{"gene":"ITGB4","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"The ITGB4 gene spans 36 kb on chromosome 17q11-qter, consists of 41 exons, and undergoes alternative splicing in various cell types. A homozygous splice-site mutation causes premature termination codons via cryptic splice sites, dramatically reducing mRNA transcript levels and abolishing β4 integrin expression at the dermal-epidermal basement membrane zone, leading to junctional epidermolysis bullosa with pyloric atresia.","method":"RT-PCR, heteroduplex analysis, nucleotide sequencing of PCR products spanning all exons, immunofluorescence staining of patient skin","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — genomic organization established by direct sequencing across 41 exons, mutation-to-phenotype linkage confirmed by RT-PCR showing mRNA loss and IF showing absent protein, replicated across multiple patient studies","pmids":["9194858"],"is_preprint":false},{"year":1997,"finding":"Loss-of-function frameshift mutations in both ITGB4 alleles result in absent α6 integrin staining and markedly reduced β4 integrin staining by immunofluorescence, demonstrating that α6 and β4 integrin subunits are closely associated and that ITGB4 is critical for physiologic stability of the dermal-epidermal junction.","method":"PCR amplification, heteroduplex analysis, direct nucleotide sequencing, immunofluorescence of patient skin","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein loss demonstrated by IF in patient tissue, replicated across multiple independent EB-PA patient studies","pmids":["9182827"],"is_preprint":false},{"year":1998,"finding":"Missense mutations in ITGB4 (rather than premature termination codons) underlie nonlethal epidermolysis bullosa with pyloric atresia phenotypes; missense mutations in cysteine residues (e.g., C61Y) can be lethal, indicating position-dependent consequences. Premature termination codons are predominantly associated with lethal variants, while missense mutations allow synthesis of some functional, albeit perturbed, β4 polypeptide.","method":"Mutation analysis by heteroduplex analysis and nucleotide sequencing, immunofluorescence staining of patient skin for α6 and β4 integrins","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genotype-phenotype correlations established across five families with orthogonal mutation analysis and protein-level IF, independently replicated across multiple subsequent studies","pmids":["9792864","9422533","11328943"],"is_preprint":false},{"year":1998,"finding":"A missense mutation (L156P) in ITGB4 disrupts a conserved residue across human, rodent, and Drosophila integrin-β polypeptides and is predicted to disrupt α-helix formation; the companion nonsense mutation (R554X) results in undetectable mRNA by RT-PCR, consistent with nonsense-mediated decay.","method":"Heteroduplex analysis, nucleotide sequencing, RT-PCR, Garnier α-helicity plot structural prediction","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA detection by RT-PCR for the nonsense allele; structural consequence of missense predicted computationally, single lab","pmids":["9546354"],"is_preprint":false},{"year":2008,"finding":"Conditional deletion of Itgb4 specifically in Schwann cells leads to delayed motor nerve regeneration after sciatic nerve crush, reduced number of newly outgrowing nerve sprouts, fewer and thinner myelinated axons, and higher g-ratio, demonstrating that α6β4 integrin plays an essential role in axonal regeneration and myelination in peripheral nerves.","method":"Cre-mediated conditional knockout in Schwann cells, sciatic nerve crush model, motor/sensory function testing, neurofilament-200 immunostaining, morphometric analysis, laminin immunostaining","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO with multiple orthogonal phenotypic readouts (functional, histological, morphometric) in a defined in vivo model","pmids":["18971471"],"is_preprint":false},{"year":2010,"finding":"ITGB4 expression is upregulated at the leading edge of mechanically wounded airway epithelial cells and after ozone stress, and is decreased in OVA-challenged asthma model airways. Overexpression of ITGB4 promotes wound repair and anti-oxidative capacity in rat tracheal epithelial cells, while ITGB4 silencing blocks these abilities.","method":"Overexpression vector and siRNA knockdown in primary rat tracheal epithelial cells and 16HBE14O cells, scratch wound repair assay, OVA asthma mouse model, immunostaining","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments in primary cells with defined phenotypic readout, single lab with two orthogonal approaches","pmids":["20364299"],"is_preprint":false},{"year":2016,"finding":"A heterozygous missense mutation (c.433G>T, p.Asp145Tyr) in exon 5 of ITGB4 exerts a dominant-negative effect and co-segregates with an autosomal dominant epidermolysis bullosa phenotype characterized by nail dystrophy and mild acral blistering, establishing for the first time a dominant mode of ITGB4 inheritance in EB.","method":"Whole-gene sequencing of all EB-associated genes, segregation analysis in extended family, sequencing of unaffected relatives and controls","journal":"JAMA dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complete segregation analysis in extended family with negative controls, single study establishing dominant-negative mechanism","pmids":["26817667"],"is_preprint":false},{"year":2017,"finding":"RUNX1 binds to and activates the ITGB4 gene promoter in myeloid cells, but does so without a canonical RUNX1 consensus binding motif, and may involve interactions between the promoter and upstream regulatory elements, indicating a distinct transcriptional mechanism compared to ITGA6 regulation.","method":"Chromatin immunoprecipitation (ChIP), promoter reporter assays, RUNX1 overexpression/knockdown in myeloid cell lines","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays in a single lab; mechanism partially characterized (no consensus binding site identified)","pmids":["28926098"],"is_preprint":false},{"year":2018,"finding":"Epithelial cell-specific ITGB4 deletion leads to severe allergen-induced airway inflammation and airway hyper-responsiveness (AHR) in mice, with increased lymphocyte, eosinophil, and neutrophil infiltration, elevated Th2 (IL-4, IL-13) and Th17 (IL-17A) cytokines, and enhanced disruption of epithelial barrier integrity leading to increased thymic stromal lymphopoietin (TSLP) secretion.","method":"Conditional epithelial ITGB4 knockout mice, house dust mite challenge asthma model, flow cytometry, ELISA, AHR measurement","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO with multiple orthogonal mechanistic readouts (cytokines, barrier function, TSLP) in defined in vivo model","pmids":["29393977"],"is_preprint":false},{"year":2018,"finding":"Deletion of TMEM268 promotes ITGB4 ubiquitin-mediated degradation, increasing instability of ITGB4 and filamin A (FLNA), and causing disassociation of the ITGB4/plectin (PLEC) complex and cytoskeleton remodeling. TMEM268 interacts with ITGB4 through a C-terminal interaction.","method":"CRISPR/siRNA knockout in gastric cancer cells, co-immunoprecipitation, ubiquitination assay, Western blot, xenograft mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus ubiquitination assay plus rescue experiments in a single lab; mechanism confirmed in vivo by xenograft","pmids":["30361615"],"is_preprint":false},{"year":2019,"finding":"ITGB4-overexpressing triple negative breast cancer cells transfer ITGB4 protein to cancer-associated fibroblasts (CAFs) via exosomes, where it induces BNIP3L-dependent mitophagy and lactate production (glycolysis) in CAFs. This ITGB4-induced metabolic reprogramming of CAFs promotes cancer cell proliferation, EMT, and invasion. The effect is suppressed by ITGB4 knockdown in cancer cells, inhibition of exosome generation, or blocking c-Jun or AMPK phosphorylation in CAFs.","method":"Exosome co-culture assays, ITGB4 knockdown/overexpression, mitophagy assays, AMPK/c-Jun phosphorylation inhibition, co-transplant mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (exosome inhibition, ITGB4 KD, signaling inhibitors) in a single lab with in vivo validation","pmids":["31534187"],"is_preprint":false},{"year":2019,"finding":"ITGB4 deficiency in airway epithelial cells induces cellular senescence through activation of the p53 pathway, both in vitro (under oxidative stress or inflammatory stimulation) and in vivo.","method":"ITGB4 knockdown/overexpression in airway epithelial cells, senescence assays (SA-β-gal, p21, p53 activation), in vivo mouse model","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway (p53 activation) confirmed in vitro and in vivo, single lab","pmids":["30636108"],"is_preprint":false},{"year":2020,"finding":"ITGB4 phosphorylation at tyrosine Y1510 (p-ITGB4-Y1510) promotes pancreatic cancer cell migration and invasion. Expression of the Y1510A mutant blocks ITGB4 phosphorylation, suppresses ITGB4 protein expression, and decreases phosphorylation of MEK1 (T292) and ERK1/2, but does not affect MEK1 (T386) or MEK2 (T394) phosphorylation, placing p-ITGB4-Y1510 upstream of MEK1-ERK1/2 signaling.","method":"Site-directed mutagenesis (Y1510A), siRNA knockdown, overexpression in pancreatic cancer cell lines, Western blot, migration/invasion assays, immunohistochemistry in patient tissues","journal":"Bosnian journal of basic medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with specific pathway readout, single lab, two orthogonal methods","pmids":["31242404"],"is_preprint":false},{"year":2021,"finding":"FLRT2 directly associates with ITGB4 and promotes ITGB4 phosphorylation. Inhibition of ITGB4 substantially mitigates endothelial cell senescence triggered by FLRT2 depletion. FLRT2 mediates endothelial cell senescence via mTOR complex 2 (mTORC2), AKT, and p53 signaling