallography (2.5 Å), mutagenesis, integrin β-tail binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation by mutagenesis and binding assays","pmids":["17690686"],"is_preprint":false},{"year":2008,"finding":"HIV-1 envelope protein gp120 binds to activated α4β7 integrin via a tripeptide motif in the V2 loop of gp120 that mimics natural α4β7 ligands. Engagement of α4β7 by gp120 on CD4+ T cells rapidly activates LFA-1, facilitating formation of virological synapses for cell-to-cell HIV spreading.","method":"Binding assays with purified gp120 and α4β7, intracellular signaling assays, antibody blocking, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstration with defined peptide motif, downstream signaling measured","pmids":["18264102"],"is_preprint":false},{"year":2009,"finding":"α4β7high CD4+ T cells are more susceptible to productive HIV-1 infection than α4β7low/neg cells, partly because this subset is metabolically active, CCR5high and CXCR4low. On these cells, α4β7 appears in a complex with CD4, and gp120's specific affinity for α4β7 targets these cells.","method":"Flow cytometry, HIV infection assays, co-immunoprecipitation of α4β7 with CD4","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP demonstrating α4β7/CD4 complex, correlated with functional infection susceptibility","pmids":["19933330"],"is_preprint":false},{"year":2009,"finding":"Tyrosine phosphorylation of the β7 integrin cytoplasmic tail is a conserved mechanism for regulating integrin activation. Talin1 binds to the NPXY motif and membrane-proximal portion of β7 tail, and tyrosine phosphorylation decreases talin affinity while greatly increasing Dok1 affinity (restricted to the NPXY region). Dok1 acts as a talin competitor that does not form activating membrane-proximal interactions, thereby inhibiting integrin activation.","method":"NMR-based protein-protein interaction assay with 15N-labeled phosphorylated β7 tail, mutagenesis, talin1 D372R mutation and live cell localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural analysis with mutagenesis and live cell validation across multiple integrin tails","pmids":["19843520"],"is_preprint":false},{"year":2011,"finding":"ITGB7 silencing in multiple myeloma (MM) cells reduces adhesion to fibronectin and E-cadherin, reverses cell-adhesion-mediated drug resistance to bortezomib and melphalan, abrogates SDF1α-driven transwell migration, reduces vessel density in xenografts, and alters in vivo BM homing. Mechanistically, ITGB7 knockdown inhibits FAK and Src phosphorylation, Rac1 activation and SUMOylation, reduces VEGF production in MM–BM stem cell co-cultures, and attenuates p65-NF-κB activity.","method":"shRNA knockdown, cell adhesion assays, transwell migration, in vivo xenograft and homing assays, Western blotting for FAK/Src/Rac1/NF-κB","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — shRNA KD with multiple orthogonal in vitro and in vivo phenotypic readouts and defined signaling pathway endpoints","pmids":["21474670"],"is_preprint":false},{"year":2011,"finding":"Mechanical strain in actin networks differentially regulates binding of β-integrin cytoplasmic tails and FilGAP to filamin A (FLNA). Strain increases β-integrin tail binding to FLNA while causing FilGAP to dissociate, providing a direct molecular basis for mechanotransduction. The β7 integrin tail was used in the reconstituted minimal system (actin + FLNA + β-integrin tail + FilGAP).","method":"In vitro reconstitution with purified components, fluorescence loss after photoconversion, rheological measurement of actin network strain","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstituted minimal system with direct measurement of strain-dependent binding","pmids":["21926999"],"is_preprint":false},{"year":2020,"finding":"In pancreatic cancer, TRIM2 activates NRF2 via ROS signaling, and NRF2 directly binds to an antioxidant response element (ARE) in the ITGB7 promoter to enhance ITGB7 transcription. ITGB7 in turn activates the FAK pathway. Antioxidant N-acetyl-L-cysteine treatment reduces ROS, NRF2, and ITGB7 levels; NRF2 nuclear translocation rescues inhibited ITGB7 transcription.","method":"siRNA/shRNA knockdown, NAC antioxidant treatment, promoter-reporter assay, ChIP-like NRF2 binding to ARE, Western blotting, in vivo tumorigenicity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — promoter binding and rescue experiments in single lab; NRF2-ARE-ITGB7 axis mechanistically defined","pmids":["32929153"],"is_preprint":false},{"year":2019,"finding":"Recombinant HPV16 capsid protein L2 (rVL2) suppresses glucose metabolism in cervical cancer cells by inhibiting the ITGB7/C/EBPβ signaling pathway, reducing expression of GLUT1, LDHA, and ALDOA. Inhibition of ITGB7 mediates rVL2-induced decreases in glucose uptake and lactate production, and consequent inhibition of proliferation.","method":"Gene-chip assay, RT-PCR, Western blot, glucose uptake and lactate production assays, in vivo animal model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — pathway placement via expression and pharmacological manipulation; single lab without genetic rescue","pmids":["31819523"],"is_preprint":false},{"year":2008,"finding":"In the pregnant mouse uterus, ITGB7-positive decidual leukocytes are predominantly dendritic cells forming three phenotypically distinct subsets defined by differential expression of ITGA4/ITGB7 vs. ITGAE/ITGB7. These subsets reside in distinct uterine microdomains: ITGA4/ITGB7+ DCs localize to the vascular zone and make direct contact with uterine NK cells, while ITGAE/ITGB7+ DCs localize to the central decidua basalis and myometrium.","method":"Multiparameter flow cytometry, confocal microscopy","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by flow cytometry and confocal microscopy; functional implication from DC–uNK cell contact","pmids":["18562709"],"is_preprint":false}],"current_model":"ITGB7 encodes the integrin β7 subunit that pairs with αE (CD103) or α4 to form αEβ7 and α4β7 heterodimers on mucosal lymphocytes; α4β7 mediates lymphocyte homing to gut-associated lymphoid tissue by binding MAdCAM-1 (preferential ligand), fibronectin CS-1, and VCAM-1 in a divalent-cation-regulated manner controlled by three metal-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain; the β7 cytoplasmic tail engages filamin A (inhibiting migration and membrane protrusion), talin (activating integrins via NPXY motif), and Dok-1 (inactivating integrins after tyrosine phosphorylation); αEβ7–E-cadherin interaction drives lytic granule polarization at the immunological synapse to promote CTL killing; α4β7 forms a complex with CD4 on T cells and is exploited by HIV-1 gp120 (V2 loop tripeptide) to activate LFA-1 and facilitate viral dissemination; TGF-β1 transcriptionally upregulates β7 via two promoter response regions in a tyrosine-phosphorylation-dependent manner; and in cancer cells, NRF2 directly transactivates ITGB7 downstream of ROS/TRIM2, with ITGB7 activating the FAK/Src/Rac1/NF-κB axis to promote adhesion, migration, and drug resistance."