{"gene":"ITGB6","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2016,"finding":"TGFβ1 upregulates ITGB6 gene transcription via canonical Smad3/Smad4 signaling: ChIP demonstrated direct binding of Smad3 and Smad4 to the ITGB6 promoter at a single Smad binding site at position -798, and dominant-negative Smad3/4 constructs abolished TGFβ1-induced ITGB6 transcriptional activity. A homeostatic autocrine loop exists where αvβ6-mediated TGFβ1 activation drives basal ITGB6 expression, which can be amplified by exogenous TGFβ1. In vivo, Smad3 was required for TGFβ1-induced αvβ6 integrin expression in alveolar epithelium.","method":"Dominant-negative Smad3/4 constructs, ITGB6 promoter reporter assays with Smad-binding-site mutation, chromatin immunoprecipitation (ChIP), adenoviral TGFβ1 overexpression mouse model","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, promoter mutagenesis, dominant-negative constructs, in vivo model) in a single rigorous study","pmids":["27494713"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutations in ITGB6 (missense and nonsense variants in the βI-domain and elsewhere) cause autosomal recessive amelogenesis imperfecta. Immunohistochemistry localized ITGB6 protein to the distal membrane of differentiating ameloblasts/pre-ameloblasts, with internalization in secretory-stage ameloblasts and strongest expression at the maturation stage, indicating that ITGB6-mediated cell-matrix interactions are required at multiple stages of amelogenesis.","method":"Whole-exome sequencing, Sanger sequencing, immunohistochemistry of mouse mandibular incisors","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across two independent papers (PMID 24305999 and 24319098) using exome sequencing plus in situ protein localization, with orthogonal genetic and histological evidence","pmids":["24305999","24319098"],"is_preprint":false},{"year":2019,"finding":"PD-L1 directly interacts with integrin β6 (ITGB6) and activates the ITGB6/FAK signaling pathway. RORC negatively regulates PD-L1 expression by binding to its promoter, thereby suppressing PD-L1/ITGB6 signaling and preventing nuclear translocation of STAT3 in bladder cancer cells.","method":"Co-immunoprecipitation (PD-L1/ITGB6 interaction), chromatin immunoprecipitation (RORC on PD-L1 promoter), western blotting, in vitro and in vivo functional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP reported for PD-L1/ITGB6 interaction plus ChIP for RORC/PD-L1 promoter, single lab","pmids":["30808674"],"is_preprint":false},{"year":2021,"finding":"In ovarian cancer spheroids, ITGB6 binds latent TGFβ1 (confirmed by anti-ITGB6 antibody inhibition and dual-luciferase reporter assays), activates it, and triggers downstream TGFβ1/Smad3 signaling to induce EMT markers (N-cadherin, Snail, Vimentin upregulation; E-cadherin downregulation). SMYD3 promotes ITGB6 expression and TGFβ1 release from spheroids, and TGFβ1 feeds back to upregulate SMYD3 and ITGB6, forming a positive feedback loop that drives invasion and adhesion.","method":"Anti-ITGB6 antibody blocking assays, dual-luciferase reporter assays, ELISA, western blotting, Transwell invasion/adhesion assays, 3D spheroid models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays and reporter confirmation of ITGB6-latent TGFβ1 binding, single lab","pmids":["34621667"],"is_preprint":false},{"year":2022,"finding":"STC1 (Stanniocalcin 1) directly binds to ITGB6 to activate the PI3K signaling pathway, promoting metastasis, lipid metabolism, and cisplatin chemoresistance in ovarian cancer. STC1 is transcriptionally regulated by FOXC2, placing ITGB6 downstream in the FOXC2/STC1/ITGB6/PI3K axis.","method":"Co-immunoprecipitation (STC1/ITGB6 direct binding), in vitro and in vivo functional assays, western blotting","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for direct binding reported, supported by multiple functional assays, single lab","pmids":["35392966"],"is_preprint":false},{"year":2022,"finding":"HAX1, delivered via extracellular vesicles (EVs) to endothelial cells, enhances the translational efficiency of ITGB6 mRNA (identified by ribosome profiling), increasing ITGB6 protein levels and activating the FAK pathway, thereby promoting angiogenesis and NPC metastasis.","method":"Ribosome profiling, in vitro EV uptake assays, in vivo angiogenesis and metastasis models, western blotting","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ribosome profiling for translational regulation plus in vivo validation, single lab","pmids":["35524442"],"is_preprint":false},{"year":2014,"finding":"ITGB6 protein expression in skeletal muscle is post-transcriptionally regulated: uninjured muscle expresses Itgb6 mRNA but no detectable ITGB6 protein; muscle injury rapidly induces ITGB6 protein accumulation in myofibers adjacent to the injury site, persisting in newly formed fibers through at least 15 days post-injury.","method":"qRT-PCR, western blotting, immunohistochemistry in injured and uninjured mouse skeletal muscle","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison of mRNA vs. protein levels in matched tissue samples with temporal kinetics, single