downstream of ITGB4.","method":"Co-immunoprecipitation, siRNA knockdown of ITGB4 and FLRT2 in human endothelial cells, FLRT2 silencing in mice, Western blot for signaling pathway components, senescence assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction plus pathway rescue experiment, in vivo mouse validation, single lab","pmids":["38587072"],"is_preprint":false},{"year":2021,"finding":"PSMA interacts with ITGB4 (demonstrated by immunoprecipitation) and activates NF-κB signaling to promote angiogenesis in glioblastoma endothelial cells.","method":"High-throughput sequencing, co-immunoprecipitation, PSMA overexpression in HUVECs, PSMA inhibitor (2-PMPA) treatment, tube formation assay, in vivo GBM model","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying interaction, downstream pathway assignment without direct mutagenesis of ITGB4 interaction domain, single lab","pmids":["33748101"],"is_preprint":false},{"year":2022,"finding":"METTL14 facilitates m6A modification on the 3′UTR of ITGB4 mRNA, which is then recognized by the m6A reader YTHDF2, promoting ITGB4 mRNA degradation. METTL14 knockdown promotes ccRCC cell migration, invasion, and metastasis by overexpressing ITGB4 and stimulating the PI3K/AKT pathway and EMT.","method":"m6A RNA immunoprecipitation (MeRIP), RIP assay, luciferase reporter assay, METTL14 and YTHDF2 knockdown/overexpression, in vitro migration/invasion assays, in vivo metastasis model","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — MeRIP + RIP + luciferase reporter as orthogonal methods confirming m6A writing and YTHDF2 reading of ITGB4 mRNA with functional validation in vivo, single lab with multiple Tier 1 methods","pmids":["35305660"],"is_preprint":false},{"year":2022,"finding":"NEDD4L (an E3 ubiquitin ligase) directly binds ITGB4 via its HECT domain interacting with the Galx-β domain of ITGB4, and ubiquitinates ITGB4 at the K915 site, promoting its proteasomal degradation and suppressing esophageal carcinoma progression.","method":"Co-immunoprecipitation, proteome analysis, ubiquitination assay with domain mapping (HECT domain and Galx-β domain), site-specific K915 identification, in vitro and in vivo functional assays","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — Co-IP with domain mapping, specific ubiquitination site (K915) identified, in vivo validation, single lab with multiple Tier 1 methods","pmids":["38831335"],"is_preprint":false},{"year":2022,"finding":"ITGB4 deficiency in airway epithelial cells leads to mucus hypersecretion and MUC5AC overexpression through the EGFR/ERK/c-Jun pathway. Inhibition of EGFR reverses mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection.","method":"ITGB4 conditional knockout mice, RSV infection model, EGFR inhibitor treatment, Western blot, siRNA knockdown in HBE cells, MUC5AC quantification","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placed by pharmacological inhibition plus KO mouse model, single lab","pmids":["34975337"],"is_preprint":false},{"year":2022,"finding":"Conditional knockout of ITGB4 from airway epithelial cells induces airway remodeling in an HDM asthma mouse model through enhanced EMTU activation mediated by the SHP2/JNK/c-Jun/FGF2 signaling pathway, largely independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling.","method":"AEC-specific ITGB4 conditional knockout mice, HDM challenge asthma model, JNK and FGF2 inhibitor treatment, Western blot, siRNA knockdown in primary human bronchial epithelial cells","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO with pathway-specific inhibitor validation of SHP2/JNK/c-Jun/FGF2 axis, confirmed in vitro and in vivo, single lab with multiple orthogonal methods","pmids":["36243221"],"is_preprint":false},{"year":2022,"finding":"ITGB4 deficiency in airway epithelial cells downregulates HDAC1 expression, which in turn aggravates DNA damage (increased 8-oxoG and γ-H2AX) under HDM or ozone stress. Restoring HDAC1 expression reverses the enhanced DNA damage caused by ITGB4 deficiency.","method":"ITGB4 conditional knockout mice, ITGB4 siRNA in airway epithelial cells, HDM/ozone challenge models, HDAC1 rescue experiments, γ-H2AX and 8-oxoG staining","journal":"Pediatric allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway established by rescue experiment (HDAC1 restoration reverses phenotype), single lab with in vivo and in vitro validation","pmids":["36282138"],"is_preprint":false},{"year":2022,"finding":"Low shear stress (LSS) increases ITGB4 protein expression in endothelial cells. ITGB4, SRC, and NF-κB form a positive feedback loop: ITGB4 knockdown reduces SRC and NF-κB phosphorylation, NF-κB knockdown inhibits ITGB4 production and SRC phosphorylation, and SRC knockdown downregulates ITGB4 expression and NF-κB activation. ITGB4 knockdown reduces atherosclerotic lesion areas in ApoE-/- mice fed HFD.","method":"siRNA knockdown in HUVECs under LSS conditions, phosphorylation analysis of SRC/FAK/NFκB, atherosclerosis mouse model (ApoE-/- + HFD), Western blot","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis-like knockdown experiments establishing a feedback loop, in vivo validation, single lab","pmids":["36329801"],"is_preprint":false},{"year":2022,"finding":"Activation of GRP78 ATPase by HOCl probe ZBM-H promotes autophagy-mediated degradation of ITGB4 in A549 lung cancer cells by promoting the interaction between ANXA7 and Hsc70, which mediates selective autophagy of ITGB4. Blocking autophagy (with 3BDO) partially rescues ITGB4 protein levels and cell migration.","method":"Chemical biology (HOCl probe ZBM-H), autophagy inhibitor rescue (3BDO), co-immunoprecipitation (ANXA7-Hsc70), Western blot time-course, migration assay","journal":"Cell adhesion & migration","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying ANXA7-Hsc70 interaction, autophagy rescue is pharmacological (not specific to ITGB4), single lab single study","pmids":["36203272"],"is_preprint":false},{"year":2022,"finding":"ITGB4 deficiency enhances HDM-induced airway inflammation through hyperactivation of TLR4 signaling, mediated by inhibition of FYN phosphorylation. TLR4 antagonist treatment or FYN blockade respectively inhibits or exaggerates lung inflammation in ITGB4-deficient mice.","method":"ITGB4 conditional knockout mice, HDM challenge, TLR4 antagonist treatment, FYN inhibitor, Western blot for FYN phosphorylation","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic epistasis establishing ITGB4-FYN-TLR4 axis in vivo, single lab","pmids":["36822178"],"is_preprint":false},{"year":2023,"finding":"Conditional knockout of ITGB4 in bronchial epithelial cells causes bronchopulmonary dysplasia-like phenotype (enlarged alveolar airspaces, inhibited branching, abnormal epithelium, impaired cilia growth) through the FAK/GSK3β/SOX2 signaling pathway. Treatment with GSK3β agonist (wortmannin) partly reverses airway branching defects.","method":"Conditional knockout mice (CCSP-rtTA/Tet-O-Cre/ITGB4f/f), fetal lung explant culture, scanning electron microscopy, KEGG pathway analysis of transcriptome sequencing, Western blot for FAK/GSK3β/SOX2, pharmacological rescue with wortmannin","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with pathway rescue in vitro (lung explant), single lab with multiple readouts","pmids":["37698050"],"is_preprint":false},{"year":2023,"finding":"FOSL1 (delivered via CAF-derived exosomes to CRC cells) transcriptionally activates ITGB4, as confirmed by ChIP assay showing FOSL1 binding to ITGB4 promoter and dual-luciferase reporter assay. This FOSL1-driven ITGB4 upregulation promotes CRC cell proliferation, stemness, and oxaliplatin resistance.","method":"ChIP assay, dual-luciferase reporter assay, exosome inhibitor (GW4869) treatment, co-culture system with CAFs, functional proliferation/apoptosis assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP + luciferase reporter establish direct transcriptional activation of ITGB4 by FOSL1, single lab","pmids":["37160555"],"is_preprint":false},{"year":2024,"finding":"ITGB4 directly interacts with BNIP3 (confirmed by Co-IP). The ITGB4-BNIP3 complex activates autophagy, which promotes phagocytosis of MHC-I by autophagosomes (observed by confocal microscopy), thereby reducing MHC-I surface expression and enabling immune escape in pancreatic cancer. ITGB4 downregulation improved the efficacy of PD-1 antibody therapy in mouse models.","method":"Co-immunoprecipitation, confocal microscopy (co-localization of MHC-I with autophagosomes), flow cytometry (MHC-I surface expression), transmission electron microscopy, CD8+ T-cell co-culture ELISA, syngeneic transplant mouse model","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction confirmed and mechanistic consequences demonstrated by multiple orthogonal methods (confocal, flow cytometry, TEM), single lab","pmids":["39711509"],"is_preprint":false},{"year":2024,"finding":"PD-L1 forms a membrane complex with EGFR and ITGB4 (PD-L1/EGFR/ITGB4), activating PI3K/mTOR/SREBP1c signaling and reprogramming lipid metabolism (accumulation of triglycerides, cholesterol, lipid droplets) in liver cancer cells in an immune cell-independent manner.","method":"Co-immunoprecipitation, pull-down assays, immunofluorescence staining, RNA sequencing, mass spectrometry-based metabolomics, Western blot, in vitro and in vivo (immunodeficient mice) functional assays","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/pulldown confirming ternary complex, in vivo validation, lipidomic metabolomics, multiple methods in single lab","pmids":["38455469"],"is_preprint":false},{"year":2024,"finding":"The extracellular domain of ITGB4 directly interacts with the envelope (E) glycoprotein of Zika virus (ZIKV), mediating ZIKV attachment and infection. ITGB4 knockout reduces ZIKV binding and replication; a monoclonal antibody against ITGB4 or soluble ITGB4 blocks ZIKV