},"narrative":{"teleology":[{"year":1991,"claim":"Cloning of β7 revealed it as a new leukocyte-restricted integrin β subunit, establishing the molecular identity of ITGB7 and its tissue-selective expression pattern.","evidence":"cDNA cloning, sequencing, and Northern blot in leukocyte vs. non-leukocyte cell lines","pmids":["2040612"],"confidence":"High","gaps":["Pairing partners and ligands unknown at this stage","Protein-level expression across tissues not characterized"]},{"year":1992,"claim":"Identification of two β7 heterodimers—α4β7 and αEβ7 (HML-1)—on mucosal lymphocytes defined the combinatorial logic of β7 pairing and showed functional divergence between α4β7 and α4β1 in ligand binding.","evidence":"Immunoprecipitation, N-terminal protein sequencing, cell adhesion assays with blocking antibodies on T and B lymphocytes","pmids":["1372909","1542691","1373725"],"confidence":"High","gaps":["Physiological in vivo homing ligand not yet identified","αEβ7 ligand unknown"]},{"year":1993,"claim":"Discovery that α4β7 is the receptor for the mucosal addressin MAdCAM-1 provided the molecular basis for lymphocyte homing to gut-associated lymphoid tissue, explaining tissue tropism.","evidence":"Antibody blocking assays, adhesion to purified MAdCAM-1 and transfectants, Mn2+ activation","pmids":["7687523"],"confidence":"High","gaps":["Structural basis of MAdCAM-1 recognition unresolved","Relative contribution to rolling vs. firm adhesion unclear"]},{"year":1998,"claim":"Mapping of TGF-β1 response elements in the ITGB7 promoter explained how mucosal cytokine milieu transcriptionally upregulates β7 to shift integrin usage from α4 to αE pairing.","evidence":"Promoter-reporter deletion analysis, gel-shift assays, genistein inhibition of tyrosine kinase signaling","pmids":["9683663"],"confidence":"High","gaps":["Identity of transcription factors binding TGFBRR1/TGFBRR2 not determined","Smad involvement not directly tested"]},{"year":2001,"claim":"Identification of filamin A as a strong binding partner of the β7 cytoplasmic tail, and demonstration that this interaction inhibits cell migration, revealed a mechanism by which β7-containing integrins restrain lymphocyte motility.","evidence":"Gain- and loss-of-function mutagenesis of the β7 tail filamin-binding site, migration and membrane protrusion assays","pmids":["11781567"],"confidence":"High","gaps":["In vivo relevance of filamin-mediated migration inhibition not tested","Filamin binding vs. talin binding competition not yet mapped"]},{"year":2003,"claim":"Mutagenesis of three metal-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain showed that divalent cation occupancy bistably switches α4β7 between rolling and firm adhesion states, providing a structural mechanism for adhesion regulation.","evidence":"Site-directed mutagenesis of metal-binding sites with adhesion assays under defined Ca2+/Mg2+/Mn2+ conditions","pmids":["14608374"],"confidence":"High","gaps":["No crystal structure of β7 I-like domain available","How inside-out signals modulate metal-site occupancy unknown"]},{"year":2003,"claim":"Systematic mapping of PTB domain interactions with β integrin tails (including β7) established that the NPXY motif is a universal docking site for talin, Dok-1, and other PTB-domain proteins, with class-specific selectivity governing activation vs. inactivation.","evidence":"Recombinant PTB domain binding to integrin tails, NPXY mutagenesis, molecular modeling","pmids":["12606711"],"confidence":"High","gaps":["Phosphorylation-dependent switching between talin and Dok-1 not yet shown"]},{"year":2003,"claim":"Peyer's patch dendritic cells were shown to specifically imprint α4β7 and CCR9 expression on T cells, establishing a tissue-specific DC–T cell instruction mechanism for gut homing.","evidence":"DC–T cell co-culture from different anatomical sites, flow cytometry, in vivo homing assays","pmids":["12840763"],"confidence":"High","gaps":["Molecular mediators of imprinting (e.g., retinoic acid) not identified in this study","Whether β7 induction is transcriptional or post-transcriptional not resolved"]},{"year":2007,"claim":"The αEβ7–E-cadherin interaction was shown to recruit the integrin to the immunological synapse and drive lytic granule polarization in CTLs, establishing a direct mechanistic link between β7 and cytotoxic effector function against tumors.","evidence":"Antibody blocking, siRNA knockdown of E-cadherin, confocal microscopy of synapse, cytotoxicity assays","pmids":["17325197"],"confidence":"High","gaps":["Signaling intermediates between αEβ7 engagement and granule polarization uncharacterized","Relevance to non-epithelial tumors not explored"]},{"year":2008,"claim":"HIV-1 gp120 was found to bind α4β7 via a V2-loop tripeptide mimicking natural ligands, activating LFA-1 to promote virological synapse formation—revealing viral exploitation of mucosal integrin signaling for dissemination.","evidence":"Purified gp120–α4β7 binding assays, intracellular signaling assays, antibody blocking","pmids":["18264102"],"confidence":"High","gaps":["Structural details of gp120–α4β7 interface not determined","In vivo contribution to HIV pathogenesis not established at this point"]},{"year":2009,"claim":"NMR analysis of phosphorylated β7 tail demonstrated that tyrosine phosphorylation switches the NPXY motif from talin binding (activating) to Dok-1 binding (inactivating), completing the molecular mechanism of integrin deactivation.","evidence":"NMR with 15N-labeled phosphorylated β7 tail, talin1 D372R mutant, live-cell localization","pmids":["19843520"],"confidence":"High","gaps":["Kinase(s) responsible for β7 tail phosphorylation in vivo not identified","Temporal dynamics of this switch during lymphocyte arrest not measured"]},{"year":2011,"claim":"Reconstitution showed that mechanical strain in actin–filamin networks enhances β integrin tail binding to filamin A while releasing FilGAP, establishing β7 integrin as part of a force-sensing mechanotransduction module.","evidence":"In vitro reconstituted actin–FLNA–β7 tail system, fluorescence loss after photoconversion, rheology","pmids":["21926999"],"confidence":"High","gaps":["Whether this mechanism operates in mucosal lymphocytes under physiological shear unknown","Filamin A conformational change not structurally resolved in this context"]},{"year":2011,"claim":"ITGB7 knockdown in multiple myeloma cells reversed cell-adhesion-mediated drug resistance and reduced FAK/Src/Rac1/NF-κB signaling, demonstrating that β7 can drive pro-survival adhesion signaling in a non-classical cancer context.","evidence":"shRNA knockdown, adhesion and migration assays, in vivo xenograft homing, Western blotting for pathway components","pmids":["21474670"],"confidence":"High","gaps":["α subunit partner in myeloma not definitively identified","Whether this is a direct FAK-interaction or requires co-receptors not resolved"]},{"year":2020,"claim":"NRF2 was identified as a direct transcriptional activator of ITGB7 via an ARE in its promoter, downstream of TRIM2/ROS signaling in pancreatic cancer, expanding known transcriptional regulation beyond TGF-β1.","evidence":"ChIP-like NRF2 binding to ITGB7 ARE, promoter-reporter assays, NAC rescue, in vivo tumorigenicity","pmids":["32929153"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Whether NRF2–ITGB7 axis operates in immune cells unknown","Direct ARE-ITGB7 binding validated only by overexpression-based ChIP approach"]},{"year":null,"claim":"Major open questions include the crystal or cryo-EM structure of β7 I-like domain bound to MAdCAM-1, the in vivo kinase(s) that phosphorylate the β7 tail to trigger talin-to-Dok-1 switching, and whether the filamin A mechanotransduction mechanism operates in mucosal lymphocytes under physiological flow conditions.