Affinage

ITGB4

Integrin beta-4 · UniProt P16144

Length
1822 aa
Mass
202.2 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    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

    PMID:9182827 PMID:9194858

    Open questions at the time
    • Did not resolve the molecular partners or signaling output of β4 integrin
    • Mechanism of α6/β4 heterodimer assembly not addressed
  2. 1998 High

    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

    PMID:11328943 PMID:9422533 PMID:9546354 PMID:9792864

    Open questions at the time
    • Structural consequences of missense alleles predicted computationally, not experimentally
    • Functional output of partially synthesized β4 polypeptide not defined
  3. 2008 High

    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

    PMID:18971471

    Open questions at the time
    • Downstream signaling mediating the myelination phenotype not identified
    • Ligand engagement in this context not defined
  4. 2010 Medium

    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

    PMID:20364299

    Open questions at the time
    • Molecular pathway downstream of ITGB4 not resolved
    • Correlative expression changes in asthma model not mechanistically linked
  5. 2018 High

    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

    PMID:29393977

    Open questions at the time
    • Did not define the intracellular signaling connecting ITGB4 loss to barrier disruption
    • TSLP induction mechanism not resolved at this stage
  6. 2018 High

    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

    PMID:30361615 PMID:38831335

    Open questions at the time
    • How stabilization and degradation are coordinated in vivo not defined
    • Upstream signals controlling NEDD4L/TMEM268 activity toward ITGB4 unknown
  7. 2020 Medium

    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

    PMID:31242404

    Open questions at the time
    • Kinase responsible for Y1510 phosphorylation not identified
    • Selectivity for MEK1 over MEK2 mechanistically unexplained
  8. 2022 High

    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

    PMID:28926098 PMID:35305660

    Open questions at the time
    • RUNX1 acts without a canonical motif, leaving the precise cis-element unresolved
    • Crosstalk between transcriptional and m6A control not addressed
  9. 2022 High

    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)

    PMID:34975337 PMID:36243221 PMID:36282138 PMID:36822178

    Open questions at the time
    • 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
  10. 2022 Medium

    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

    PMID:31534187 PMID:36329801

    Open questions at the time
    • Direct physical basis of ITGB4-SRC-NF-κB loop not structurally defined
    • Mechanism of ITGB4 exosomal packaging not resolved
  11. 2019 Medium

    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

    PMID:30636108 PMID:38587072

    Open questions at the time
    • How ITGB4 mechanistically couples to p53/mTORC2 not detailed
    • Phosphorylation event promoted by FLRT2 on ITGB4 not site-mapped
  12. 2024 Medium

    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

    PMID:38455469 PMID:39711509

    Open questions at the time
    • Stoichiometry and assembly order of the PD-L1/EGFR/ITGB4 complex unknown
    • Direct ITGB4–BNIP3 interface not structurally defined
  13. 2024 Medium

    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

    PMID:37160555 PMID:39430326

    Open questions at the time
    • Mechanism by which ITGB4-IκBα interaction triggers NF-κB activation not resolved
    • Single Co-IP for IκBα interaction without reciprocal/structural validation
  14. 2024 High

    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

    PMID:39737945

    Open questions at the time
    • Precise E-glycoprotein binding interface on ITGB4 not mapped
    • Whether α6 heterodimerization is required for viral entry not tested
  15. 2025 Medium

    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

    PMID:40784455 PMID:41957134

    Open questions at the time
    • How H3K18 lactylation is targeted to the ITGB4 first intron not defined
    • Mechanism by which ITGB4 promotes MDM2-p53 binding not structurally resolved
  16. 2026 Medium

    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

    PMID:41832564

    Open questions at the time
    • Functional necessity of E88 confirmed only by docking and binding assays
    • Whether CSTA competes with canonical laminin ligands unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-168256 Immune System 2 R-HSA-8953854 Metabolism of RNA 1
Partners
BNIP3EGFRFLRT2ITGA6NEDD4LNFKBIATMEM268USP44
Complex memberships
ITGB4/plectinPD-L1/EGFR/ITGB4α6β4 integrin