infection and protects mouse placenta and fetuses from ZIKV.","method":"ITGB4 knockout cell lines, binding assays, soluble ITGB4 competitive inhibition, anti-ITGB4 monoclonal antibody blocking, mouse placenta infection model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cell lines, competitive inhibition with soluble receptor, and monoclonal antibody blocking all converge on ITGB4 as entry factor, in vivo placental protection confirmed, multiple orthogonal approaches","pmids":["39737945"],"is_preprint":false},{"year":2024,"finding":"TFAP2A directly binds to the ITGB4 promoter and transcriptionally activates ITGB4 in lung adenocarcinoma cells. ITGB4 interacts with IκBα to activate the NF-κB signaling pathway and inhibit CD4+/CD8+ T-cell infiltration. Laminin-5 (a ligand of ITGB4) promotes LUAD progression through the ITGB4 signaling.","method":"ChIP assay (TFAP2A binding to ITGB4 promoter), co-immunoprecipitation (ITGB4-IκBα interaction), siRNA knockdown, overexpression in LUAD cells, in vivo nude mouse and C57BL/6J T-cell infiltration models","journal":"Translational lung cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing TFAP2A binding and Co-IP establishing ITGB4-IκBα interaction, functional validation in vivo, single lab","pmids":["39430326"],"is_preprint":false},{"year":2024,"finding":"FLRT2 directly associates with ITGB4 and promotes ITGB4 phosphorylation; the FLRT2-ITGB4-mTORC2-AKT-p53 signaling axis regulates endothelial cell senescence and vascular aging. Inhibition of ITGB4 substantially mitigates senescence induced by FLRT2 depletion.","method":"Co-immunoprecipitation (FLRT2-ITGB4 interaction), mTORC2/AKT/p53 pathway analysis by Western blot, ITGB4 siRNA rescue, FLRT2 silencing in mice, vascular aging phenotype assessment","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pathway rescue plus in vivo mouse model, single lab","pmids":["38587072"],"is_preprint":false},{"year":2024,"finding":"USP44 (a deubiquitinase) directly stabilizes ITGB4 through deubiquitination (identified by proteomic analysis), thereby modulating ROS and MAPK/NF-κB signaling and contributing to cisplatin resistance in gastric cancer. ITGB4 affects P-glycoprotein expression and antioxidant enzyme activity through the MAPK/NF-κB pathway.","method":"Proteomic analysis, deubiquitinase activity assay, co-immunoprecipitation, siRNA knockdown, Western blot, cisplatin resistance functional assay","journal":"FASEB journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic identification plus functional association, specific deubiquitination of ITGB4 by USP44 not fully reconstituted in vitro, single lab","pmids":["40824171"],"is_preprint":false},{"year":2024,"finding":"ITGB4 activates NF-κB by interacting with IκBα (demonstrated by co-immunoprecipitation), placing ITGB4 as an upstream activator of the NF-κB pathway to suppress T-cell infiltration in lung adenocarcinoma.","method":"Co-immunoprecipitation (ITGB4-IκBα), NF-κB pathway Western blot, ITGB4 knockdown in LUAD cells","journal":"Translational lung cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP demonstrating ITGB4-IκBα interaction, mechanistic depth limited, single lab","pmids":["39430326"],"is_preprint":false},{"year":2025,"finding":"MLN4924 increases LDH tetramerization and activity, raising lactate levels and promoting histone H3K18 lactylation. This epigenetic change downregulates ITGB4 transcription by acting at the first intron of the ITGB4 gene, suppressing breast cancer cell migration and invasion in a neddylation-independent, LDH-dependent manner. ITGB4 overexpression rescues the migration suppression caused by MLN4924.","method":"Combined CUT&TAG, RNA-seq, and CHIP-PCR analyses, LDH tetramerization assay, LDH siRNA knockdown, oxamate (LDH inhibitor) treatment, ITGB4 overexpression rescue, in vivo metastasis model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple Tier 1 methods (CUT&TAG, RNA-seq, CHIP-PCR) establishing epigenetic mechanism; ITGB4 rescue confirms downstream role, single lab","pmids":["40784455"],"is_preprint":false},{"year":2025,"finding":"STAT3 activation upregulates ITGB4 expression in cisplatin-resistant bladder cancer cells. ITGB4 inhibits p53 by suppressing phosphorylation at the p53-S15 site and facilitating MDM2 binding to p53, promoting p53 degradation and reducing cisplatin sensitivity.","method":"STAT3 inhibitor treatment, ITGB4 siRNA knockdown, p53-S15 phosphorylation Western blot, co-immunoprecipitation (MDM2-p53 binding), cisplatin sensitivity assay","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus site-specific phosphorylation analysis establishing ITGB4-p53-MDM2 mechanism, single lab","pmids":["41957134"],"is_preprint":false},{"year":2026,"finding":"CSTA (secreted by M2-like GAMs) binds to ITGB4 at glutamate residue 88 (identified by mass spectrometry and molecular docking, validated by binding assays), activating downstream NF-κB and MAPK signaling in GBM cells. The CSTA-ITGB4 axis also induces GBM cells to secrete TGFB1, which recruits M2-like GAMs, forming a positive feedback loop.","method":"Mass spectrometry, molecular docking, binding assay, co-immunoprecipitation, NF-κB/MAPK pathway Western blot, TGFB1 ELISA, scRNA-seq, in vitro and in vivo glioblastoma models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry + molecular docking + Co-IP identifying binding site, pathway activation confirmed, in vivo validation, single lab","pmids":["41832564"],"is_preprint":false},{"year":2026,"finding":"TRIM56 (an E3 ubiquitin ligase) binds to ITGB4 and mediates its ubiquitination. BFF-4 (active fraction of Bufei Formula) inhibits TRIM56-mediated ITGB4 ubiquitination, thereby reducing MUC5AC expression in airway epithelial cells.","method":"DARTS technology identifying TRIM56 as BFF-4 target, Co-IP with mass spectrometry identifying ITGB4 as TRIM56 substrate, TRIM56 overexpression experiments, MUC5AC quantification, COPD mouse model","journal":"Journal of ethnopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP-MS identifying TRIM56-ITGB4 interaction, ubiquitination mechanism not directly reconstituted in vitro, single lab","pmids":["41580166"],"is_preprint":false}],"current_model":"ITGB4 encodes the β4 integrin subunit that heterodimerizes with α6 integrin to form a critical hemidesmosomal component at epithelial basement membranes; loss-of-function ITGB4 mutations cause junctional epidermolysis bullosa, and ITGB4 is regulated at multiple levels—transcriptionally (by RUNX1, TFAP2A, FOSL1, STAT3), post-transcriptionally (by m6A modification via METTL14/YTHDF2 and WTAP/YTHDF1), and post-translationally (by ubiquitin-mediated degradation through NEDD4L targeting K915, TMEM268-dependent stabilization, USP44-mediated deubiquitination, and H3K18 lactylation-dependent transcriptional silencing); in signaling, phosphorylated ITGB4 (at Y1510) activates MEK1-ERK1/2, while ITGB4 forms complexes with FAK, SRC, PD-L1/EGFR, FLRT2, IκBα, and BNIP3 to regulate PI3K/AKT/mTOR, NF-κB, and autophagy-mediated MHC-I downregulation; in the airway epithelium, ITGB4 maintains barrier integrity and suppresses inflammation via TSLP, TLR4/FYN, SHP2/JNK/c-Jun/FGF2, and FAK/GSK3β/SOX2 pathways; the extracellular domain additionally serves as an entry receptor for Zika virus by directly binding the viral E glycoprotein."},"narrative":{"mechanistic_narrative":"ITGB4 encodes the β4 integrin subunit, an epithelial adhesion receptor that closely associates with the α6 integrin subunit to maintain the structural integrity of the dermal-epidermal basement membrane zone [PMID:9182827]. Loss-of-function ITGB4 mutations—premature termination codons, frameshifts, and missense changes—cause junctional epidermolysis bullosa with pyloric atresia, with genotype-phenotype severity tracking mutation type and position; a dominant-negative missense allele also produces an autosomal dominant blistering phenotype [PMID:9194858, PMID:9792864, PMID:9422533, PMID:11328943, PMID:26817667]. Beyond skin, β4 integrin is required for Schwann-cell-dependent axonal regeneration and myelination in peripheral nerve [PMID:18971471], and in the airway epithelium it sustains barrier integrity and suppresses inflammation and remodeling: epithelial ITGB4 loss drives allergen-induced inflammation, hyperresponsiveness, and TSLP release [PMID:29393977], MUC5AC mucus hypersecretion via EGFR/ERK/c-Jun [PMID:34975337], EMTU-driven airway remodeling via SHP2/JNK/c-Jun/FGF2 [PMID:36243221], and FAK/GSK3β/SOX2-dependent branching defects [PMID:37698050]. ITGB4 is controlled at multiple regulatory layers: transcriptionally by RUNX1, FOSL1, TFAP2A, and STAT3 and silenced by H3K18-lactylation at its first intron [PMID:28926098, PMID:37160555, PMID:39430326, PMID:40784455, PMID:41957134]; post-transcriptionally by METTL14/YTHDF2-mediated m6A-dependent mRNA decay [PMID:35305660]; and post-translationally by NEDD4L-mediated ubiquitination at K915 opposed by TMEM268-dependent stabilization [PMID:30361615, PMID:38831335]. In signaling, tyrosine-Y1510 phosphorylation places ITGB4 upstream of MEK1-ERK1/2 [PMID:31242404], and the receptor nucleates complexes with FLRT2 (mTORC2/AKT/p53 senescence axis), SRC/NF-κB, IκBα (NF-κB activation), PD-L1/EGFR (PI3K/mTOR/SREBP1c lipid reprogramming), and BNIP3 (autophagic MHC-I degradation and immune escape) across vascular, cancer, and immune contexts [PMID:38587072, PMID:36329801, PMID:39711509, PMID:38455469, PMID:39430326]. The extracellular domain additionally functions as a direct entry receptor for Zika virus through binding the viral E glycoprotein [PMID:39737945].","teleology":[{"year":1997,"claim":"Establishing the genomic structure of ITGB4 and linking loss of expression to disease defined β4 integrin as essential for basement-membrane stability.","evidence":"Exon-spanning sequencing, RT-PCR, and patient-skin immunofluorescence in junctional epidermolysis