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of α4β7–MAdCAM-1 complex","In vivo kinase for β7 tail tyrosine phosphorylation unknown","Filamin-mediated mechanosensing not validated in gut-homing lymphocytes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,4,5,8,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,12,17]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,4,11,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10,11,13,14]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,4,5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,18]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,5]}],"complexes":["α4β7 integrin","αEβ7 integrin"],"partners":["ITGA4","ITGAE","FLNA","TLN1","DOK1","MADCAM1","CDH1","CD4"],"other_free_text":[]},"mechanistic_narrative":"ITGB7 encodes the integrin β7 subunit, which pairs with either α4 to form α4β7 or with αE (CD103) to form αEβ7, both of which are central to mucosal immune cell trafficking and tissue retention. α4β7 mediates lymphocyte homing to gut-associated lymphoid tissue by binding MAdCAM-1 as its preferential ligand, as well as fibronectin (CS-1 region) and VCAM-1, with adhesive strength bistably regulated by three divalent cation-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain [PMID:7687523, PMID:14608374]. The β7 cytoplasmic tail engages filamin A to inhibit migration by suppressing membrane protrusion, talin to activate integrin via the NPXY motif, and Dok-1—recruited by tyrosine phosphorylation—to competitively displace talin and inactivate the integrin [PMID:11781567, PMID:19843520]. αEβ7 interaction with E-cadherin at the immunological synapse drives lytic granule polarization in CTLs to promote tumor cell killing, and α4β7 is exploited by HIV-1 gp120 via a V2-loop tripeptide to activate LFA-1 and facilitate viral dissemination [PMID:17325197, PMID:18264102]."},"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 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TGFBRR2: nt -122 to +32) that interact with nuclear protein complexes in a phosphorylation-dependent manner, and TGF-β1-induced beta7 expression requires tyrosine phosphorylation (inhibited by genistein), mediating a switch from LPAM-1 (α4β7) to M290 (αEβ7) expression on T cells.\",\n      \"method\": \"Reporter gene assays, DNase I hypersensitivity mapping, deletion analysis, electrophoretic mobility shift assay (EMSA), protein tyrosine kinase inhibitor (genistein) treatment\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter assay, EMSA, deletion mapping) in a single lab\",\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, linking ROS/NRF2 signaling to integrin/FAK pathway activation in pancreatic cancer cells; TRIM2 drives this axis upstream of NRF2.\",\n      \"method\": \"ChIP/promoter binding assay, luciferase reporter assay, RNAi knockdown, Western blot, N-acetyl-L-cysteine antioxidant rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (promoter reporter, ChIP, rescue) in a single lab\",\n      \"pmids\": [\"32929153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGB7 mediates HPV16 capsid protein L2 (rVL2)-dependent regulation of glucose metabolism in cervical cancer cells; rVL2 suppresses the ITGB7/C/EBPβ signaling axis, reducing expression of glycolytic enzymes GLUT1, LDHA, and ALDOA and inhibiting cell proliferation.\",\n      \"method\": \"Gene-chip assay, RT-PCR, Western blot, glucose uptake/lactate production assay, in vivo animal model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (functional metabolic assays, gene expression, in vivo) in a single lab\",\n      \"pmids\": [\"31819523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ITGB7 pairs with ITGA4 (forming α4β7) or ITGAE (forming αEβ7) on phenotypically distinct decidual dendritic cell subsets that reside in distinct uterine microdomains during pregnancy; ITGA4/ITGB7+ DCs localize to the vascular zone while ITGAE/ITGB7+ DCs localize to the central decidua basalis and myometrium, with ITGA4/ITGB7+ DCs in direct contact with uterine NK cells.\",\n      \"method\": \"Multiparameter flow cytometry, confocal microscopy, immunophenotyping\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional context (DC subset identity, spatial segregation, NK cell contact) using orthogonal imaging and flow cytometry\",\n      \"pmids\": [\"18562709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In pancreatic cancer cells, ITGB7 expression promotes M2 macrophage polarization and modulates immune-related signaling pathways; proteomic (TMT/PRM) analysis identified ITGB7-associated immune and inflammation-related proteins.\",\n      \"method\": \"TMT and PRM proteomic analysis, in vitro and in vivo macrophage polarization assays, RNAi/overexpression, TCGA dataset analysis\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic follow-up is partial; macrophage polarization assay provides functional readout but pathway placement is incomplete\",\n      \"pmids\": [\"41426254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB7 on host HaCaT cells interacts with Trichomonas vaginalis adhesion protein TvAP65 and facilitates HPV infection; knockdown of ITGB7 in HaCaT cells significantly reduced HPV infection rate after T. vaginalis infection.\",\n      \"method\": \"siRNA knockdown, HPV infection rate assay, co-knockdown experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single preprint, single method (knockdown + infection assay), no direct binding characterization of ITGB7-TvAP65 interaction\",\n      \"pmids\": [\"bio_10.1101_2024.09.27.615334\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ITGB7 encodes integrin β7, which heterodimerizes with α4 (forming α4β7/LPAM-1) or αE (forming αEβ7/M290) to mediate lymphocyte homing to gut-associated lymphoid tissue and retention of intraepithelial lymphocytes; its transcription is controlled by TGF-β1 via defined promoter response regions requiring tyrosine phosphorylation, and by NRF2 binding to an ARE element downstream of ROS signaling, while downstream it activates FAK and C/EBPβ signaling pathways and influences macrophage polarization and immune cell localization in multiple tissue contexts.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"The complete amino acid sequence of integrin β7 was determined from overlapping cDNA clones obtained from leukocyte libraries. The β7 protein is predicted to contain a large extracellular portion, a transmembrane domain, and a cytoplasmic tail, with 32–46% identity to other human integrin β subunits and closest similarity to β2 (CD18). β7 mRNA was detected in T and B cell lines and macrophage-like cell lines but not in non-leukocyte cell lines, and phorbol ester stimulation markedly increased β7 mRNA levels in peripheral T cells.