lab","pmids":["24488487"],"is_preprint":false},{"year":2021,"finding":"ITGB6 knockout in cholangiocarcinoma (HuCCT1) cells using CRISPR/Cas9 significantly inhibited cell migration, invasion, wound healing, colony formation, and caused cell cycle dysregulation. RNA sequencing identified a marked decrease in PODXL2 (podocalyxin-like protein 2) expression in ITGB6-KO cells, and co-localization of ITGB6 and PODXL2 was observed by immunofluorescence, placing PODXL2 downstream of ITGB6.","method":"CRISPR/Cas9 knockout, RNA sequencing, flow cytometry, immunofluorescence co-localization, migration/invasion assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with multiple orthogonal phenotypic readouts and downstream target identification by RNA-seq, single lab","pmids":["34208313"],"is_preprint":false},{"year":2021,"finding":"Silencing of ITGB6 in cervical carcinoma cells suppresses JAK1, JAK2, and STAT3 phosphorylation, reduces EMT marker expression (Snail, Vimentin, N-cadherin), and increases E-cadherin. Reactivation of the JAK/STAT3 pathway with an activator (RO8191) reversed the effects of ITGB6 silencing on proliferation, migration, invasion, and EMT markers, placing ITGB6 upstream of JAK/STAT3 signaling.","method":"siRNA knockdown, western blotting, JAK/STAT3 pathway activator rescue experiment, Transwell and wound-healing assays","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic epistasis by rescue experiment placing ITGB6 upstream of JAK/STAT3, single lab","pmids":["34268416"],"is_preprint":false},{"year":2021,"finding":"Transgenic overexpression of ITGB6 specifically in intestinal epithelial cells exacerbated DSS-induced colitis in mice, associated with increased macrophage infiltration, pro-inflammatory cytokine secretion, increased integrin ligand expression, and activation of the STAT1 signaling pathway.","method":"Intestinal epithelial cell-specific ITGB6 transgenic mouse model, DSS colitis induction, histopathology, cytokine measurement, western blotting","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic in vivo model with defined pathway readout (STAT1), single lab","pmids":["33491282"],"is_preprint":false},{"year":2016,"finding":"miR-17 and miR-20a target TGFβR2 and SARA (components of the TGFβ pathway), reducing Smad2/3 phosphorylation and thereby decreasing ITGB6 expression, which impedes ESCC cell migration and invasion. This epistasis places ITGB6 as a downstream effector of TGFβ/Smad2-3 signaling in ESCC motility.","method":"miRNA overexpression, luciferase reporter assays (for TGFBR2 and SARA as targets), TGFβ treatment/rescue experiments, in vitro migration/invasion assays, in vivo pulmonary arrest model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway epistasis established by TGFβ rescue and Smad phosphorylation readout, multiple assays, single lab","pmids":["27508097"],"is_preprint":false},{"year":2023,"finding":"Exosomal ITGB6 from dormant lung adenocarcinoma cells is transferred into fibroblasts, where it activates a KLF10 positive feedback loop and the TGFβ pathway, converting normal fibroblasts into cancer-associated fibroblasts (CAFs) and promoting ECM remodeling.","method":"Exosome isolation and transfer assays, RNA-seq of recipient fibroblasts, exosomal proteomics, functional CAF activation assays","journal":"Translational lung cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — exosomal protein transfer demonstrated with proteomics and RNA-seq pathway readout, single lab","pmids":["38205211"],"is_preprint":false},{"year":2024,"finding":"ITGB6 regulates tumor-associated chemokine CX3CL1 expression in head and neck squamous cell carcinoma; ITGB6-expressing tumors recruit PF4+ macrophages expressing high CX3CR1 via CX3CL1. These macrophages secrete CXCL16 to suppress CXCR6+ CD8+ T cell activity. Inhibition of CX3CL1-CX3CR1 axis or ITGB6 knockout restored sensitivity to anti-CD276 and anti-PD1 therapies.","method":"Single-cell RNA sequencing, ITGB6 gene-knockout mouse models, chemically-induced and orthotopic carcinogenesis models, CX3CL1-CX3CR1 axis inhibition","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in immunocompetent mouse models with scRNA-seq pathway dissection, single lab","pmids":["39152118"],"is_preprint":false},{"year":2025,"finding":"ITGB6 promotes anoikis resistance in daughter cells of polyploid giant cancer cells (PGCCs) in HNSCC by activating the FAK/PI3K/AKT signaling pathway, facilitating tumor recurrence and metastasis. In vitro and in vivo experiments confirmed that ITGB6 upregulation in these daughter cells suppresses anoikis via this pathway.","method":"RNA-seq, in vitro anoikis assays, in vivo metastasis models, western blotting for FAK/PI3K/AKT pathway markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro and in vivo models with pathway mechanistic readout, single lab","pmids":["41022988"],"is_preprint":false},{"year":2025,"finding":"TGFβ upregulates ITGB6 expression through a SMAD4-dependent pathway (confirmed by ChIP-qPCR and dual-luciferase reporter assays). Elevated ITGB6 promotes pancreatic cancer cell migration/invasion and activates hepatic stellate cells (HSCs) to create a pro-fibrotic metastatic niche. An ITGB6 monoclonal antibody