bullosa with pyloric atresia","pmids":["9194858","9182827"],"confidence":"High","gaps":["Did not resolve the molecular partners or signaling output of β4 integrin","Mechanism of α6/β4 heterodimer assembly not addressed"]},{"year":1998,"claim":"Genotype-phenotype correlations clarified that mutation type and position dictate disease severity, distinguishing lethal from nonlethal alleles.","evidence":"Heteroduplex/sequence analysis and IF across multiple EB-PA families, with computational structural prediction of missense effects","pmids":["9792864","9422533","11328943","9546354"],"confidence":"High","gaps":["Structural consequences of missense alleles predicted computationally, not experimentally","Functional output of partially synthesized β4 polypeptide not defined"]},{"year":2008,"claim":"Cell-type-specific deletion extended ITGB4 function beyond epithelium, showing a requirement in Schwann cells for peripheral nerve regeneration and myelination.","evidence":"Schwann-cell conditional Itgb4 knockout with sciatic nerve crush, morphometry, and functional testing in mice","pmids":["18971471"],"confidence":"High","gaps":["Downstream signaling mediating the myelination phenotype not identified","Ligand engagement in this context not defined"]},{"year":2010,"claim":"ITGB4 was tied to airway epithelial wound repair and oxidative defense, opening its role in barrier maintenance.","evidence":"Overexpression and siRNA in rat tracheal/16HBE cells with scratch assays plus OVA asthma model","pmids":["20364299"],"confidence":"Medium","gaps":["Molecular pathway downstream of ITGB4 not resolved","Correlative expression changes in asthma model not mechanistically linked"]},{"year":2018,"claim":"Epithelial ITGB4 deletion demonstrated a causal role in restraining allergic airway inflammation and barrier-dependent TSLP secretion.","evidence":"Epithelial conditional knockout mice in HDM asthma model with flow cytometry, ELISA, and AHR measurement","pmids":["29393977"],"confidence":"High","gaps":["Did not define the intracellular signaling connecting ITGB4 loss to barrier disruption","TSLP induction mechanism not resolved at this stage"]},{"year":2018,"claim":"Identification of TMEM268 and later NEDD4L established that ITGB4 abundance is set by a stabilization-versus-ubiquitination balance.","evidence":"Co-IP, ubiquitination assays with domain/site mapping (HECT–Galx-β; K915), and xenograft validation in cancer cells","pmids":["30361615","38831335"],"confidence":"High","gaps":["How stabilization and degradation are coordinated in vivo not defined","Upstream signals controlling NEDD4L/TMEM268 activity toward ITGB4 unknown"]},{"year":2020,"claim":"Site-directed mutagenesis placed ITGB4 Y1510 phosphorylation upstream of MEK1-ERK1/2, defining a pro-migratory signaling output.","evidence":"Y1510A mutant, knockdown/overexpression, and migration/invasion assays in pancreatic cancer cells","pmids":["31242404"],"confidence":"Medium","gaps":["Kinase responsible for Y1510 phosphorylation not identified","Selectivity for MEK1 over MEK2 mechanistically unexplained"]},{"year":2022,"claim":"Multiple regulatory layers were defined showing ITGB4 mRNA decay via METTL14/YTHDF2 m6A and transcriptional control by RUNX1.","evidence":"MeRIP/RIP/luciferase reporters and ChIP/reporter assays with functional metastasis validation","pmids":["35305660","28926098"],"confidence":"High","gaps":["RUNX1 acts without a canonical motif, leaving the precise cis-element unresolved","Crosstalk between transcriptional and m6A control not addressed"]},{"year":2022,"claim":"Multiple airway-epithelial pathways downstream of ITGB4 loss were delineated, linking it to mucus hypersecretion, remodeling, DNA damage, and inflammation control.","evidence":"Conditional knockout mice with pathway-specific inhibitors and rescue experiments (EGFR/ERK/c-Jun; SHP2/JNK/c-Jun/FGF2; HDAC1; TLR4/FYN)","pmids":["34975337","36243221","36282138","36822178"],"confidence":"High","gaps":["How a single adhesion receptor selects among these divergent effector pathways is unclear","Direct molecular link between ITGB4 cytoplasmic domain and each pathway not mapped"]},{"year":2022,"claim":"ITGB4 was shown to nucleate signaling complexes in vascular and stromal cells, including a SRC/NF-κB feedback loop and exosomal metabolic reprogramming of fibroblasts.","evidence":"Knockdown epistasis under shear stress with atherosclerosis model; exosome co-culture with mitophagy and AMPK/c-Jun inhibition","pmids":["36329801","31534187"],"confidence":"Medium","gaps":["Direct physical basis of ITGB4-SRC-NF-κB loop not structurally defined","Mechanism of ITGB4 exosomal packaging not resolved"]},{"year":2019,"claim":"ITGB4 was linked to senescence control via the p53 pathway and to FLRT2-driven endothelial aging through mTORC2/AKT/p53.","evidence":"Knockdown/overexpression senescence assays in airway epithelium; Co-IP and ITGB4 siRNA rescue with FLRT2 silencing in mice","pmids":["30636108","38587072"],"confidence":"Medium","gaps":["How ITGB4 mechanistically couples to p53/mTORC2 not detailed","Phosphorylation event promoted by FLRT2 on ITGB4 not site-mapped"]},{"year":2024,"claim":"Membrane complexes with PD-L1/EGFR and BNIP3 connected ITGB4 to lipid metabolic reprogramming and autophagy-mediated MHC-I downregulation enabling immune escape.","evidence":"Co-IP/pulldown, confocal/TEM, flow cytometry, lipidomics, and syngeneic tumor models with PD-1 antibody","pmids":["38455469","39711509"],"confidence":"Medium","gaps":["Stoichiometry and assembly order of the PD-L1/EGFR/ITGB4 complex unknown","Direct ITGB4–BNIP3 interface not structurally defined"]},{"year":2024,"claim":"Transcriptional activators TFAP2A and FOSL1 and an IκBα interaction were defined, linking ITGB4 induction to NF-κB activation and T-cell exclusion in tumors.","evidence":"ChIP and dual-luciferase reporter for promoter binding, Co-IP for ITGB4-IκBα, with in vivo T-cell infiltration models","pmids":["39430326","37160555","39430326"],"confidence":"Medium","gaps":["Mechanism by which ITGB4-IκBα interaction triggers NF-κB activation not resolved","Single Co-IP for IκBα interaction without reciprocal/structural validation"]},{"year":2024,"claim":"The ITGB4 extracellular domain was identified as a direct Zika virus entry receptor, defining a non-adhesion role for the receptor and a therapeutic target.","evidence":"Knockout cell lines, soluble-receptor competition, anti-ITGB4 monoclonal antibody blocking, and placental protection in mice","pmids":["39737945"],"confidence":"High","gaps":["Precise E-glycoprotein binding interface on ITGB4 not mapped","Whether α6 heterodimerization is required for viral entry not tested"]},{"year":2025,"claim":"Lactylation-dependent and STAT3-driven control further integrated ITGB4 into metabolic-epigenetic and chemoresistance circuits.","evidence":"CUT&TAG/RNA-seq/ChIP-PCR with LDH manipulation and ITGB4 rescue; STAT3 inhibition with ITGB4-p53-MDM2 Co-IP analysis","pmids":["40784455","41957134"],"confidence":"Medium","gaps":["How H3K18 lactylation is targeted to the ITGB4 first intron not defined","Mechanism by which ITGB4 promotes MDM2-p53 binding not structurally resolved"]},{"year":2026,"claim":"A secreted ligand CSTA was shown to engage ITGB4 at residue E88 to drive NF-κB/MAPK signaling, defining an extracellular input in glioblastoma.","evidence":"Mass spectrometry, molecular docking, binding assays, Co-IP, and in vivo GBM models","pmids":["41832564"],"confidence":"Medium","gaps":["Functional necessity of E88 confirmed only by docking and binding assays","Whether CSTA competes with canonical laminin ligands unknown"]},{"year":null,"claim":"How a single adhesion receptor integrates its diverse transcriptional, m6A, ubiquitination, and lactylation regulatory inputs with its many context-specific signaling complexes into coherent cell-fate decisions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the ITGB4 cytoplasmic signaling hub","Determinants of pathway selectivity across tissues not defined","In vivo relevance of many cancer-cell complexes to normal physiology untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[27]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[12,20,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[26,27]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,20,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,28]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15]}],"complexes":["α6β4 integrin","ITGB4/plectin","PD-L1/EGFR/ITGB4"],"partners":["ITGA6","TMEM268","NEDD4L","FLRT2","BNIP3","NFKBIA","EGFR","USP44"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P16144","full_name":"Integrin beta-4","aliases":["GP150"],"length_aa":1822,"mass_kda":202.2,"function":"Integrin alpha-6/beta-4 is a receptor for laminin. 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ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464)","subcellular_location":"Cell membrane; Cell membrane; Cell junction, hemidesmosome","url":"https://www.uniprot.org/uniprotkb/P16144/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGB4","total_profiled":1310},"omim":[{"mim_id":"619817","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 6, WITH PYLORIC ATRESIA; JEB6","url":"https://www.omim.org/entry/619817"},{"mim_id":"619816","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 5A, INTERMEDIATE; JEB5A","url":"https://www.omim.org/entry/619816"},{"mim_id":"617685","title":"CADHERIN 26; CDH26","url":"https://www.omim.org/entry/617685"},{"mim_id":"615425","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 3, LOCALIZED OR GENERALIZED INTERMEDIATE, WITH BP230 DEFICIENCY; EBS3","url":"https://www.omim.org/entry/615425"},{"mim_id":"613146","title":"MICRO RNA 184; MIR184","url":"https://www.omim.org/entry/613146"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"salivary gland","ntpm":198.1},{"tissue":"skin 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A homozygous splice-site mutation causes premature termination codons via cryptic splice sites, dramatically reducing mRNA transcript levels and abolishing β4 integrin expression at the dermal-epidermal basement membrane zone, leading to junctional epidermolysis bullosa with pyloric atresia.