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 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. RT-PCR, heteroduplex analysis, nucleotide sequencing of PCR products spanning all exons, immunofluorescence staining of patient skin Laboratory investigation High 9194858
1997 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. PCR amplification, heteroduplex analysis, direct nucleotide sequencing, immunofluorescence of patient skin The Journal of investigative dermatology High 9182827
1998 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. Mutation analysis by heteroduplex analysis and nucleotide sequencing, immunofluorescence staining of patient skin for α6 and β4 integrins American journal of human genetics High 11328943 9422533 9792864
1998 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. Heteroduplex analysis, nucleotide sequencing, RT-PCR, Garnier α-helicity plot structural prediction The American journal of pathology Medium 9546354
2008 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. Cre-mediated conditional knockout in Schwann cells, sciatic nerve crush model, motor/sensory function testing, neurofilament-200 immunostaining, morphometric analysis, laminin immunostaining The Journal of neuroscience High 18971471
2010 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. Overexpression vector and siRNA knockdown in primary rat tracheal epithelial cells and 16HBE14O cells, scratch wound repair assay, OVA asthma mouse model, immunostaining Molecular and cellular biochemistry Medium 20364299
2016 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. Whole-gene sequencing of all EB-associated genes, segregation analysis in extended family, sequencing of unaffected relatives and controls JAMA dermatology Medium 26817667
2017 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. Chromatin immunoprecipitation (ChIP), promoter reporter assays, RUNX1 overexpression/knockdown in myeloid cell lines Journal of cellular physiology Medium 28926098
2018 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. Conditional epithelial ITGB4 knockout mice, house dust mite challenge asthma model, flow cytometry, ELISA, AHR measurement Journal of leukocyte biology High 29393977
2018 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. CRISPR/siRNA knockout in gastric cancer cells, co-immunoprecipitation, ubiquitination assay, Western blot, xenograft mouse model Cell death and differentiation Medium 30361615
2019 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. Exosome co-culture assays, ITGB4 knockdown/overexpression, mitophagy assays, AMPK/c-Jun phosphorylation inhibition, co-transplant mouse model Oncogene Medium 31534187
2019 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. ITGB4 knockdown/overexpression in airway epithelial cells, senescence assays (SA-β-gal, p21, p53 activation), in vivo mouse model The FEBS journal Medium 30636108
2020 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. Site-directed mutagenesis (Y1510A), siRNA knockdown, overexpression in pancreatic cancer cell lines, Western blot, migration/invasion assays, immunohistochemistry in patient tissues Bosnian journal of basic medical sciences Medium 31242404
2021 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. Co-immunoprecipitation, siRNA knockdown of ITGB4 and FLRT2 in human endothelial cells, FLRT2 silencing in mice, Western blot for signaling pathway components, senescence assays JCI insight Medium 38587072
2021 PSMA interacts with ITGB4 (demonstrated by immunoprecipitation) and activates NF-κB signaling to promote angiogenesis in glioblastoma endothelial cells. High-throughput sequencing, co-immunoprecipitation, PSMA overexpression in HUVECs, PSMA inhibitor (2-PMPA) treatment, tube formation assay, in vivo GBM model Frontiers in cell and developmental biology Low 33748101
2022 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. m6A RNA immunoprecipitation (MeRIP), RIP assay, luciferase reporter assay, METTL14 and YTHDF2 knockdown/overexpression, in vitro migration/invasion assays, in vivo metastasis model Cell communication and signaling High 35305660
2022 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. 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 Cell communication and signaling High 38831335
2022 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. ITGB4 conditional knockout mice, RSV infection model, EGFR inhibitor treatment, Western blot, siRNA knockdown in HBE cells, MUC5AC quantification International journal of biological sciences Medium 34975337
2022 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. 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 The Journal of allergy and clinical immunology High 36243221
2022 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. ITGB4 conditional knockout mice, ITGB4 siRNA in airway epithelial cells, HDM/ozone challenge models, HDAC1 rescue experiments, γ-H2AX and 8-oxoG staining Pediatric allergy and immunology Medium 36282138
2022 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. siRNA knockdown in HUVECs under LSS conditions, phosphorylation analysis of SRC/FAK/NFκB, atherosclerosis mouse model (ApoE-/- + HFD), Western blot Oxidative medicine and cellular longevity Medium 36329801
2022 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. Chemical biology (HOCl probe ZBM-H), autophagy inhibitor rescue (3BDO), co-immunoprecipitation (ANXA7-Hsc70), Western blot time-course, migration assay Cell adhesion & migration Low 36203272
2022 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. ITGB4 conditional knockout mice, HDM challenge, TLR4 antagonist treatment, FYN inhibitor, Western blot for FYN phosphorylation Journal of leukocyte biology Medium 36822178
2023 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. 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 of cellular and molecular medicine Medium 37698050
2023 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. ChIP assay, dual-luciferase reporter assay, exosome inhibitor (GW4869) treatment, co-culture system with CAFs, functional proliferation/apoptosis assays Molecular and cellular biochemistry Medium 37160555
2024 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. 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 Immunology Medium 39711509
2024 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. Co-immunoprecipitation, pull-down assays, immunofluorescence staining, RNA sequencing, mass spectrometry-based metabolomics, Western blot, in vitro and in vivo (immunodeficient mice) functional assays JHEP reports Medium 38455469
2024 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. ITGB4 knockout cell lines, binding assays, soluble ITGB4 competitive inhibition, anti-ITGB4 monoclonal antibody blocking, mouse placenta infection model Nature communications High 39737945
2024 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. 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 Translational lung cancer research Medium 39430326
2024 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. Co-immunoprecipitation (FLRT2-ITGB4 interaction), mTORC2/AKT/p53 pathway analysis by Western blot, ITGB4 siRNA rescue, FLRT2 silencing in mice, vascular aging phenotype assessment JCI insight Medium 38587072
2024 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. Proteomic analysis, deubiquitinase activity assay, co-immunoprecipitation, siRNA knockdown, Western blot, cisplatin resistance functional assay FASEB journal Low 40824171
2024 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. Co-immunoprecipitation (ITGB4-IκBα), NF-κB pathway Western blot, ITGB4 knockdown in LUAD cells Translational lung cancer research Low 39430326
2025 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. 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 The Journal of biological chemistry Medium 40784455
2025 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. STAT3 inhibitor treatment, ITGB4 siRNA knockdown, p53-S15 phosphorylation Western blot, co-immunoprecipitation (MDM2-p53 binding), cisplatin sensitivity assay British journal of cancer Medium 41957134
2026 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. 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 of translational medicine Medium 41832564
2026 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. 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 of ethnopharmacology Low 41580166