\",\n      \"method\": \"cDNA cloning and sequencing, Northern blot analysis, reverse transcription-PCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete sequence determination with expression analysis; foundational characterization paper\",\n      \"pmids\": [\"2040612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Integrin α4β7 (also called α4βP) was identified as the β7-containing heterodimer expressed in TK-1 T lymphoma cells and activated peripheral blood T cells. α4β7 functions as a fibronectin receptor that binds to the CS-1 region (not the RGD sequence) of fibronectin, and also supports adhesion to VCAM-1, both of which are markedly enhanced by PMA stimulation. Anti-α4 and anti-β7 antibodies induce homotypic cell clustering.\",\n      \"method\": \"Anti-peptide antiserum and mAb immunoprecipitation, affinity chromatography, cell adhesion assays, antibody blocking\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IP, affinity chromatography, adhesion assays, blocking) in a single rigorous study\",\n      \"pmids\": [\"1372909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"A family of β7 integrins on human mucosal lymphocytes was characterized: the HML-1 antigen (αEβ7) and α4β7 both use the β7 chain. The HML-1 α-subunit was designated αE (a novel integrin α chain). TGF-β1 reciprocally regulated HML-1 (αEβ7) and LFA-1 expression.\",\n      \"method\": \"N-terminal protein sequencing of purified HML-1 subunit, biochemical characterization, immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — protein sequencing and biochemical identification; foundational paper with multiple methods\",\n      \"pmids\": [\"1542691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"On the JY B lymphoblastoid cell line expressing α4β7 without α4β1, α4β7 makes little or no contribution to fibronectin or VCAM-1 binding under basal conditions; a minor contribution emerges only after PMA stimulation. α4β1 is the functionally dominant VCAM-1 and fibronectin receptor. This demonstrated that the β subunit partner determines the adhesive specificity of α4 integrins.\",\n      \"method\": \"Northern blotting, immunoprecipitation, cell adhesion assays with blocking antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal comparison of α4β7 vs. α4β1 with multiple assays and blocking antibodies\",\n      \"pmids\": [\"1373725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"α4β7 integrin was identified as the receptor for the mucosal vascular addressin MAdCAM-1. Antibodies to α4 and β7 (but not β2/LFA-1) inhibit lymphocyte binding to purified MAdCAM-1 and to MAdCAM-1 transfectants. Mn2+-induced integrin activation enhances binding. MAdCAM-1 is a preferential ligand for α4β7 over α4β1; α4β7 can also bind VCAM-1 but requires greater integrin activation.\",\n      \"method\": \"Antibody blocking assays, cell adhesion to purified MAdCAM-1 and transfectants, Mn2+ activation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal adhesion assays, transfectants, activation studies; highly replicated foundational finding\",\n      \"pmids\": [\"7687523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"α4β7 on human B lymphocytes mediates adhesion to fibronectin and VCAM-1 through distinct epitopes on the integrin. α4β7 expression is absent on resting lymphoid tissue B cells but induced upon activation. α4β7 also participates in homotypic B cell aggregation and co-clusters with α4β1 at fibronectin/VCAM-1-coated surfaces.\",\n      \"method\": \"Immunoprecipitation, cell adhesion assays, antibody blocking, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple adhesion assays with blocking antibodies and multiple cell populations\",\n      \"pmids\": [\"7689608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The β7 integrin gene promoter contains TGF-β1 response regions at nucleotides -509 to -398 (TGFBRR1) and -122 to +32 (TGFBRR2) that drive TGF-β1-induced gene expression. TGF-β1 increases β7 and αE subunit mRNA and M290 (αEβ7) surface expression on T cells while decreasing α4 transcripts. Induced β7 expression is inhibited by the tyrosine kinase inhibitor genistein. TGFBRR1 and TGFBRR2 interact with distinct nuclear protein complexes in a phosphorylation-dependent manner.\",\n      \"method\": \"Promoter-reporter deletion analysis, DNase I hypersensitivity mapping, gel-shift assays, RT-PCR, genistein inhibition\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — deletion analysis with reporter assays, protein-DNA binding, pharmacological inhibition\",\n      \"pmids\": [\"9683663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The β7 integrin cytoplasmic tail binds strongly to filamin A, and this tight filamin binding inhibits integrin-dependent cell migration by suppressing transient membrane protrusion and cell polarization. Amino acid substitutions that selectively ablate filamin binding from the β7 tail (or confer it onto β1A) confirm this mechanistic link: increased filamin binding correlates with reduced migration without affecting fibronectin matrix assembly or focal adhesion formation.\",\n      \"method\": \"Mutagenesis mapping of filamin-binding site, cell migration assays, membrane protrusion analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function mutagenesis with defined phenotypic readouts; replicated mechanistic conclusion\",\n      \"pmids\": [\"11781567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Integrin α4β7 adhesiveness is bistably regulated by a linear array of three divalent cation-binding sites in the β7 I-like domain: MIDAS is required for both rolling and firm adhesion; ADMIDAS (adjacent to MIDAS) negatively regulates via Ca2+ to permit rolling; LIMBS positively responds to low Ca2+ to promote firm adhesion. ADMIDAS mutation converts rolling to firm adhesion; LIMBS mutation converts firm adhesion to rolling.\",\n      \"method\": \"Site-directed mutagenesis of metal-binding sites, adhesion assays under defined ionic conditions (Ca2+, Mg2+, Mn2+)\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of defined structural sites with quantitative adhesion phenotypes\",\n      \"pmids\": [\"14608374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Multiple PTB domain-containing proteins (talin, ICAP1-α, Numb, Dok-1) bind to the NPXY motifs in integrin β cytoplasmic tails via a conserved PTB domain–NPXY ligand interaction. β7 and β3 tail mutations of the NPXY motif block these interactions. Gain- and loss-of-function mutations in the β7 tail confirmed class-specific interactions with particular PTB domains (e.g., Dab, EPS8, tensin show integrin class-specific binding).\",\n      \"method\": \"Recombinant PTB domain binding to integrin tails, mutagenesis, molecular modeling, Co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding with mutagenesis across multiple integrin tails and PTB domains\",\n      \"pmids\": [\"12606711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Peyer's patch dendritic cells selectively imprint gut-homing specificity on T cells by inducing high levels of α4β7 (ITGB7-containing integrin) and CCR9, enabling small intestinal homing. This imprinting is specific to Peyer's patch DCs: peripheral lymph node and spleen DCs induced equivalent activation but did not upregulate α4β7 or gut-homing ability.