significantly attenuated HSC activation and suppressed liver metastasis formation in mouse models.","method":"ChIP-qPCR, dual-luciferase reporter assay, subcutaneous and liver metastasis xenograft models, ELISA, western blotting, monoclonal antibody intervention","journal":"Chinese medical journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP and reporter assays for transcriptional regulation plus in vivo therapeutic model, single lab","pmids":["41424019"],"is_preprint":false},{"year":2025,"finding":"ODAPH interacts directly with Lamininγ2 (LAMC2), confirmed by co-immunoprecipitation. ODAPH overexpression enhances the LAMC2/ITGB6/TGFβ1/ALP signaling pathway in ameloblast-lineage cells. ITGB6 activates the TGFβ1/ALP cascade, and inhibition of integrin with CWHM-12 abrogates ODAPH-mediated TGFβ1/ALP induction, placing ITGB6 as an obligate mediator between LAMC2 and TGFβ1 signaling in ameloblast adhesion and mineralization.","method":"Co-immunoprecipitation (ODAPH-LAMC2), overexpression in ameloblast-lineage cells, integrin inhibitor (CWHM-12) rescue experiment, western blotting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus pharmacological rescue placing ITGB6 in signaling cascade, single lab","pmids":["40680053"],"is_preprint":false},{"year":2024,"finding":"ETS1 transcription factor directly binds the ITGB6 promoter and promotes its transcription in an acidic tumor microenvironment. ChIP-qPCR demonstrated ETS1 enrichment at the ITGB6 promoter, and dual-luciferase reporter assays confirmed ETS1-mediated transcriptional activation of ITGB6. Acidity-induced ITGB6 expression then activates EMT and focal adhesion signaling pathways to promote NSCLC cell migration and invasion.","method":"ChIP-qPCR, dual-luciferase reporter assay, ITGB6 knockdown rescue experiments, migration/invasion assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP-qPCR and reporter assay directly demonstrate ETS1 binding and transcriptional activation of ITGB6 promoter, single lab","pmids":["38316250"],"is_preprint":false},{"year":1994,"finding":"The human ITGB6 gene was regionally localized to chromosome 2q24-q31 by fluorescence in situ hybridization (FISH) with GTG-banding. Double-labeling FISH showed ITGB6 is located proximal to ITGAV on this integrin gene cluster.","method":"Fluorescence in situ hybridization (FISH) with GTG-banding, double-labeling FISH","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct cytogenetic mapping, replicated in the same study with double-label FISH","pmids":["7959743"],"is_preprint":false},{"year":2024,"finding":"CRISPR/Cas9 knockout of ITGB6 in human OSCC cells (HN cell line) significantly reduced cell migration and proliferation, establishing ITGB6 as required for these behaviors in oral squamous cell carcinoma.","method":"CRISPR/Cas9 knockout, MTT proliferation assay, scratch migration assay, Sanger sequencing, FACS verification","journal":"Head & face medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — clean CRISPR KO but only basic phenotypic readouts with no molecular pathway mechanistic follow-up, single lab","pmids":["38890650"],"is_preprint":false},{"year":2025,"finding":"ITGB6 knockout in porcine intestinal epithelial cells (IPEC-J2) significantly reduced DON-induced reactive oxygen species levels and cell apoptosis. Transcriptomic analysis of ITGB6-KO cells after DON treatment showed differential gene enrichment in the PI3K/AKT signaling pathway, implicating ITGB6 in PI3K/AKT-mediated cell survival/apoptosis under toxin exposure.","method":"CRISPR/Cas9 knockout, ROS measurement, flow cytometry apoptosis assay, transcriptomic analysis","journal":"Toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO with pathway enrichment analysis but no direct mechanistic validation of PI3K/AKT link, single lab","pmids":["41161376"],"is_preprint":false}],"current_model":"ITGB6 encodes the β6 subunit of the epithelial integrin αvβ6; as the rate-limiting partner it controls heterodimer expression and availability. Its own transcription is driven by TGFβ1 via direct Smad3/Smad4 binding to a single promoter element (and by ETS1 under acidic conditions), creating an autocrine amplification loop. At the cell surface, αvβ6 binds and activates latent TGFβ1, enabling downstream Smad3 and FAK/PI3K/AKT signaling that drives EMT, invasion, anoikis resistance, and fibroblast/stellate-cell activation; ITGB6 also interacts with binding partners including PD-L1, STC1, and ODAPH-associated LAMC2, and regulates immune microenvironment composition through CX3CL1-mediated macrophage recruitment. Loss-of-function mutations in ITGB6 abolish the cell-matrix interactions required for ameloblast maturation, causing autosomal recessive amelogenesis imperfecta."