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 ITGB4-mediated metabolic reprogramming of cancer-associated fibroblasts. Oncogene 143 31534187
2013 A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer cell 130 23845442
1998 Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense. American journal of human genetics 95 9792864
2013 Epigenetic regulation of miR-21 in colorectal cancer: ITGB4 as a novel miR-21 target and a three-gene network (miR-21-ITGΒ4-PDCD4) as predictor of metastatic tumor potential. Epigenetics 94 24149370
2001 Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations. Pediatric research 84 11328943
2008 Differential expression of pyloric atresia in junctional epidermolysis bullosa with ITGB4 mutations suggests that pyloric atresia is due to factors other than the mutations and not predictive of a poor outcome: three novel mutations and a review of the literature. Acta dermato-venereologica 56 18779879
2016 Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway. Biochemical and biophysical research communications 54 27109471
2013 ITGA3 and ITGB4 expression biomarkers estimate the risks of locoregional and hematogenous dissemination of oral squamous cell carcinoma. BMC cancer 49 24006899
1997 Genomic organization of the integrin beta 4 gene (ITGB4): a homozygous splice-site mutation in a patient with junctional epidermolysis bullosa associated with pyloric atresia. Laboratory investigation; a journal of technical methods and pathology 46 9194858
1998 Epidermolysis bullosa with pyloric atresia: novel mutations in the beta4 integrin gene (ITGB4). The American journal of pathology 45 9422533
1997 Novel ITGB4 mutations in a patient with junctional epidermolysis bullosa-pyloric atresia syndrome and altered basement membrane zone immunofluorescence for the alpha6beta4 integrin. The Journal of investigative dermatology 45 9182827
2016 Netrin-1 suppresses the MEK/ERK pathway and ITGB4 in pancreatic cancer. Oncotarget 40 27034160
2022 METTL14-mediated N6-methyladenosine modification of ITGB4 mRNA inhibits metastasis of clear cell renal cell carcinoma. Cell communication and signaling : CCS 39 35305660
2019 ITGB4 deficiency induces senescence of airway epithelial cells through p53 activation. The FEBS journal 38 30636108
1998 Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease. The British journal of dermatology 38 9892956
2020 Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway. Bosnian journal of basic medical sciences 35 31242404
2021 Prostate-Specific Membrane Antigen (PSMA) Promotes Angiogenesis of Glioblastoma Through Interacting With ITGB4 and Regulating NF-κB Signaling Pathway. Frontiers in cell and developmental biology 32 33748101
2004 L1CAM, INP10, P-cadherin, tPA and ITGB4 over-expression in malignant pleural mesotheliomas revealed by combined use of cDNA and tissue microarray. Carcinogenesis 31 15447976
2018 Deletion of TMEM268 inhibits growth of gastric cancer cells by downregulating the ITGB4 signaling pathway. Cell death and differentiation 29 30361615
2022 Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model. The Journal of allergy and clinical immunology 28 36243221
2008 Conditional deletion of the Itgb4 integrin gene in Schwann cells leads to delayed peripheral nerve regeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 18971471
2022 SPC25 promotes hepatocellular carcinoma metastasis via activating the FAK/PI3K/AKT signaling pathway through ITGB4. Oncology reports 27 35293598
2018 ITGB4 is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness. Journal of leukocyte biology 24 29393977
2018 ITGB4 deficiency in bronchial epithelial cells directs airway inflammation and bipolar disorder-related behavior. Journal of neuroinflammation 23 30170608
1998 Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of epidermolysis bullosa with pyloric atresia. The American journal of pathology 23 9546354