\",\n      \"method\": \"T cell stimulation with DCs from different anatomical sites, flow cytometry for α4β7 expression, in vivo homing assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular assay with in vivo validation and controlled comparisons across DC populations\",\n      \"pmids\": [\"12840763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"αEβ7 (CD103/ITGB7) interaction with E-cadherin on tumor cells promotes antitumor CTL activity by recruiting αEβ7 to the immunological synapse and driving lytic granule polarization and exocytosis. Blocking anti-CD103 antibody or siRNA knockdown of E-cadherin abrogates tumor cell killing. TGF-β1 treatment of CD103- CTL clones upregulates αEβ7 and potentiates cytotoxicity.\",\n      \"method\": \"Antibody blocking, RNA interference, confocal microscopy of immunological synapse, cytotoxicity assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (antibody blocking, RNAi, confocal imaging) with defined mechanistic readout\",\n      \"pmids\": [\"17325197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of filamin A domains IgFLNa19-21 at 2.5 Å reveals auto-inhibition: the N-terminus of IgFLNa20 forms a β-strand that occupies the integrin β-tail binding site on IgFLNa21. Disrupting this auto-inhibitory IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin β-tails including β7.\",\n      \"method\": \"X-ray crystallography (2.5 Å), mutagenesis, integrin β-tail binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by mutagenesis and binding assays\",\n      \"pmids\": [\"17690686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIV-1 envelope protein gp120 binds to activated α4β7 integrin via a tripeptide motif in the V2 loop of gp120 that mimics natural α4β7 ligands. Engagement of α4β7 by gp120 on CD4+ T cells rapidly activates LFA-1, facilitating formation of virological synapses for cell-to-cell HIV spreading.\",\n      \"method\": \"Binding assays with purified gp120 and α4β7, intracellular signaling assays, antibody blocking, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstration with defined peptide motif, downstream signaling measured\",\n      \"pmids\": [\"18264102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"α4β7high CD4+ T cells are more susceptible to productive HIV-1 infection than α4β7low/neg cells, partly because this subset is metabolically active, CCR5high and CXCR4low. On these cells, α4β7 appears in a complex with CD4, and gp120's specific affinity for α4β7 targets these cells.\",\n      \"method\": \"Flow cytometry, HIV infection assays, co-immunoprecipitation of α4β7 with CD4\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating α4β7/CD4 complex, correlated with functional infection susceptibility\",\n      \"pmids\": [\"19933330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tyrosine phosphorylation of the β7 integrin cytoplasmic tail is a conserved mechanism for regulating integrin activation. Talin1 binds to the NPXY motif and membrane-proximal portion of β7 tail, and tyrosine phosphorylation decreases talin affinity while greatly increasing Dok1 affinity (restricted to the NPXY region). Dok1 acts as a talin competitor that does not form activating membrane-proximal interactions, thereby inhibiting integrin activation.\",\n      \"method\": \"NMR-based protein-protein interaction assay with 15N-labeled phosphorylated β7 tail, mutagenesis, talin1 D372R mutation and live cell localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural analysis with mutagenesis and live cell validation across multiple integrin tails\",\n      \"pmids\": [\"19843520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ITGB7 silencing in multiple myeloma (MM) cells reduces adhesion to fibronectin and E-cadherin, reverses cell-adhesion-mediated drug resistance to bortezomib and melphalan, abrogates SDF1α-driven transwell migration, reduces vessel density in xenografts, and alters in vivo BM homing. Mechanistically, ITGB7 knockdown inhibits FAK and Src phosphorylation, Rac1 activation and SUMOylation, reduces VEGF production in MM–BM stem cell co-cultures, and attenuates p65-NF-κB activity.\",\n      \"method\": \"shRNA knockdown, cell adhesion assays, transwell migration, in vivo xenograft and homing assays, Western blotting for FAK/Src/Rac1/NF-κB\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — shRNA KD with multiple orthogonal in vitro and in vivo phenotypic readouts and defined signaling pathway endpoints\",\n      \"pmids\": [\"21474670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mechanical strain in actin networks differentially regulates binding of β-integrin cytoplasmic tails and FilGAP to filamin A (FLNA). Strain increases β-integrin tail binding to FLNA while causing FilGAP to dissociate, providing a direct molecular basis for mechanotransduction. The β7 integrin tail was used in the reconstituted minimal system (actin + FLNA + β-integrin tail + FilGAP).\",\n      \"method\": \"In vitro reconstitution with purified components, fluorescence loss after photoconversion, rheological measurement of actin network strain\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted minimal system with direct measurement of strain-dependent binding\",\n      \"pmids\": [\"21926999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In pancreatic cancer, TRIM2 activates NRF2 via ROS signaling, and NRF2 directly binds to an antioxidant response element (ARE) in the ITGB7 promoter to enhance ITGB7 transcription. ITGB7 in turn activates the FAK pathway. Antioxidant N-acetyl-L-cysteine treatment reduces ROS, NRF2, and ITGB7 levels; NRF2 nuclear translocation rescues inhibited ITGB7 transcription.\",\n      \"method\": \"siRNA/shRNA knockdown, NAC antioxidant treatment, promoter-reporter assay, ChIP-like NRF2 binding to ARE, Western blotting, in vivo tumorigenicity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — promoter binding and rescue experiments in single lab; NRF2-ARE-ITGB7 axis mechanistically defined\",\n      \"pmids\": [\"32929153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Recombinant HPV16 capsid protein L2 (rVL2) suppresses glucose metabolism in cervical cancer cells by inhibiting the ITGB7/C/EBPβ signaling pathway, reducing expression of GLUT1, LDHA, and ALDOA. Inhibition of ITGB7 mediates rVL2-induced decreases in glucose uptake and lactate production, and consequent inhibition of proliferation.\",\n      \"method\": \"Gene-chip assay, RT-PCR, Western blot, glucose uptake and lactate production assays, in vivo animal model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement via expression and pharmacological manipulation; single lab without genetic rescue\",\n      \"pmids\": [\"31819523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In the pregnant mouse uterus, ITGB7-positive decidual leukocytes are predominantly dendritic cells forming three phenotypically distinct subsets defined by differential expression of ITGA4/ITGB7 vs. ITGAE/ITGB7. These subsets reside in distinct uterine microdomains: ITGA4/ITGB7+ DCs localize to the vascular zone and make direct contact with uterine NK cells, while ITGAE/ITGB7+ DCs localize to the central decidua basalis and myometrium.