},"narrative":{"mechanistic_narrative":"ITGB6 encodes the β6 subunit of the epithelial integrin αvβ6, which binds and activates latent TGFβ1 at the cell surface and thereby couples cell-matrix engagement to TGFβ/Smad signaling [PMID:34621667]. Its own transcription is driven by TGFβ1 through canonical Smad3/Smad4 binding to a single Smad element at promoter position -798, establishing an autocrine amplification loop in which αvβ6-mediated TGFβ1 activation sustains basal ITGB6 expression [PMID:27494713]; SMAD4-dependent induction is recapitulated in pancreatic cancer, and ETS1 provides an alternative route to ITGB6 transcription in an acidic microenvironment [PMID:41424019, PMID:38316250]. Downstream of ligand engagement, ITGB6 activates FAK/PI3K/AKT signaling to confer anoikis resistance and JAK/STAT3 signaling to drive EMT, migration, and invasion, with ITGB6 placed genetically upstream of these cascades by rescue and epistasis experiments [PMID:41022988, PMID:34268416, PMID:27508097]. ITGB6 additionally shapes the tumor microenvironment: it activates fibroblasts and hepatic stellate cells to remodel the ECM and build a pro-metastatic niche [PMID:38205211, PMID:41424019], and regulates CX3CL1-mediated recruitment of macrophages that suppress CD8+ T-cell activity and limit immunotherapy response [PMID:39152118]. The β6 subunit physically engages additional partners including PD-L1 (activating ITGB6/FAK signaling) and STC1 (activating PI3K signaling), and acts downstream of LAMC2 to relay ODAPH-driven TGFβ1/ALP signaling in ameloblast-lineage cells [PMID:30808674, PMID:35392966, PMID:40680053]. Loss-of-function mutations in ITGB6 cause autosomal recessive amelogenesis imperfecta, reflecting a requirement for ITGB6-mediated cell-matrix interactions during ameloblast maturation [PMID:24305999, PMID:24319098].","teleology":[{"year":1994,"claim":"Establishing the genomic position of ITGB6 within the integrin gene cluster anchored it physically next to its heterodimer partner ITGAV.","evidence":"FISH with GTG-banding and double-labeling FISH on human chromosomes","pmids":["7959743"],"confidence":"Medium","gaps":["Mapping alone establishes no function","Does not address regulation or protein partners"]},{"year":2013,"claim":"Linking ITGB6 mutations to a Mendelian disease answered whether ITGB6 has a non-redundant physiological role, showing it is required for ameloblast-driven enamel formation.","evidence":"Whole-exome/Sanger sequencing of amelogenesis imperfecta families plus immunohistochemistry of mouse incisors, replicated across two papers","pmids":["24305999","24319098"],"confidence":"High","gaps":["Does not define the matrix ligand engaged during amelogenesis","Mechanism connecting ITGB6 loss to enamel defect not fully resolved at the signaling level"]},{"year":2014,"claim":"Revealing that ITGB6 protein is undetectable in resting muscle despite mRNA presence and is induced post-transcriptionally upon injury established that ITGB6 is a context-induced, not constitutive, protein.","evidence":"Matched qRT-PCR, western blot, and IHC in injured vs uninjured mouse skeletal muscle with temporal kinetics","pmids":["24488487"],"confidence":"Medium","gaps":["Mechanism of post-transcriptional control not identified","Functional consequence in muscle repair not tested"]},{"year":2016,"claim":"Defining how ITGB6 transcription is controlled answered whether the integrin's TGFβ-activating output feeds back on its own expression, establishing a Smad3/Smad4 autocrine amplification loop.","evidence":"ChIP, promoter reporter with Smad-site mutation, dominant-negative Smad3/4, and adenoviral TGFβ1 mouse model; plus miRNA-driven TGFβR2/SARA epistasis placing ITGB6 downstream of TGFβ/Smad2-3","pmids":["27494713","27508097"],"confidence":"High","gaps":["Single Smad site characterized; other regulatory inputs not mapped","Loop kinetics and thresholds for amplification not defined"]},{"year":2021,"claim":"Demonstrating that ITGB6 binds and activates latent TGFβ1 to trigger Smad3-driven EMT connected the integrin's matrix-binding role to a defined invasion-promoting transcriptional program.","evidence":"Anti-ITGB6 blocking, dual-luciferase reporter, ELISA, and EMT marker western blots in ovarian cancer 3D spheroids; SMYD3 positive feedback loop","pmids":["34621667"],"confidence":"Medium","gaps":["Single lab; structural basis of latent TGFβ1 engagement not resolved","In vivo confirmation limited"]},{"year":2021,"claim":"Genetic and epistasis experiments placed ITGB6 upstream of distinct effector cascades — PODXL2, JAK/STAT3, and STAT1 — and downstream of TGFβ, defining the signaling architecture around the integrin.","evidence":"CRISPR KO with RNA-seq (PODXL2) in cholangiocarcinoma; siRNA plus JAK/STAT3 activator rescue in cervical carcinoma; intestinal epithelial ITGB6 transgenic mouse with STAT1 readout in DSS colitis","pmids":["34208313","34268416","33491282"],"confidence":"Medium","gaps":["Each link shown in a single tumor/tissue context","Direct physical coupling between ITGB6 and these kinases not demonstrated"]},{"year":2022,"claim":"Identifying STC1 as a direct ITGB6 partner activating PI3K, and HAX1-driven translational upregulation of ITGB6, expanded the inputs that elevate ITGB6 activity beyond transcription.","evidence":"Co-IP (STC1/ITGB6) with functional assays in ovarian cancer; ribosome profiling and EV transfer with in vivo angiogenesis/metastasis models for HAX1","pmids":["35392966","35524442"],"confidence":"Medium","gaps":["Reciprocal validation of STC1/ITGB6 binding limited","Translational control mechanism by HAX1 not molecularly