2023 Exosome-transmitted FOSL1 from cancer-associated fibroblasts drives colorectal cancer stemness and chemo-resistance through transcriptionally activating ITGB4. Molecular and cellular biochemistry 22 37160555
2023 Targeting ITGB4/SOX2-driven lung cancer stem cells using proteasome inhibitors. iScience 22 37554452
2024 Ac4C modification of lncRNA SIMALR promotes nasopharyngeal carcinoma progression through activating eEF1A2 to facilitate ITGB4/ITGA6 translation. Oncogene 21 39154122
2021 A Pan-Cancer Analysis of the Oncogenic Role of Integrin Beta4 (ITGB4) in Human Tumors. International journal of general medicine 21 34924769
2019 Ziyuglycoside II suppresses the aggressive phenotype of triple negative breast cancer cells through regulating Src/EGFR-dependent ITGB4/FAK signaling. Toxicology in vitro : an international journal published in association with BIBRA 21 31525383
2010 Wound repair and anti-oxidative capacity is regulated by ITGB4 in airway epithelial cells. Molecular and cellular biochemistry 20 20364299
2024 Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer. JHEP reports : innovation in hepatology 19 38455469
2021 Valproic Acid Protects Chondrocytes from LPS-Stimulated Damage via Regulating miR-302d-3p/ITGB4 Axis and Mediating the PI3K-AKT Signaling Pathway. Frontiers in molecular biosciences 19 33968981
2021 ITGB4 as a novel serum diagnosis biomarker and potential therapeutic target for colorectal cancer. Cancer medicine 19 34414684
2020 Epigenetic regulation of the ITGB4 gene in prostate cancer. Experimental cell research 19 32376286
2016 Heterozygosity for a Novel Missense Mutation in the ITGB4 Gene Associated With Autosomal Dominant Epidermolysis Bullosa. JAMA dermatology 17 26817667
2024 IDH1-mutant metabolite D-2-hydroxyglutarate inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT. Cell death discovery 14 38982076
2022 ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells. International journal of biological sciences 14 34975337
2022 ARRDC3 inhibits liver fibrosis and epithelial-to-mesenchymal transition via the ITGB4/PI3K/Akt signaling pathway. Immunopharmacology and immunotoxicology 14 36154540
2024 Up-regulated ITGB4 promotes hepatocellular carcinoma metastasis by activating hypoxia-mediated glycolysis and cancer-associated fibroblasts. European journal of pharmacology 13 39603378
2022 KCNF1 promotes lung cancer by modulating ITGB4 expression. Cancer gene therapy 13 36385523
2017 Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells. Journal of cellular physiology 13 28926098
2024 The mechanism of ITGB4 in tumor migration and invasion. Frontiers in oncology 12 39169946
2022 TCN1 Deficiency Inhibits the Malignancy of Colorectal Cancer Cells by Regulating the ITGB4 Pathway. Gut and liver 12 35686504
2015 DNA-based diagnosis of rare diseases in veterinary medicine: a 4.4 kb deletion of ITGB4 is associated with epidermolysis bullosa in Charolais cattle. BMC veterinary research 12 25890340
2016 Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia. Experimental dermatology 11 26739954
2004 Pyloric atresia-junctional epidermolysis bullosa syndrome showing novel 594insC/Q425P mutations in integrin beta4 gene (ITGB4). Experimental dermatology 11 15009117
2024 MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway. Cancer biology & therapy 10 38375821
2024 FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway. JCI insight 10 38587072
2024 Bufotalin Induces Oxidative Stress-Mediated Apoptosis by Blocking the ITGB4/FAK/ERK Pathway in Glioblastoma. Antioxidants (Basel, Switzerland) 10 39456433
2021 Epidermolysis bullosa with pyloric atresia associated with compound heterozygous ITGB4 pathogenic variants: Minimal skin involvement but severe mucocutaneous disease. Pediatric dermatology 10 34152038
2021 Case Report: Uncommon Association of ITGB4 and KRT10 Gene Mutation in a Case of Epidermolysis Bullosa With Pyloric Atresia and Aplasia Cutis Congenita. Frontiers in genetics 9 34306001