\",\n      \"method\": \"Multiparameter flow cytometry, confocal microscopy\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by flow cytometry and confocal microscopy; functional implication from DC–uNK cell contact\",\n      \"pmids\": [\"18562709\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB7 encodes the integrin β7 subunit that pairs with αE (CD103) or α4 to form αEβ7 and α4β7 heterodimers on mucosal lymphocytes; α4β7 mediates lymphocyte homing to gut-associated lymphoid tissue by binding MAdCAM-1 (preferential ligand), fibronectin CS-1, and VCAM-1 in a divalent-cation-regulated manner controlled by three metal-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain; the β7 cytoplasmic tail engages filamin A (inhibiting migration and membrane protrusion), talin (activating integrins via NPXY motif), and Dok-1 (inactivating integrins after tyrosine phosphorylation); αEβ7–E-cadherin interaction drives lytic granule polarization at the immunological synapse to promote CTL killing; α4β7 forms a complex with CD4 on T cells and is exploited by HIV-1 gp120 (V2 loop tripeptide) to activate LFA-1 and facilitate viral dissemination; TGF-β1 transcriptionally upregulates β7 via two promoter response regions in a tyrosine-phosphorylation-dependent manner; and in cancer cells, NRF2 directly transactivates ITGB7 downstream of ROS/TRIM2, with ITGB7 activating the FAK/Src/Rac1/NF-κB axis to promote adhesion, migration, and drug resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGB7 encodes integrin β7, which heterodimerizes with integrin α4 (forming α4β7/LPAM-1) or αE (forming αE β7/M290) to direct lymphocyte and dendritic cell localization in tissue-specific microenvironments [PMID:9683663, PMID:18562709]. Transcription of ITGB7 is regulated by TGF-β1 through two promoter response regions in a tyrosine-phosphorylation-dependent manner, controlling the switch between α4β7 and αEβ7 expression on T cells, and independently by NRF2 binding to an antioxidant response element in the promoter downstream of ROS signaling, which couples ITGB7 to FAK pathway activation in pancreatic cancer cells [PMID:9683663, PMID:32929153]. ITGB7 also signals through a C/EBPβ axis to regulate glycolytic enzyme expression and glucose metabolism in cervical cancer cells [PMID:31819523].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining how TGF-β1 transcriptionally controls integrin β7 resolved the mechanism by which T cells switch from α4β7 to αEβ7 surface expression, establishing that the ITGB7 promoter contains two distinct TGF-β1-response regions whose activity depends on tyrosine phosphorylation.\",\n      \"evidence\": \"Reporter gene assays, DNase I hypersensitivity mapping, EMSA, and genistein inhibitor treatment in T cell lines\",\n      \"pmids\": [\"9683663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the transcription factors binding TGFBRR1 and TGFBRR2 was not determined\",\n        \"Specific tyrosine kinase(s) required downstream of TGF-β1 remain unidentified\",\n        \"Findings from a single laboratory without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that α4β7+ and αEβ7+ decidual dendritic cell subsets segregate to distinct uterine microdomains established that ITGB7-containing integrins direct immune cell positioning in non-gut tissues and mediate direct contact with uterine NK cells.\",\n      \"evidence\": \"Multiparameter flow cytometry and confocal microscopy on human decidual tissue\",\n      \"pmids\": [\"18562709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ligands mediating DC retention in each uterine microdomain were not identified\",\n        \"Functional consequence of α4β7+ DC–NK cell contact was not tested\",\n        \"No loss-of-function experiments to confirm ITGB7 requirement for spatial segregation\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that ITGB7 signals through C/EBPβ to sustain glycolytic enzyme expression revealed a non-canonical downstream signaling role for integrin β7 in cancer cell metabolism, distinct from its canonical adhesion/homing functions.\",\n      \"evidence\": \"Gene-chip, RT-PCR, Western blot, glucose uptake and lactate production assays, and in vivo tumor model in cervical cancer cells\",\n      \"pmids\": [\"31819523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How ITGB7 activates C/EBPβ is mechanistically undefined\",\n        \"Whether this metabolic axis operates outside of HPV-associated cervical cancer is unknown\",\n        \"Alpha subunit partner mediating this signaling was not specified\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying NRF2 as a direct transcriptional activator of ITGB7 via an ARE element connected ROS sensing to integrin/FAK signaling and placed TRIM2 upstream of this regulatory axis in pancreatic cancer.\",\n      \"evidence\": \"ChIP, luciferase reporter, RNAi knockdown, and NAC antioxidant rescue in pancreatic cancer cell lines\",\n      \"pmids\": [\"32929153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NRF2-driven ITGB7 transcription operates in normal immune cells or only in cancer is untested\",\n        \"No structural or biochemical detail on the ARE element or NRF2 binding mode\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proteomic profiling linked ITGB7 expression in pancreatic cancer to M2 macrophage polarization and immune-related protein networks, suggesting a tumor-microenvironment-shaping role, though the mechanistic pathway remains incompletely defined.\",\n      \"evidence\": \"TMT/PRM proteomics, macrophage polarization assays in vitro and in vivo, TCGA analysis\",\n      \"pmids\": [\"41426254\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic pathway from ITGB7 to macrophage polarization is not established\",\n        \"Proteomic associations lack validation by targeted perturbation of individual mediators\",\n        \"No receptor–ligand interaction identified between cancer cell ITGB7 and macrophage surface molecules\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the identity of transcription factors at the TGF-β1 response regions, the mechanism linking ITGB7 to C/EBPβ activation, whether NRF2-driven ITGB7 induction is relevant in normal immune biology, and the structural basis for β7 heterodimer partner selectivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of β7 integrin heterodimer selectivity\",\n        \"Downstream signaling intermediates between ITGB7 and C/EBPβ are undefined\",\n        \"Physiological relevance of NRF2-ITGB7 axis in non-cancer contexts is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA4\", \"ITGAE\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in the pathway section. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"ITGB7 encodes integrin β7, which heterodimerizes with integrin α4 (forming α4β7/LPAM-1) or αE (forming αEβ7/M290) to direct lymphocyte and dendritic cell localization in tissue-specific microenvironments [PMID:9683663, PMID:18562709]. Transcription of ITGB7 is regulated by TGF-β1 through two promoter response regions in a tyrosine-phosphorylation-dependent manner, controlling the switch between α4β7 and αEβ7 expression on T cells, and independently by NRF2 binding to an antioxidant response element downstream of ROS signaling, which couples ITGB7 to FAK pathway activation in pancreatic cancer cells [PMID:9683663, PMID:32929153]. ITGB7 also signals through a C/EBPβ axis to regulate glycolytic enzyme expression and glucose metabolism in cervical cancer cells [PMID:31819523].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining how TGF-β1 transcriptionally controls integrin β7 resolved the mechanism by which T cells switch from α4β7 to αEβ7 surface expression, establishing that the ITGB7 promoter contains two distinct TGF-β1-response regions whose activity depends on tyrosine phosphorylation.