resolved"]},{"year":2023,"claim":"Showing that exosomal ITGB6 transferred to fibroblasts converts them into cancer-associated fibroblasts established a non-cell-autonomous, microenvironment-remodeling function for the integrin.","evidence":"Exosome isolation/transfer, recipient fibroblast RNA-seq, exosomal proteomics, and CAF activation assays in lung adenocarcinoma","pmids":["38205211"],"confidence":"Medium","gaps":["Mechanism of ITGB6 packaging into exosomes unknown","KLF10 feedback loop dissection incomplete"]},{"year":2024,"claim":"Linking ITGB6 to CX3CL1-driven macrophage recruitment and CD8+ T-cell suppression connected the integrin to immune evasion and immunotherapy resistance.","evidence":"scRNA-seq, ITGB6 KO immunocompetent mouse models, and CX3CL1-CX3CR1 axis inhibition restoring anti-CD276/anti-PD1 sensitivity","pmids":["39152118"],"confidence":"Medium","gaps":["How ITGB6 regulates CX3CL1 transcriptionally not defined","Single lab; human relevance from mouse models not confirmed"]},{"year":2025,"claim":"Multiple 2025 studies consolidated ITGB6's roles in FAK/PI3K/AKT-mediated anoikis resistance, SMAD4-dependent transcription with a stellate-cell pro-fibrotic niche, and as an obligate LAMC2-to-TGFβ1 mediator in ameloblasts.","evidence":"RNA-seq/in vivo metastasis models (FAK/PI3K/AKT anoikis); ChIP-qPCR, reporter, and therapeutic monoclonal antibody xenograft (SMAD4/HSC niche); Co-IP and CWHM-12 integrin-inhibitor rescue (LAMC2/ODAPH/TGFβ1/ALP)","pmids":["41022988","41424019","40680053"],"confidence":"Medium","gaps":["Each mechanism shown in a single model system","Therapeutic antibody efficacy not extended beyond mouse models"]},{"year":null,"claim":"Whether the diverse downstream cascades (FAK/PI3K/AKT, JAK/STAT3, STAT1) and physical partners (PD-L1, STC1, LAMC2) reflect a single unified ITGB6 signaling mechanism or context-specific outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ITGB6 partner-binding interfaces","No cross-context comparison of which effectors dominate in which tissue","Mechanism converting matrix engagement into distinct kinase outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,13,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,13]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[11,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1]}],"complexes":["αvβ6 integrin"],"partners":["ITGAV","PD-L1","STC1","LAMC2","TGFB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P18564","full_name":"Integrin beta-6","aliases":[],"length_aa":788,"mass_kda":85.9,"function":"Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin (PubMed:17158881, PubMed:17545607). It recognizes the sequence R-G-D in its ligands (PubMed:17158881, PubMed:17545607). Internalization of integrin alpha-V/beta-6 via clathrin-mediated endocytosis promotes carcinoma cell invasion (PubMed:17158881, PubMed:17545607). ITGAV:ITGB6 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:17158881). Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation (PubMed:15184403, PubMed:22278742, PubMed:28117447) (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Coxsackievirus A9 and Coxsackievirus B1 (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Herpes simplex virus-1/HHV-1 (PubMed:24367260)","subcellular_location":"Cell membrane; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/P18564/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGB6","total_profiled":1310},"omim":[{"mim_id":"616221","title":"AMELOGENESIS IMPERFECTA, TYPE IH; AI1H","url":"https://www.omim.org/entry/616221"},{"mim_id":"601046","title":"MATRIX METALLOPROTEINASE 12; MMP12","url":"https://www.omim.org/entry/601046"},{"mim_id":"193210","title":"INTEGRIN, ALPHA-V; ITGAV","url":"https://www.omim.org/entry/193210"},{"mim_id":"190180","title":"TRANSFORMING GROWTH FACTOR, BETA-1; TGFB1","url":"https://www.omim.org/entry/190180"},{"mim_id":"147561","title":"INTEGRIN, BETA-5; ITGB5","url":"https://www.omim.org/entry/147561"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Acrosome","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":74.9},{"tissue":"tongue","ntpm":60.3}],"url":"https://www.proteinatlas.org/search/ITGB6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P18564","domains":[{"cath_id":"3.30.1680.10","chopping":"21-79","consensus_level":"medium","plddt":78.9031,"start":21,"end":79},{"cath_id":"2.60.40.1510","chopping":"82-130_378-451","consensus_level":"high","plddt":88.3751,"start":82,"end":451},{"cath_id":"3.40.50.410","chopping":"134-374","consensus_level":"high","plddt":93.8087,"start":134,"end":374},{"cath_id":"4.10.1240,4.10.1240","chopping":"624-701","consensus_level":"high","plddt":74.2428,"start":624,"end":701}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P18564","model_url":"https://alphafold.ebi.ac.uk/files/AF-P18564-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P18564-F1-predicted_aligned_error_v6.png","plddt_mean":82.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB6","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB6"},"sequence":{"accession":"P18564","fasta_url":"https://rest.uniprot.org/uniprotkb/P18564.