2019 Dose dependency PM2.5 aggravated airway inflammation in asthmatic mice via down-regulating expression of ITGB4. European review for medical and pharmacological sciences 9 30840294
2017 Epidermolysis Bullosa with Pyloric Atresia and Aplasia Cutis in a Newborn Due to Homozygous Mutation in ITGB4. Fetal and pediatric pathology 9 28557647
2022 Activation of GRP78 ATPase suppresses A549 lung cancer cell migration by promoting ITGB4 degradation. Cell adhesion & migration 8 36203272
2010 A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing. Experimental dermatology 8 20955205
2024 NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression. Cell communication and signaling : CCS 7 38831335
2024 TFAP2A-activated ITGB4 promotes lung adenocarcinoma progression and inhibits CD4+/CD8+ T-cell infiltrations by targeting NF-κB signaling pathway. Translational lung cancer research 7 39430326
2024 ITGB4/BNIP3 Activates Autophagy and Reduces MHC-I Expression to Mediate Tumour Immune Escape in Pancreatic Cancer Cell Lines. Immunology 7 39711509
2023 SPTBN2 regulates endometroid ovarian cancer cell proliferation, invasion and migration via ITGB4‑mediated focal adhesion and ECM receptor signalling pathway. Experimental and therapeutic medicine 7 37206547
2023 Identification of ITGB4 as a novel tumor promoting gene in lung adenocarcinoma (LUAD). Oncology reports 7 38131229
2022 Shear-Induced ITGB4 Promotes Endothelial Cell Inflammation and Atherosclerosis. Oxidative medicine and cellular longevity 7 36329801
2022 ITGB4 Deficiency in Airway Epithelium Aggravates RSV Infection and Increases HDM Sensitivity. Frontiers in immunology 6 35958591
2021 Identification of novel compound heterozygous ITGB4 mutations in a Chinese woman with junctional epidermolysis bullosa without pylori atresia but profound urinary symptoms: A case report and review of the literature. The Journal of dermatology 6 34462954
2015 Splicing abnormality of integrin β4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome. Journal of dermatological science 6 25728941
2024 ITGB4/GNB5 axis promotes M2 macrophage reprogramming in NSCLC metastasis. International immunopharmacology 5 39577216
2024 ITGB4/CD104 mediates zika virus attachment and infection. Nature communications 5 39737945
2025 Enhanced ZBTB10 expression induced by betulinic acid inhibits gastric cancer progression by inactivating the ARRDC3/ITGB4/PI3K/AKT pathway. Cellular oncology (Dordrecht, Netherlands) 4 39873948
2024 ITGB4 upregulation is associated with progression of lower grade glioma. Scientific reports 4 38172503
2024 Blue light promotes conjunctival epithelial-mesenchymal transition and collagen deposition through ITGB4. Ecotoxicology and environmental safety 4 39732060
2023 Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia. Journal of cellular and molecular medicine 4 37698050
2022 Epidermolysis Bullosa With Congenital Absence of Skin: Congenital Corneal Cloudiness and Esophagogastric Obstruction Including Extended Genotypic Spectrum of PLEC, LAMC2, ITGB4 and COL7A1. Frontiers in genetics 4 35432467
2025 GALNT4 promotes the stemness of non-small cell lung cancer through O-glycosylation of MUC5AC via ITGB4/PI3K/AKT signaling pathway. Cellular signalling 3 40505844
2025 PD-L1/ITGB4 Axis Modulates Sensitivity of Hepatocellular Carcinoma to Sorafenib via FAK/AKT/mTOR Signaling Pathway. ImmunoTargets and therapy 3 40827229
2022 ITGB4 deficiency induces DNA damage by downregulating HDAC1 in airway epithelial cells under stress stimulation. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology 3 36282138
2015 Pyloric atresia-junctional epidermolysis bullosa syndrome showing novel c.4505-4508insACTC mutations in integrin b4 gene (ITGB4). The Turkish journal of pediatrics 3 27186702
2025 Neddylation inhibitor MLN4924 enhances H3K18 lactylation via binding to LDH and downregulates ITGB4 to block metastasis. The Journal of biological chemistry 2 40784455