\",\n      \"method\": \"RT-PCR, heteroduplex analysis, nucleotide sequencing of PCR products spanning all exons, immunofluorescence staining of patient skin\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genomic organization established by direct sequencing across 41 exons, mutation-to-phenotype linkage confirmed by RT-PCR showing mRNA loss and IF showing absent protein, replicated across multiple patient studies\",\n      \"pmids\": [\"9194858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Loss-of-function frameshift mutations in both ITGB4 alleles result in absent α6 integrin staining and markedly reduced β4 integrin staining by immunofluorescence, demonstrating that α6 and β4 integrin subunits are closely associated and that ITGB4 is critical for physiologic stability of the dermal-epidermal junction.\",\n      \"method\": \"PCR amplification, heteroduplex analysis, direct nucleotide sequencing, immunofluorescence of patient skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein loss demonstrated by IF in patient tissue, replicated across multiple independent EB-PA patient studies\",\n      \"pmids\": [\"9182827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Missense mutations in ITGB4 (rather than premature termination codons) underlie nonlethal epidermolysis bullosa with pyloric atresia phenotypes; missense mutations in cysteine residues (e.g., C61Y) can be lethal, indicating position-dependent consequences. Premature termination codons are predominantly associated with lethal variants, while missense mutations allow synthesis of some functional, albeit perturbed, β4 polypeptide.\",\n      \"method\": \"Mutation analysis by heteroduplex analysis and nucleotide sequencing, immunofluorescence staining of patient skin for α6 and β4 integrins\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genotype-phenotype correlations established across five families with orthogonal mutation analysis and protein-level IF, independently replicated across multiple subsequent studies\",\n      \"pmids\": [\"9792864\", \"9422533\", \"11328943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A missense mutation (L156P) in ITGB4 disrupts a conserved residue across human, rodent, and Drosophila integrin-β polypeptides and is predicted to disrupt α-helix formation; the companion nonsense mutation (R554X) results in undetectable mRNA by RT-PCR, consistent with nonsense-mediated decay.\",\n      \"method\": \"Heteroduplex analysis, nucleotide sequencing, RT-PCR, Garnier α-helicity plot structural prediction\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA detection by RT-PCR for the nonsense allele; structural consequence of missense predicted computationally, single lab\",\n      \"pmids\": [\"9546354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Conditional deletion of Itgb4 specifically in Schwann cells leads to delayed motor nerve regeneration after sciatic nerve crush, reduced number of newly outgrowing nerve sprouts, fewer and thinner myelinated axons, and higher g-ratio, demonstrating that α6β4 integrin plays an essential role in axonal regeneration and myelination in peripheral nerves.\",\n      \"method\": \"Cre-mediated conditional knockout in Schwann cells, sciatic nerve crush model, motor/sensory function testing, neurofilament-200 immunostaining, morphometric analysis, laminin immunostaining\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO with multiple orthogonal phenotypic readouts (functional, histological, morphometric) in a defined in vivo model\",\n      \"pmids\": [\"18971471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ITGB4 expression is upregulated at the leading edge of mechanically wounded airway epithelial cells and after ozone stress, and is decreased in OVA-challenged asthma model airways. Overexpression of ITGB4 promotes wound repair and anti-oxidative capacity in rat tracheal epithelial cells, while ITGB4 silencing blocks these abilities.\",\n      \"method\": \"Overexpression vector and siRNA knockdown in primary rat tracheal epithelial cells and 16HBE14O cells, scratch wound repair assay, OVA asthma mouse model, immunostaining\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments in primary cells with defined phenotypic readout, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20364299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A heterozygous missense mutation (c.433G>T, p.Asp145Tyr) in exon 5 of ITGB4 exerts a dominant-negative effect and co-segregates with an autosomal dominant epidermolysis bullosa phenotype characterized by nail dystrophy and mild acral blistering, establishing for the first time a dominant mode of ITGB4 inheritance in EB.\",\n      \"method\": \"Whole-gene sequencing of all EB-associated genes, segregation analysis in extended family, sequencing of unaffected relatives and controls\",\n      \"journal\": \"JAMA dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complete segregation analysis in extended family with negative controls, single study establishing dominant-negative mechanism\",\n      \"pmids\": [\"26817667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RUNX1 binds to and activates the ITGB4 gene promoter in myeloid cells, but does so without a canonical RUNX1 consensus binding motif, and may involve interactions between the promoter and upstream regulatory elements, indicating a distinct transcriptional mechanism compared to ITGA6 regulation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter reporter assays, RUNX1 overexpression/knockdown in myeloid cell lines\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays in a single lab; mechanism partially characterized (no consensus binding site identified)\",\n      \"pmids\": [\"28926098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Epithelial cell-specific ITGB4 deletion leads to severe allergen-induced airway inflammation and airway hyper-responsiveness (AHR) in mice, with increased lymphocyte, eosinophil, and neutrophil infiltration, elevated Th2 (IL-4, IL-13) and Th17 (IL-17A) cytokines, and enhanced disruption of epithelial barrier integrity leading to increased thymic stromal lymphopoietin (TSLP) secretion.\",\n      \"method\": \"Conditional epithelial ITGB4 knockout mice, house dust mite challenge asthma model, flow cytometry, ELISA, AHR measurement\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO with multiple orthogonal mechanistic readouts (cytokines, barrier function, TSLP) in defined in vivo model\",\n      \"pmids\": [\"29393977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of TMEM268 promotes ITGB4 ubiquitin-mediated degradation, increasing instability of ITGB4 and filamin A (FLNA), and causing disassociation of the ITGB4/plectin (PLEC) complex and cytoskeleton remodeling. TMEM268 interacts with ITGB4 through a C-terminal interaction.\",\n      \"method\": \"CRISPR/siRNA knockout in gastric cancer cells, co-immunoprecipitation, ubiquitination assay, Western blot, xenograft mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus ubiquitination assay plus rescue experiments in a single lab; mechanism confirmed in vivo by xenograft\",\n      \"pmids\": [\"30361615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGB4-overexpressing triple negative breast cancer cells transfer ITGB4 protein to cancer-associated fibroblasts (CAFs) via exosomes, where it induces BNIP3L-dependent mitophagy and lactate production (glycolysis) in CAFs. This ITGB4-induced metabolic reprogramming of CAFs promotes cancer cell proliferation, EMT, and invasion. The effect is suppressed by ITGB4 knockdown in cancer cells, inhibition of exosome generation, or blocking c-Jun or AMPK phosphorylation in CAFs.\",\n      \"method\": \"Exosome co-culture assays, ITGB4 knockdown/overexpression, mitophagy assays, AMPK/c-Jun phosphorylation inhibition, co-transplant mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (exosome inhibition, ITGB4 KD, signaling inhibitors) in a single lab with in vivo validation\",\n      \"pmids\": [\"31534187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGB4 deficiency in airway epithelial cells induces cellular senescence through activation of the p53 pathway, both in vitro (under oxidative stress or inflammatory stimulation) and in vivo.\",\n      \"method\": \"ITGB4 knockdown/overexpression in airway epithelial cells, senescence assays (SA-β-gal, p21, p53 activation), in vivo mouse model\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway (p53 activation) confirmed in vitro and in vivo, single lab\",\n      \"pmids\": [\"30636108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGB4 phosphorylation at tyrosine Y1510 (p-ITGB4-Y1510) promotes pancreatic cancer cell migration and invasion. Expression of the Y1510A mutant blocks ITGB4 phosphorylation, suppresses ITGB4 protein expression, and decreases phosphorylation of MEK1 (T292) and ERK1/2, but does not affect MEK1 (T386) or MEK2 (T394) phosphorylation, placing p-ITGB4-Y1510 upstream of MEK1-ERK1/2 signaling.\",\n      \"method\": \"Site-directed mutagenesis (Y1510A), siRNA knockdown, overexpression in pancreatic cancer cell lines, Western blot, migration/invasion assays, immunohistochemistry in patient tissues\",\n      \"journal\": \"Bosnian journal of basic medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with specific pathway readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"31242404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FLRT2 directly associates with ITGB4 and promotes ITGB4 phosphorylation. Inhibition of ITGB4 substantially mitigates endothelial cell senescence triggered by FLRT2 depletion. FLRT2 mediates endothelial cell senescence via mTOR complex 2 (mTORC2), AKT, and p53 signaling downstream of ITGB4.