\",\n      \"evidence\": \"Reporter gene assays, DNase I hypersensitivity mapping, EMSA, and genistein inhibitor treatment in T cell lines\",\n      \"pmids\": [\"9683663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the transcription factors binding TGFBRR1 and TGFBRR2 was not determined\",\n        \"Specific tyrosine kinase(s) required downstream of TGF-β1 remain unidentified\",\n        \"Findings from a single laboratory without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that α4β7+ and αEβ7+ decidual dendritic cell subsets segregate to distinct uterine microdomains established that ITGB7-containing integrins direct immune cell positioning in non-gut tissues and mediate direct contact with uterine NK cells.\",\n      \"evidence\": \"Multiparameter flow cytometry and confocal microscopy on human decidual tissue\",\n      \"pmids\": [\"18562709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ligands mediating DC retention in each uterine microdomain were not identified\",\n        \"Functional consequence of α4β7+ DC–NK cell contact was not tested\",\n        \"No loss-of-function experiments to confirm ITGB7 requirement for spatial segregation\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that ITGB7 signals through C/EBPβ to sustain glycolytic enzyme expression revealed a non-canonical downstream signaling role for integrin β7 in cancer cell metabolism, distinct from its canonical adhesion/homing functions.\",\n      \"evidence\": \"Gene-chip, RT-PCR, Western blot, glucose uptake and lactate production assays, and in vivo tumor model in cervical cancer cells\",\n      \"pmids\": [\"31819523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How ITGB7 activates C/EBPβ is mechanistically undefined\",\n        \"Whether this metabolic axis operates outside of HPV-associated cervical cancer is unknown\",\n        \"Alpha subunit partner mediating this signaling was not specified\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying NRF2 as a direct transcriptional activator of ITGB7 via an ARE element connected ROS sensing to integrin/FAK signaling and placed TRIM2 upstream of this regulatory axis in pancreatic cancer.\",\n      \"evidence\": \"ChIP, luciferase reporter, RNAi knockdown, and NAC antioxidant rescue in pancreatic cancer cell lines\",\n      \"pmids\": [\"32929153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NRF2-driven ITGB7 transcription operates in normal immune cells or only in cancer is untested\",\n        \"No structural or biochemical detail on the ARE element or NRF2 binding mode\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proteomic profiling linked ITGB7 expression in pancreatic cancer to M2 macrophage polarization and immune-related protein networks, suggesting a tumor-microenvironment-shaping role, though the mechanistic pathway remains incompletely defined.\",\n      \"evidence\": \"TMT/PRM proteomics, macrophage polarization assays in vitro and in vivo, TCGA analysis\",\n      \"pmids\": [\"41426254\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic pathway from ITGB7 to macrophage polarization is not established\",\n        \"Proteomic associations lack validation by targeted perturbation of individual mediators\",\n        \"No receptor–ligand interaction identified between cancer cell ITGB7 and macrophage surface molecules\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the identity of transcription factors at the TGF-β1 response regions, the mechanism linking ITGB7 to C/EBPβ activation, whether NRF2-driven ITGB7 induction is relevant in normal immune biology, and the structural basis for β7 heterodimer partner selectivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of β7 integrin heterodimer selectivity\",\n        \"Downstream signaling intermediates between ITGB7 and C/EBPβ are undefined\",\n        \"Physiological relevance of NRF2-ITGB7 axis in non-cancer contexts is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA4\", \"ITGAE\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ITGB7 encodes the integrin β7 subunit, which pairs with either α4 to form α4β7 or with αE (CD103) to form αEβ7, both of which are central to mucosal immune cell trafficking and tissue retention. α4β7 mediates lymphocyte homing to gut-associated lymphoid tissue by binding MAdCAM-1 as its preferential ligand, as well as fibronectin (CS-1 region) and VCAM-1, with adhesive strength bistably regulated by three divalent cation-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain [PMID:7687523, PMID:14608374]. The β7 cytoplasmic tail engages filamin A to inhibit migration by suppressing membrane protrusion, talin to activate integrin via the NPXY motif, and Dok-1—recruited by tyrosine phosphorylation—to competitively displace talin and inactivate the integrin [PMID:11781567, PMID:19843520]. αEβ7 interaction with E-cadherin at the immunological synapse drives lytic granule polarization in CTLs to promote tumor cell killing, and α4β7 is exploited by HIV-1 gp120 via a V2-loop tripeptide to activate LFA-1 and facilitate viral dissemination [PMID:17325197, PMID:18264102].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Cloning of β7 revealed it as a new leukocyte-restricted integrin β subunit, establishing the molecular identity of ITGB7 and its tissue-selective expression pattern.\",\n      \"evidence\": \"cDNA cloning, sequencing, and Northern blot in leukocyte vs. non-leukocyte cell lines\",\n      \"pmids\": [\"2040612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pairing partners and ligands unknown at this stage\", \"Protein-level expression across tissues not characterized\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Identification of two β7 heterodimers—α4β7 and αEβ7 (HML-1)—on mucosal lymphocytes defined the combinatorial logic of β7 pairing and showed functional divergence between α4β7 and α4β1 in ligand binding.\",\n      \"evidence\": \"Immunoprecipitation, N-terminal protein sequencing, cell adhesion assays with blocking antibodies on T and B lymphocytes\",\n      \"pmids\": [\"1372909\", \"1542691\", \"1373725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological in vivo homing ligand not yet identified\", \"αEβ7 ligand unknown\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Discovery that α4β7 is the receptor for the mucosal addressin MAdCAM-1 provided the molecular basis for lymphocyte homing to gut-associated lymphoid tissue, explaining tissue tropism.\",\n      \"evidence\": \"Antibody blocking assays, adhesion to purified MAdCAM-1 and transfectants, Mn2+ activation\",\n      \"pmids\": [\"7687523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MAdCAM-1 recognition unresolved\", \"Relative contribution to rolling vs. firm adhesion unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping of TGF-β1 response elements in the ITGB7 promoter explained how mucosal cytokine milieu transcriptionally upregulates β7 to shift integrin usage from α4 to αE pairing.