2025 Compound Heterozygous Null Variants in ITGB4 Gene Causing Severe Phenotype of Junctional Epidermolysis Bullosa With Pyloric Atresia in Thai Newborn: Genotype-Phenotype Correlation From a Case Report and Review of the Literature. International journal of genomics 2 41035785
2024 ING3 inhibits the malignant progression of lung adenocarcinoma by negatively regulating ITGB4 expression to inactivate Src/FAK signaling. Cellular signalling 2 38281617
2023 Unraveling dedifferentiation and metastasis traces in pancreatic ductal adenocarcinoma ductal cells: Insights from single-cell RNA sequencing analysis of ITGB4 and C19orf33. Pathology, research and practice 2 38071887
2022 Autosomal recessive inheritance of a novel missense mutation of ITGB4 for Epidermolysis-Bullosa pyloric-atresia: a case report. Molecular genetics and genomics : MGG 2 35997841
2021 Biallelic ITGB4 variants in familial pyloric atresia without epidermolysis bullosa: Report of two families with five siblings. American journal of medical genetics. Part A 2 34403180
2026 A novel variant c.A527G in ITGB4 leads to autosomal dominant epidermolysis bullosa in China. Frontiers in medicine 1 41728014
2023 ITGB4 deficiency in airway epithelia enhances HDM-induced airway inflammation through hyperactivation of TLR4 signaling pathway. Journal of leukocyte biology 1 36822178
2023 Association analysis for SNPs of LIPE and ITGB4 genes with cashmere production performance, body measurement traits and milk production traits in Liaoning cashmere goats. Animal biotechnology 1 37428531
2020 Common variants of NRG1 and ITGB4 confer risk of Hirschsprung disease in Han Chinese population. Journal of pediatric surgery 1 32418639
2001 Nine novel single-nucleotide polymorphisms in the integrin beta4 (ITGB4) gene in the Japanese population. Journal of human genetics 1 11289717
2026 Lenvatinib and everolimus synergistically inhibit neuroendocrine neoplasms by upregulating ITGB4 expression. Endocrine-related cancer 0 41439601
2026 Bufei formula attenuates airway mucus hypersecretion in COPD through inhibition of TRIM56-mediated ITGB4 ubiquitination. Journal of ethnopharmacology 0 41580166
2026 The FN1-ITGB4 Axis Drives Acquired Chemoresistance in Bladder Cancer by Activating FAK Signaling. Oncology research 0 41613793
2026 M2-like GAMs secreting CSTA drive glioblastoma progression via the ITGB4-TGFB1 feedback axis. Journal of translational medicine 0 41832564
2026 Non-enzymatic function of QSOX2 directly regulates the JUNB-ITGB4 axis and enhanced resistance to osimertinib in EGFR-mutation lung adenocarcinoma. Cell death discovery 0 41922310
2026 ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53. British journal of cancer 0 41957134
2026 Strategy based on liquid crystal elastomer active tensile to accelerate bone repair: Mechanistic analysis of LAMB1-ITGB4 mediated PI3K-AKT signaling. Materials today. Bio 0 42211061
2025 USP44 Regulates Chemoresistance Induced by ROS and the MAPK/NF-κB Pathway Through the Stabilization of ITGB4 in Gastric Cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 40824171
2025 WTAP contributes to the malignancy and stemness of hepatocellular carcinoma through upregulating N6-methyladenosine modification of ITGB4. Pathology, research and practice 0 41456451
2025 Prenatal Identification of a Novel ITGB4 Gene Mutation Associated With Junctional Epidermolysis Bullosa: A Case Report. Clinical case reports 0 41476816
2024 ITGB4-Related pyloric atresia without epidermolysis in two siblings. European journal of medical genetics 0 39322060
2023 A heterozygous mutation in ITGB4 causing a mild phenotype of junctional epidermolysis bullosa. Pediatric dermatology 0 36813478
2023 A comprehensive investigation regarding the clinical significance of ITGB4 in oral squamous cell carcinoma combining immunohistochemistry, RNA-seq, and microarray data. Computational biology and chemistry 0 36934520

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