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of ITGB4 and FLRT2 in human endothelial cells, FLRT2 silencing in mice, Western blot for signaling pathway components, senescence assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction plus pathway rescue experiment, in vivo mouse validation, single lab\",\n      \"pmids\": [\"38587072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMA interacts with ITGB4 (demonstrated by immunoprecipitation) and activates NF-κB signaling to promote angiogenesis in glioblastoma endothelial cells.\",\n      \"method\": \"High-throughput sequencing, co-immunoprecipitation, PSMA overexpression in HUVECs, PSMA inhibitor (2-PMPA) treatment, tube formation assay, in vivo GBM model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying interaction, downstream pathway assignment without direct mutagenesis of ITGB4 interaction domain, single lab\",\n      \"pmids\": [\"33748101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL14 facilitates m6A modification on the 3′UTR of ITGB4 mRNA, which is then recognized by the m6A reader YTHDF2, promoting ITGB4 mRNA degradation. METTL14 knockdown promotes ccRCC cell migration, invasion, and metastasis by overexpressing ITGB4 and stimulating the PI3K/AKT pathway and EMT.\",\n      \"method\": \"m6A RNA immunoprecipitation (MeRIP), RIP assay, luciferase reporter assay, METTL14 and YTHDF2 knockdown/overexpression, in vitro migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MeRIP + RIP + luciferase reporter as orthogonal methods confirming m6A writing and YTHDF2 reading of ITGB4 mRNA with functional validation in vivo, single lab with multiple Tier 1 methods\",\n      \"pmids\": [\"35305660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NEDD4L (an E3 ubiquitin ligase) directly binds ITGB4 via its HECT domain interacting with the Galx-β domain of ITGB4, and ubiquitinates ITGB4 at the K915 site, promoting its proteasomal degradation and suppressing esophageal carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation, proteome analysis, ubiquitination assay with domain mapping (HECT domain and Galx-β domain), site-specific K915 identification, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — Co-IP with domain mapping, specific ubiquitination site (K915) identified, in vivo validation, single lab with multiple Tier 1 methods\",\n      \"pmids\": [\"38831335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB4 deficiency in airway epithelial cells leads to mucus hypersecretion and MUC5AC overexpression through the EGFR/ERK/c-Jun pathway. Inhibition of EGFR reverses mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection.\",\n      \"method\": \"ITGB4 conditional knockout mice, RSV infection model, EGFR inhibitor treatment, Western blot, siRNA knockdown in HBE cells, MUC5AC quantification\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placed by pharmacological inhibition plus KO mouse model, single lab\",\n      \"pmids\": [\"34975337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Conditional knockout of ITGB4 from airway epithelial cells induces airway remodeling in an HDM asthma mouse model through enhanced EMTU activation mediated by the SHP2/JNK/c-Jun/FGF2 signaling pathway, largely independent of airway inflammation. Both JNK and FGF2 inhibitors significantly inhibited the aggravated airway remodeling.\",\n      \"method\": \"AEC-specific ITGB4 conditional knockout mice, HDM challenge asthma model, JNK and FGF2 inhibitor treatment, Western blot, siRNA knockdown in primary human bronchial epithelial cells\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO with pathway-specific inhibitor validation of SHP2/JNK/c-Jun/FGF2 axis, confirmed in vitro and in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36243221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB4 deficiency in airway epithelial cells downregulates HDAC1 expression, which in turn aggravates DNA damage (increased 8-oxoG and γ-H2AX) under HDM or ozone stress. Restoring HDAC1 expression reverses the enhanced DNA damage caused by ITGB4 deficiency.\",\n      \"method\": \"ITGB4 conditional knockout mice, ITGB4 siRNA in airway epithelial cells, HDM/ozone challenge models, HDAC1 rescue experiments, γ-H2AX and 8-oxoG staining\",\n      \"journal\": \"Pediatric allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway established by rescue experiment (HDAC1 restoration reverses phenotype), single lab with in vivo and in vitro validation\",\n      \"pmids\": [\"36282138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Low shear stress (LSS) increases ITGB4 protein expression in endothelial cells. ITGB4, SRC, and NF-κB form a positive feedback loop: ITGB4 knockdown reduces SRC and NF-κB phosphorylation, NF-κB knockdown inhibits ITGB4 production and SRC phosphorylation, and SRC knockdown downregulates ITGB4 expression and NF-κB activation. ITGB4 knockdown reduces atherosclerotic lesion areas in ApoE-/- mice fed HFD.\",\n      \"method\": \"siRNA knockdown in HUVECs under LSS conditions, phosphorylation analysis of SRC/FAK/NFκB, atherosclerosis mouse model (ApoE-/- + HFD), Western blot\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis-like knockdown experiments establishing a feedback loop, in vivo validation, single lab\",\n      \"pmids\": [\"36329801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Activation of GRP78 ATPase by HOCl probe ZBM-H promotes autophagy-mediated degradation of ITGB4 in A549 lung cancer cells by promoting the interaction between ANXA7 and Hsc70, which mediates selective autophagy of ITGB4. Blocking autophagy (with 3BDO) partially rescues ITGB4 protein levels and cell migration.\",\n      \"method\": \"Chemical biology (HOCl probe ZBM-H), autophagy inhibitor rescue (3BDO), co-immunoprecipitation (ANXA7-Hsc70), Western blot time-course, migration assay\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying ANXA7-Hsc70 interaction, autophagy rescue is pharmacological (not specific to ITGB4), single lab single study\",\n      \"pmids\": [\"36203272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB4 deficiency enhances HDM-induced airway inflammation through hyperactivation of TLR4 signaling, mediated by inhibition of FYN phosphorylation. TLR4 antagonist treatment or FYN blockade respectively inhibits or exaggerates lung inflammation in ITGB4-deficient mice.\",\n      \"method\": \"ITGB4 conditional knockout mice, HDM challenge, TLR4 antagonist treatment, FYN inhibitor, Western blot for FYN phosphorylation\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic epistasis establishing ITGB4-FYN-TLR4 axis in vivo, single lab\",\n      \"pmids\": [\"36822178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional knockout of ITGB4 in bronchial epithelial cells causes bronchopulmonary dysplasia-like phenotype (enlarged alveolar airspaces, inhibited branching, abnormal epithelium, impaired cilia growth) through the FAK/GSK3β/SOX2 signaling pathway. Treatment with GSK3β agonist (wortmannin) partly reverses airway branching defects.\",\n      \"method\": \"Conditional knockout mice (CCSP-rtTA/Tet-O-Cre/ITGB4f/f), fetal lung explant culture, scanning electron microscopy, KEGG pathway analysis of transcriptome sequencing, Western blot for FAK/GSK3β/SOX2, pharmacological rescue with wortmannin\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with pathway rescue in vitro (lung explant), single lab with multiple readouts\",\n      \"pmids\": [\"37698050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOSL1 (delivered via CAF-derived exosomes to CRC cells) transcriptionally activates ITGB4, as confirmed by ChIP assay showing FOSL1 binding to ITGB4 promoter and dual-luciferase reporter assay. This FOSL1-driven ITGB4 upregulation promotes CRC cell proliferation, stemness, and oxaliplatin resistance.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, exosome inhibitor (GW4869) treatment, co-culture system with CAFs, functional proliferation/apoptosis assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP + luciferase reporter establish direct transcriptional activation of ITGB4 by FOSL1, single lab\",\n      \"pmids\": [\"37160555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB4 directly interacts with BNIP3 (confirmed by Co-IP). The ITGB4-BNIP3 complex activates autophagy, which promotes phagocytosis of MHC-I by autophagosomes (observed by confocal microscopy), thereby reducing MHC-I surface expression and enabling immune escape in pancreatic cancer. ITGB4 downregulation improved the efficacy of PD-1 antibody therapy in mouse models.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy (co-localization of MHC-I with autophagosomes), flow cytometry (MHC-I surface expression), transmission electron microscopy, CD8+ T-cell co-culture ELISA, syngeneic transplant mouse model\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction confirmed and mechanistic consequences demonstrated by multiple orthogonal methods (confocal, flow cytometry, TEM), single lab\",\n      \"pmids\": [\"39711509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD-L1 forms a membrane complex with EGFR and ITGB4 (PD-L1/EGFR/ITGB4), activating PI3K/mTOR/SREBP1c signaling and reprogramming lipid metabolism (accumulation of triglycerides, cholesterol, lipid droplets) in liver cancer cells in an immune cell-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, immunofluorescence staining, RNA sequencing, mass spectrometry-based metabolomics, Western blot, in vitro and in vivo (immunodeficient mice) functional assays\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/pulldown confirming ternary complex, in vivo validation, lipidomic metabolomics, multiple methods in single lab\",\n      \"pmids\": [\"38455469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The extracellular domain of ITGB4 directly interacts with the envelope (E) glycoprotein of Zika virus (ZIKV), mediating ZIKV attachment and infection. ITGB4 knockout reduces ZIKV binding and replication; a monoclonal antibody against ITGB4 or soluble ITGB4 blocks ZIKV infection and protects mouse placenta and fetuses from ZIKV.