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P18564/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P18564"}},"corpus_meta":[{"pmid":"30808674","id":"PMC_30808674","title":"Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30808674","citation_count":112,"is_preprint":false},{"pmid":"35392966","id":"PMC_35392966","title":"Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35392966","citation_count":78,"is_preprint":false},{"pmid":"24305999","id":"PMC_24305999","title":"ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24305999","citation_count":56,"is_preprint":false},{"pmid":"24319098","id":"PMC_24319098","title":"A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24319098","citation_count":48,"is_preprint":false},{"pmid":"27494713","id":"PMC_27494713","title":"Amplification of TGFβ Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27494713","citation_count":41,"is_preprint":false},{"pmid":"35524442","id":"PMC_35524442","title":"Extracellular vesicles rich in HAX1 promote angiogenesis by modulating ITGB6 translation.","date":"2022","source":"Journal of extracellular vesicles","url":"https://pubmed.ncbi.nlm.nih.gov/35524442","citation_count":38,"is_preprint":false},{"pmid":"32550552","id":"PMC_32550552","title":"The ITGB6 gene: its role in experimental and clinical biology.","date":"2019","source":"Gene: 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A homeostatic autocrine loop exists where αvβ6-mediated TGFβ1 activation drives basal ITGB6 expression, which can be amplified by exogenous TGFβ1. In vivo, Smad3 was required for TGFβ1-induced αvβ6 integrin expression in alveolar epithelium.\",\n      \"method\": \"Dominant-negative Smad3/4 constructs, ITGB6 promoter reporter assays with Smad-binding-site mutation, chromatin immunoprecipitation (ChIP), adenoviral TGFβ1 overexpression mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, promoter mutagenesis, dominant-negative constructs, in vivo model) in a single rigorous study\",\n      \"pmids\": [\"27494713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutations in ITGB6 (missense and nonsense variants in the βI-domain and elsewhere) cause autosomal recessive amelogenesis imperfecta. Immunohistochemistry localized ITGB6 protein to the distal membrane of differentiating ameloblasts/pre-ameloblasts, with internalization in secretory-stage ameloblasts and strongest expression at the maturation stage, indicating that ITGB6-mediated cell-matrix interactions are required at multiple stages of amelogenesis.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, immunohistochemistry of mouse mandibular incisors\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across two independent papers (PMID 24305999 and 24319098) using exome sequencing plus in situ protein localization, with orthogonal genetic and histological evidence\",\n      \"pmids\": [\"24305999\", \"24319098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PD-L1 directly interacts with integrin β6 (ITGB6) and activates the ITGB6/FAK signaling pathway. RORC negatively regulates PD-L1 expression by binding to its promoter, thereby suppressing PD-L1/ITGB6 signaling and preventing nuclear translocation of STAT3 in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (PD-L1/ITGB6 interaction), chromatin immunoprecipitation (RORC on PD-L1 promoter), western blotting, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP reported for PD-L1/ITGB6 interaction plus ChIP for RORC/PD-L1 promoter, single lab\",\n      \"pmids\": [\"30808674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In ovarian cancer spheroids, ITGB6 binds latent TGFβ1 (confirmed by anti-ITGB6 antibody inhibition and dual-luciferase reporter assays), activates it, and triggers downstream TGFβ1/Smad3 signaling to induce EMT markers (N-cadherin, Snail, Vimentin upregulation; E-cadherin downregulation). SMYD3 promotes ITGB6 expression and TGFβ1 release from spheroids, and TGFβ1 feeds back to upregulate SMYD3 and ITGB6, forming a positive feedback loop that drives invasion and adhesion.\",\n      \"method\": \"Anti-ITGB6 antibody blocking assays, dual-luciferase reporter assays, ELISA, western blotting, Transwell invasion/adhesion assays, 3D spheroid models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays and reporter confirmation of ITGB6-latent TGFβ1 binding, single lab\",\n      \"pmids\": [\"34621667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STC1 (Stanniocalcin 1) directly binds to ITGB6 to activate the PI3K signaling pathway, promoting metastasis, lipid metabolism, and cisplatin chemoresistance in ovarian cancer. STC1 is transcriptionally regulated by FOXC2, placing ITGB6 downstream in the FOXC2/STC1/ITGB6/PI3K axis.\",\n      \"method\": \"Co-immunoprecipitation (STC1/ITGB6 direct binding), in vitro and in vivo functional assays, western blotting\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for direct binding reported, supported by multiple functional assays, single lab\",\n      \"pmids\": [\"35392966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HAX1, delivered via extracellular vesicles (EVs) to endothelial cells, enhances the translational efficiency of ITGB6 mRNA (identified by ribosome profiling), increasing ITGB6 protein levels and activating the FAK pathway, thereby promoting angiogenesis and NPC metastasis.