\",\n      \"evidence\": \"Promoter-reporter deletion analysis, gel-shift assays, genistein inhibition of tyrosine kinase signaling\",\n      \"pmids\": [\"9683663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of transcription factors binding TGFBRR1/TGFBRR2 not determined\", \"Smad involvement not directly tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of filamin A as a strong binding partner of the β7 cytoplasmic tail, and demonstration that this interaction inhibits cell migration, revealed a mechanism by which β7-containing integrins restrain lymphocyte motility.\",\n      \"evidence\": \"Gain- and loss-of-function mutagenesis of the β7 tail filamin-binding site, migration and membrane protrusion assays\",\n      \"pmids\": [\"11781567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of filamin-mediated migration inhibition not tested\", \"Filamin binding vs. talin binding competition not yet mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mutagenesis of three metal-binding sites (MIDAS, ADMIDAS, LIMBS) in the β7 I-like domain showed that divalent cation occupancy bistably switches α4β7 between rolling and firm adhesion states, providing a structural mechanism for adhesion regulation.\",\n      \"evidence\": \"Site-directed mutagenesis of metal-binding sites with adhesion assays under defined Ca2+/Mg2+/Mn2+ conditions\",\n      \"pmids\": [\"14608374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of β7 I-like domain available\", \"How inside-out signals modulate metal-site occupancy unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Systematic mapping of PTB domain interactions with β integrin tails (including β7) established that the NPXY motif is a universal docking site for talin, Dok-1, and other PTB-domain proteins, with class-specific selectivity governing activation vs. inactivation.\",\n      \"evidence\": \"Recombinant PTB domain binding to integrin tails, NPXY mutagenesis, molecular modeling\",\n      \"pmids\": [\"12606711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation-dependent switching between talin and Dok-1 not yet shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Peyer's patch dendritic cells were shown to specifically imprint α4β7 and CCR9 expression on T cells, establishing a tissue-specific DC–T cell instruction mechanism for gut homing.\",\n      \"evidence\": \"DC–T cell co-culture from different anatomical sites, flow cytometry, in vivo homing assays\",\n      \"pmids\": [\"12840763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mediators of imprinting (e.g., retinoic acid) not identified in this study\", \"Whether β7 induction is transcriptional or post-transcriptional not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The αEβ7–E-cadherin interaction was shown to recruit the integrin to the immunological synapse and drive lytic granule polarization in CTLs, establishing a direct mechanistic link between β7 and cytotoxic effector function against tumors.\",\n      \"evidence\": \"Antibody blocking, siRNA knockdown of E-cadherin, confocal microscopy of synapse, cytotoxicity assays\",\n      \"pmids\": [\"17325197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between αEβ7 engagement and granule polarization uncharacterized\", \"Relevance to non-epithelial tumors not explored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"HIV-1 gp120 was found to bind α4β7 via a V2-loop tripeptide mimicking natural ligands, activating LFA-1 to promote virological synapse formation—revealing viral exploitation of mucosal integrin signaling for dissemination.\",\n      \"evidence\": \"Purified gp120–α4β7 binding assays, intracellular signaling assays, antibody blocking\",\n      \"pmids\": [\"18264102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of gp120–α4β7 interface not determined\", \"In vivo contribution to HIV pathogenesis not established at this point\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"NMR analysis of phosphorylated β7 tail demonstrated that tyrosine phosphorylation switches the NPXY motif from talin binding (activating) to Dok-1 binding (inactivating), completing the molecular mechanism of integrin deactivation.\",\n      \"evidence\": \"NMR with 15N-labeled phosphorylated β7 tail, talin1 D372R mutant, live-cell localization\",\n      \"pmids\": [\"19843520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for β7 tail phosphorylation in vivo not identified\", \"Temporal dynamics of this switch during lymphocyte arrest not measured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reconstitution showed that mechanical strain in actin–filamin networks enhances β integrin tail binding to filamin A while releasing FilGAP, establishing β7 integrin as part of a force-sensing mechanotransduction module.\",\n      \"evidence\": \"In vitro reconstituted actin–FLNA–β7 tail system, fluorescence loss after photoconversion, rheology\",\n      \"pmids\": [\"21926999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates in mucosal lymphocytes under physiological shear unknown\", \"Filamin A conformational change not structurally resolved in this context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"ITGB7 knockdown in multiple myeloma cells reversed cell-adhesion-mediated drug resistance and reduced FAK/Src/Rac1/NF-κB signaling, demonstrating that β7 can drive pro-survival adhesion signaling in a non-classical cancer context.\",\n      \"evidence\": \"shRNA knockdown, adhesion and migration assays, in vivo xenograft homing, Western blotting for pathway components\",\n      \"pmids\": [\"21474670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"α subunit partner in myeloma not definitively identified\", \"Whether this is a direct FAK-interaction or requires co-receptors not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"NRF2 was identified as a direct transcriptional activator of ITGB7 via an ARE in its promoter, downstream of TRIM2/ROS signaling in pancreatic cancer, expanding known transcriptional regulation beyond TGF-β1.\",\n      \"evidence\": \"ChIP-like NRF2 binding to ITGB7 ARE, promoter-reporter assays, NAC rescue, in vivo tumorigenicity\",\n      \"pmids\": [\"32929153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication needed\", \"Whether NRF2–ITGB7 axis operates in immune cells unknown\", \"Direct ARE-ITGB7 binding validated only by overexpression-based ChIP approach\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the crystal or cryo-EM structure of β7 I-like domain bound to MAdCAM-1, the in vivo kinase(s) that phosphorylate the β7 tail to trigger talin-to-Dok-1 switching, and whether the filamin A mechanotransduction mechanism operates in mucosal lymphocytes under physiological flow conditions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of α4β7–MAdCAM-1 complex\", \"In vivo kinase for β7 tail tyrosine phosphorylation unknown\", \"Filamin-mediated mechanosensing not validated in gut-homing lymphocytes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 4, 5, 8, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 12, 17]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 4, 11, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"complexes\": [\n      \"α4β7 integrin\",\n      \"αEβ7 integrin\"\n    ],\n    \"partners\": [\n      \"ITGA4\",\n      \"ITGAE\",\n      \"FLNA\",\n      \"TLN1\",\n      \"DOK1\",\n      \"MADCAM1\",\n      \"CDH1\",\n      \"CD4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}