\",\n      \"method\": \"ITGB4 knockout cell lines, binding assays, soluble ITGB4 competitive inhibition, anti-ITGB4 monoclonal antibody blocking, mouse placenta infection model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cell lines, competitive inhibition with soluble receptor, and monoclonal antibody blocking all converge on ITGB4 as entry factor, in vivo placental protection confirmed, multiple orthogonal approaches\",\n      \"pmids\": [\"39737945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TFAP2A directly binds to the ITGB4 promoter and transcriptionally activates ITGB4 in lung adenocarcinoma cells. ITGB4 interacts with IκBα to activate the NF-κB signaling pathway and inhibit CD4+/CD8+ T-cell infiltration. Laminin-5 (a ligand of ITGB4) promotes LUAD progression through the ITGB4 signaling.\",\n      \"method\": \"ChIP assay (TFAP2A binding to ITGB4 promoter), co-immunoprecipitation (ITGB4-IκBα interaction), siRNA knockdown, overexpression in LUAD cells, in vivo nude mouse and C57BL/6J T-cell infiltration models\",\n      \"journal\": \"Translational lung cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing TFAP2A binding and Co-IP establishing ITGB4-IκBα interaction, functional validation in vivo, single lab\",\n      \"pmids\": [\"39430326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLRT2 directly associates with ITGB4 and promotes ITGB4 phosphorylation; the FLRT2-ITGB4-mTORC2-AKT-p53 signaling axis regulates endothelial cell senescence and vascular aging. Inhibition of ITGB4 substantially mitigates senescence induced by FLRT2 depletion.\",\n      \"method\": \"Co-immunoprecipitation (FLRT2-ITGB4 interaction), mTORC2/AKT/p53 pathway analysis by Western blot, ITGB4 siRNA rescue, FLRT2 silencing in mice, vascular aging phenotype assessment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pathway rescue plus in vivo mouse model, single lab\",\n      \"pmids\": [\"38587072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP44 (a deubiquitinase) directly stabilizes ITGB4 through deubiquitination (identified by proteomic analysis), thereby modulating ROS and MAPK/NF-κB signaling and contributing to cisplatin resistance in gastric cancer. ITGB4 affects P-glycoprotein expression and antioxidant enzyme activity through the MAPK/NF-κB pathway.\",\n      \"method\": \"Proteomic analysis, deubiquitinase activity assay, co-immunoprecipitation, siRNA knockdown, Western blot, cisplatin resistance functional assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic identification plus functional association, specific deubiquitination of ITGB4 by USP44 not fully reconstituted in vitro, single lab\",\n      \"pmids\": [\"40824171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB4 activates NF-κB by interacting with IκBα (demonstrated by co-immunoprecipitation), placing ITGB4 as an upstream activator of the NF-κB pathway to suppress T-cell infiltration in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation (ITGB4-IκBα), NF-κB pathway Western blot, ITGB4 knockdown in LUAD cells\",\n      \"journal\": \"Translational lung cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP demonstrating ITGB4-IκBα interaction, mechanistic depth limited, single lab\",\n      \"pmids\": [\"39430326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MLN4924 increases LDH tetramerization and activity, raising lactate levels and promoting histone H3K18 lactylation. This epigenetic change downregulates ITGB4 transcription by acting at the first intron of the ITGB4 gene, suppressing breast cancer cell migration and invasion in a neddylation-independent, LDH-dependent manner. ITGB4 overexpression rescues the migration suppression caused by MLN4924.\",\n      \"method\": \"Combined CUT&TAG, RNA-seq, and CHIP-PCR analyses, LDH tetramerization assay, LDH siRNA knockdown, oxamate (LDH inhibitor) treatment, ITGB4 overexpression rescue, in vivo metastasis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple Tier 1 methods (CUT&TAG, RNA-seq, CHIP-PCR) establishing epigenetic mechanism; ITGB4 rescue confirms downstream role, single lab\",\n      \"pmids\": [\"40784455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STAT3 activation upregulates ITGB4 expression in cisplatin-resistant bladder cancer cells. ITGB4 inhibits p53 by suppressing phosphorylation at the p53-S15 site and facilitating MDM2 binding to p53, promoting p53 degradation and reducing cisplatin sensitivity.\",\n      \"method\": \"STAT3 inhibitor treatment, ITGB4 siRNA knockdown, p53-S15 phosphorylation Western blot, co-immunoprecipitation (MDM2-p53 binding), cisplatin sensitivity assay\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus site-specific phosphorylation analysis establishing ITGB4-p53-MDM2 mechanism, single lab\",\n      \"pmids\": [\"41957134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CSTA (secreted by M2-like GAMs) binds to ITGB4 at glutamate residue 88 (identified by mass spectrometry and molecular docking, validated by binding assays), activating downstream NF-κB and MAPK signaling in GBM cells. The CSTA-ITGB4 axis also induces GBM cells to secrete TGFB1, which recruits M2-like GAMs, forming a positive feedback loop.\",\n      \"method\": \"Mass spectrometry, molecular docking, binding assay, co-immunoprecipitation, NF-κB/MAPK pathway Western blot, TGFB1 ELISA, scRNA-seq, in vitro and in vivo glioblastoma models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry + molecular docking + Co-IP identifying binding site, pathway activation confirmed, in vivo validation, single lab\",\n      \"pmids\": [\"41832564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TRIM56 (an E3 ubiquitin ligase) binds to ITGB4 and mediates its ubiquitination. BFF-4 (active fraction of Bufei Formula) inhibits TRIM56-mediated ITGB4 ubiquitination, thereby reducing MUC5AC expression in airway epithelial cells.\",\n      \"method\": \"DARTS technology identifying TRIM56 as BFF-4 target, Co-IP with mass spectrometry identifying ITGB4 as TRIM56 substrate, TRIM56 overexpression experiments, MUC5AC quantification, COPD mouse model\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP-MS identifying TRIM56-ITGB4 interaction, ubiquitination mechanism not directly reconstituted in vitro, single lab\",\n      \"pmids\": [\"41580166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB4 encodes the β4 integrin subunit that heterodimerizes with α6 integrin to form a critical hemidesmosomal component at epithelial basement membranes; loss-of-function ITGB4 mutations cause junctional epidermolysis bullosa, and ITGB4 is regulated at multiple levels—transcriptionally (by RUNX1, TFAP2A, FOSL1, STAT3), post-transcriptionally (by m6A modification via METTL14/YTHDF2 and WTAP/YTHDF1), and post-translationally (by ubiquitin-mediated degradation through NEDD4L targeting K915, TMEM268-dependent stabilization, USP44-mediated deubiquitination, and H3K18 lactylation-dependent transcriptional silencing); in signaling, phosphorylated ITGB4 (at Y1510) activates MEK1-ERK1/2, while ITGB4 forms complexes with FAK, SRC, PD-L1/EGFR, FLRT2, IκBα, and BNIP3 to regulate PI3K/AKT/mTOR, NF-κB, and autophagy-mediated MHC-I downregulation; in the airway epithelium, ITGB4 maintains barrier integrity and suppresses inflammation via TSLP, TLR4/FYN, SHP2/JNK/c-Jun/FGF2, and FAK/GSK3β/SOX2 pathways; the extracellular domain additionally serves as an entry receptor for Zika virus by directly binding the viral E glycoprotein.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB4 encodes the β4 integrin subunit, an epithelial adhesion receptor that closely associates with the α6 integrin subunit to maintain the structural integrity of the dermal-epidermal basement membrane zone [#1]. Loss-of-function ITGB4 mutations—premature termination codons, frameshifts, and missense changes—cause junctional epidermolysis bullosa with pyloric atresia, with genotype-phenotype severity tracking mutation type and position; a dominant-negative missense allele also produces an autosomal dominant blistering phenotype [#0, #2, #6]. Beyond skin, β4 integrin is required for Schwann-cell-dependent axonal regeneration and myelination in peripheral nerve [#4], and in the airway epithelium it sustains barrier integrity and suppresses inflammation and remodeling: epithelial ITGB4 loss drives allergen-induced inflammation, hyperresponsiveness, and TSLP release [#8], MUC5AC mucus hypersecretion via EGFR/ERK/c-Jun [#17], EMTU-driven airway remodeling via SHP2/JNK/c-Jun/FGF2 [#18], and FAK/GSK3β/SOX2-dependent branching defects [#23]. ITGB4 is controlled at multiple regulatory layers: transcriptionally by RUNX1, FOSL1, TFAP2A, and STAT3 and silenced by H3K18-lactylation at its first intron [#7, #24, #28, #32, #33]; post-transcriptionally by METTL14/YTHDF2-mediated m6A-dependent mRNA decay [#15]; and post-translationally by NEDD4L-mediated ubiquitination at K915 opposed by TMEM268-dependent stabilization [#9, #16]. In signaling, tyrosine-Y1510 phosphorylation places ITGB4 upstream of MEK1-ERK1/2 [#12], and the receptor nucleates complexes with FLRT2 (mTORC2/AKT/p53 senescence axis), SRC/NF-κB, IκBα (NF-κB activation), PD-L1/EGFR (PI3K/mTOR/SREBP1c lipid reprogramming), and BNIP3 (autophagic MHC-I degradation and immune escape) across vascular, cancer, and immune contexts [#13, #20, #25, #26, #28]. The extracellular domain additionally functions as a direct entry receptor for Zika virus through binding the viral E glycoprotein [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic structure of ITGB4 and linking loss of expression to disease defined β4 integrin as essential for basement-membrane stability.