\",\n      \"method\": \"Ribosome profiling, in vitro EV uptake assays, in vivo angiogenesis and metastasis models, western blotting\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ribosome profiling for translational regulation plus in vivo validation, single lab\",\n      \"pmids\": [\"35524442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ITGB6 protein expression in skeletal muscle is post-transcriptionally regulated: uninjured muscle expresses Itgb6 mRNA but no detectable ITGB6 protein; muscle injury rapidly induces ITGB6 protein accumulation in myofibers adjacent to the injury site, persisting in newly formed fibers through at least 15 days post-injury.\",\n      \"method\": \"qRT-PCR, western blotting, immunohistochemistry in injured and uninjured mouse skeletal muscle\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison of mRNA vs. protein levels in matched tissue samples with temporal kinetics, single lab\",\n      \"pmids\": [\"24488487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGB6 knockout in cholangiocarcinoma (HuCCT1) cells using CRISPR/Cas9 significantly inhibited cell migration, invasion, wound healing, colony formation, and caused cell cycle dysregulation. RNA sequencing identified a marked decrease in PODXL2 (podocalyxin-like protein 2) expression in ITGB6-KO cells, and co-localization of ITGB6 and PODXL2 was observed by immunofluorescence, placing PODXL2 downstream of ITGB6.\",\n      \"method\": \"CRISPR/Cas9 knockout, RNA sequencing, flow cytometry, immunofluorescence co-localization, migration/invasion assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with multiple orthogonal phenotypic readouts and downstream target identification by RNA-seq, single lab\",\n      \"pmids\": [\"34208313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing of ITGB6 in cervical carcinoma cells suppresses JAK1, JAK2, and STAT3 phosphorylation, reduces EMT marker expression (Snail, Vimentin, N-cadherin), and increases E-cadherin. Reactivation of the JAK/STAT3 pathway with an activator (RO8191) reversed the effects of ITGB6 silencing on proliferation, migration, invasion, and EMT markers, placing ITGB6 upstream of JAK/STAT3 signaling.\",\n      \"method\": \"siRNA knockdown, western blotting, JAK/STAT3 pathway activator rescue experiment, Transwell and wound-healing assays\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic epistasis by rescue experiment placing ITGB6 upstream of JAK/STAT3, single lab\",\n      \"pmids\": [\"34268416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Transgenic overexpression of ITGB6 specifically in intestinal epithelial cells exacerbated DSS-induced colitis in mice, associated with increased macrophage infiltration, pro-inflammatory cytokine secretion, increased integrin ligand expression, and activation of the STAT1 signaling pathway.\",\n      \"method\": \"Intestinal epithelial cell-specific ITGB6 transgenic mouse model, DSS colitis induction, histopathology, cytokine measurement, western blotting\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic in vivo model with defined pathway readout (STAT1), single lab\",\n      \"pmids\": [\"33491282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-17 and miR-20a target TGFβR2 and SARA (components of the TGFβ pathway), reducing Smad2/3 phosphorylation and thereby decreasing ITGB6 expression, which impedes ESCC cell migration and invasion. This epistasis places ITGB6 as a downstream effector of TGFβ/Smad2-3 signaling in ESCC motility.\",\n      \"method\": \"miRNA overexpression, luciferase reporter assays (for TGFBR2 and SARA as targets), TGFβ treatment/rescue experiments, in vitro migration/invasion assays, in vivo pulmonary arrest model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway epistasis established by TGFβ rescue and Smad phosphorylation readout, multiple assays, single lab\",\n      \"pmids\": [\"27508097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exosomal ITGB6 from dormant lung adenocarcinoma cells is transferred into fibroblasts, where it activates a KLF10 positive feedback loop and the TGFβ pathway, converting normal fibroblasts into cancer-associated fibroblasts (CAFs) and promoting ECM remodeling.\",\n      \"method\": \"Exosome isolation and transfer assays, RNA-seq of recipient fibroblasts, exosomal proteomics, functional CAF activation assays\",\n      \"journal\": \"Translational lung cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — exosomal protein transfer demonstrated with proteomics and RNA-seq pathway readout, single lab\",\n      \"pmids\": [\"38205211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGB6 regulates tumor-associated chemokine CX3CL1 expression in head and neck squamous cell carcinoma; ITGB6-expressing tumors recruit PF4+ macrophages expressing high CX3CR1 via CX3CL1. These macrophages secrete CXCL16 to suppress CXCR6+ CD8+ T cell activity. Inhibition of CX3CL1-CX3CR1 axis or ITGB6 knockout restored sensitivity to anti-CD276 and anti-PD1 therapies.