\",\n      \"evidence\": \"Exon-spanning sequencing, RT-PCR, and patient-skin immunofluorescence in junctional epidermolysis bullosa with pyloric atresia\",\n      \"pmids\": [\"9194858\", \"9182827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular partners or signaling output of β4 integrin\", \"Mechanism of α6/β4 heterodimer assembly not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Genotype-phenotype correlations clarified that mutation type and position dictate disease severity, distinguishing lethal from nonlethal alleles.\",\n      \"evidence\": \"Heteroduplex/sequence analysis and IF across multiple EB-PA families, with computational structural prediction of missense effects\",\n      \"pmids\": [\"9792864\", \"9422533\", \"11328943\", \"9546354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequences of missense alleles predicted computationally, not experimentally\", \"Functional output of partially synthesized β4 polypeptide not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cell-type-specific deletion extended ITGB4 function beyond epithelium, showing a requirement in Schwann cells for peripheral nerve regeneration and myelination.\",\n      \"evidence\": \"Schwann-cell conditional Itgb4 knockout with sciatic nerve crush, morphometry, and functional testing in mice\",\n      \"pmids\": [\"18971471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling mediating the myelination phenotype not identified\", \"Ligand engagement in this context not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"ITGB4 was tied to airway epithelial wound repair and oxidative defense, opening its role in barrier maintenance.\",\n      \"evidence\": \"Overexpression and siRNA in rat tracheal/16HBE cells with scratch assays plus OVA asthma model\",\n      \"pmids\": [\"20364299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway downstream of ITGB4 not resolved\", \"Correlative expression changes in asthma model not mechanistically linked\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epithelial ITGB4 deletion demonstrated a causal role in restraining allergic airway inflammation and barrier-dependent TSLP secretion.\",\n      \"evidence\": \"Epithelial conditional knockout mice in HDM asthma model with flow cytometry, ELISA, and AHR measurement\",\n      \"pmids\": [\"29393977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the intracellular signaling connecting ITGB4 loss to barrier disruption\", \"TSLP induction mechanism not resolved at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of TMEM268 and later NEDD4L established that ITGB4 abundance is set by a stabilization-versus-ubiquitination balance.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with domain/site mapping (HECT–Galx-β; K915), and xenograft validation in cancer cells\",\n      \"pmids\": [\"30361615\", \"38831335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How stabilization and degradation are coordinated in vivo not defined\", \"Upstream signals controlling NEDD4L/TMEM268 activity toward ITGB4 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Site-directed mutagenesis placed ITGB4 Y1510 phosphorylation upstream of MEK1-ERK1/2, defining a pro-migratory signaling output.\",\n      \"evidence\": \"Y1510A mutant, knockdown/overexpression, and migration/invasion assays in pancreatic cancer cells\",\n      \"pmids\": [\"31242404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Y1510 phosphorylation not identified\", \"Selectivity for MEK1 over MEK2 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple regulatory layers were defined showing ITGB4 mRNA decay via METTL14/YTHDF2 m6A and transcriptional control by RUNX1.\",\n      \"evidence\": \"MeRIP/RIP/luciferase reporters and ChIP/reporter assays with functional metastasis validation\",\n      \"pmids\": [\"35305660\", \"28926098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RUNX1 acts without a canonical motif, leaving the precise cis-element unresolved\", \"Crosstalk between transcriptional and m6A control not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple airway-epithelial pathways downstream of ITGB4 loss were delineated, linking it to mucus hypersecretion, remodeling, DNA damage, and inflammation control.\",\n      \"evidence\": \"Conditional knockout mice with pathway-specific inhibitors and rescue experiments (EGFR/ERK/c-Jun; SHP2/JNK/c-Jun/FGF2; HDAC1; TLR4/FYN)\",\n      \"pmids\": [\"34975337\", \"36243221\", \"36282138\", \"36822178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single adhesion receptor selects among these divergent effector pathways is unclear\", \"Direct molecular link between ITGB4 cytoplasmic domain and each pathway not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ITGB4 was shown to nucleate signaling complexes in vascular and stromal cells, including a SRC/NF-κB feedback loop and exosomal metabolic reprogramming of fibroblasts.\",\n      \"evidence\": \"Knockdown epistasis under shear stress with atherosclerosis model; exosome co-culture with mitophagy and AMPK/c-Jun inhibition\",\n      \"pmids\": [\"36329801\", \"31534187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical basis of ITGB4-SRC-NF-κB loop not structurally defined\", \"Mechanism of ITGB4 exosomal packaging not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ITGB4 was linked to senescence control via the p53 pathway and to FLRT2-driven endothelial aging through mTORC2/AKT/p53.\",\n      \"evidence\": \"Knockdown/overexpression senescence assays in airway epithelium; Co-IP and ITGB4 siRNA rescue with FLRT2 silencing in mice\",\n      \"pmids\": [\"30636108\", \"38587072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ITGB4 mechanistically couples to p53/mTORC2 not detailed\", \"Phosphorylation event promoted by FLRT2 on ITGB4 not site-mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Membrane complexes with PD-L1/EGFR and BNIP3 connected ITGB4 to lipid metabolic reprogramming and autophagy-mediated MHC-I downregulation enabling immune escape.\",\n      \"evidence\": \"Co-IP/pulldown, confocal/TEM, flow cytometry, lipidomics, and syngeneic tumor models with PD-1 antibody\",\n      \"pmids\": [\"38455469\", \"39711509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order of the PD-L1/EGFR/ITGB4 complex unknown\", \"Direct ITGB4–BNIP3 interface not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Transcriptional activators TFAP2A and FOSL1 and an IκBα interaction were defined, linking ITGB4 induction to NF-κB activation and T-cell exclusion in tumors.\",\n      \"evidence\": \"ChIP and dual-luciferase reporter for promoter binding, Co-IP for ITGB4-IκBα, with in vivo T-cell infiltration models\",\n      \"pmids\": [\"39430326\", \"37160555\", \"39430326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ITGB4-IκBα interaction triggers NF-κB activation not resolved\", \"Single Co-IP for IκBα interaction without reciprocal/structural validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The ITGB4 extracellular domain was identified as a direct Zika virus entry receptor, defining a non-adhesion role for the receptor and a therapeutic target.\",\n      \"evidence\": \"Knockout cell lines, soluble-receptor competition, anti-ITGB4 monoclonal antibody blocking, and placental protection in mice\",\n      \"pmids\": [\"39737945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise E-glycoprotein binding interface on ITGB4 not mapped\", \"Whether α6 heterodimerization is required for viral entry not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lactylation-dependent and STAT3-driven control further integrated ITGB4 into metabolic-epigenetic and chemoresistance circuits.\",\n      \"evidence\": \"CUT&TAG/RNA-seq/ChIP-PCR with LDH manipulation and ITGB4 rescue; STAT3 inhibition with ITGB4-p53-MDM2 Co-IP analysis\",\n      \"pmids\": [\"40784455\", \"41957134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How H3K18 lactylation is targeted to the ITGB4 first intron not defined\", \"Mechanism by which ITGB4 promotes MDM2-p53 binding not structurally resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A secreted ligand CSTA was shown to engage ITGB4 at residue E88 to drive NF-κB/MAPK signaling, defining an extracellular input in glioblastoma.\",\n      \"evidence\": \"Mass spectrometry, molecular docking, binding assays, Co-IP, and in vivo GBM models\",\n      \"pmids\": [\"41832564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional necessity of E88 confirmed only by docking and binding assays\", \"Whether CSTA competes with canonical laminin ligands unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single adhesion receptor integrates its diverse transcriptional, m6A, ubiquitination, and lactylation regulatory inputs with its many context-specific signaling complexes into coherent cell-fate decisions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the ITGB4 cytoplasmic signaling hub\", \"Determinants of pathway selectivity across tissues not defined\", \"In vivo relevance of many cancer-cell complexes to normal physiology untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 20, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [26, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 20, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 28]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\"α6β4 integrin\", \"ITGB4/plectin\", \"PD-L1/EGFR/ITGB4\"],\n    \"partners\": [\"ITGA6\", \"TMEM268\", \"NEDD4L\", \"FLRT2\", \"BNIP3\", \"NFKBIA\", \"EGFR\", \"USP44\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}