\",\n      \"method\": \"Single-cell RNA sequencing, ITGB6 gene-knockout mouse models, chemically-induced and orthotopic carcinogenesis models, CX3CL1-CX3CR1 axis inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in immunocompetent mouse models with scRNA-seq pathway dissection, single lab\",\n      \"pmids\": [\"39152118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGB6 promotes anoikis resistance in daughter cells of polyploid giant cancer cells (PGCCs) in HNSCC by activating the FAK/PI3K/AKT signaling pathway, facilitating tumor recurrence and metastasis. In vitro and in vivo experiments confirmed that ITGB6 upregulation in these daughter cells suppresses anoikis via this pathway.\",\n      \"method\": \"RNA-seq, in vitro anoikis assays, in vivo metastasis models, western blotting for FAK/PI3K/AKT pathway markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro and in vivo models with pathway mechanistic readout, single lab\",\n      \"pmids\": [\"41022988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGFβ upregulates ITGB6 expression through a SMAD4-dependent pathway (confirmed by ChIP-qPCR and dual-luciferase reporter assays). Elevated ITGB6 promotes pancreatic cancer cell migration/invasion and activates hepatic stellate cells (HSCs) to create a pro-fibrotic metastatic niche. An ITGB6 monoclonal antibody significantly attenuated HSC activation and suppressed liver metastasis formation in mouse models.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter assay, subcutaneous and liver metastasis xenograft models, ELISA, western blotting, monoclonal antibody intervention\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP and reporter assays for transcriptional regulation plus in vivo therapeutic model, single lab\",\n      \"pmids\": [\"41424019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ODAPH interacts directly with Lamininγ2 (LAMC2), confirmed by co-immunoprecipitation. ODAPH overexpression enhances the LAMC2/ITGB6/TGFβ1/ALP signaling pathway in ameloblast-lineage cells. ITGB6 activates the TGFβ1/ALP cascade, and inhibition of integrin with CWHM-12 abrogates ODAPH-mediated TGFβ1/ALP induction, placing ITGB6 as an obligate mediator between LAMC2 and TGFβ1 signaling in ameloblast adhesion and mineralization.\",\n      \"method\": \"Co-immunoprecipitation (ODAPH-LAMC2), overexpression in ameloblast-lineage cells, integrin inhibitor (CWHM-12) rescue experiment, western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus pharmacological rescue placing ITGB6 in signaling cascade, single lab\",\n      \"pmids\": [\"40680053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETS1 transcription factor directly binds the ITGB6 promoter and promotes its transcription in an acidic tumor microenvironment. ChIP-qPCR demonstrated ETS1 enrichment at the ITGB6 promoter, and dual-luciferase reporter assays confirmed ETS1-mediated transcriptional activation of ITGB6. Acidity-induced ITGB6 expression then activates EMT and focal adhesion signaling pathways to promote NSCLC cell migration and invasion.\",\n      \"method\": \"ChIP-qPCR, dual-luciferase reporter assay, ITGB6 knockdown rescue experiments, migration/invasion assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP-qPCR and reporter assay directly demonstrate ETS1 binding and transcriptional activation of ITGB6 promoter, single lab\",\n      \"pmids\": [\"38316250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human ITGB6 gene was regionally localized to chromosome 2q24-q31 by fluorescence in situ hybridization (FISH) with GTG-banding. Double-labeling FISH showed ITGB6 is located proximal to ITGAV on this integrin gene cluster.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) with GTG-banding, double-labeling FISH\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cytogenetic mapping, replicated in the same study with double-label FISH\",\n      \"pmids\": [\"7959743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR/Cas9 knockout of ITGB6 in human OSCC cells (HN cell line) significantly reduced cell migration and proliferation, establishing ITGB6 as required for these behaviors in oral squamous cell carcinoma.\",\n      \"method\": \"CRISPR/Cas9 knockout, MTT proliferation assay, scratch migration assay, Sanger sequencing, FACS verification\",\n      \"journal\": \"Head & face medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — clean CRISPR KO but only basic phenotypic readouts with no molecular pathway mechanistic follow-up, single lab\",\n      \"pmids\": [\"38890650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGB6 knockout in porcine intestinal epithelial cells (IPEC-J2) significantly reduced DON-induced reactive oxygen species levels and cell apoptosis. Transcriptomic analysis of ITGB6-KO cells after DON treatment showed differential gene enrichment in the PI3K/AKT signaling pathway, implicating ITGB6 in PI3K/AKT-mediated cell survival/apoptosis under toxin exposure.\",\n      \"method\": \"CRISPR/Cas9 knockout, ROS measurement, flow cytometry apoptosis assay, transcriptomic analysis\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO with pathway enrichment analysis but no direct mechanistic validation of PI3K/AKT link, single lab\",\n      \"pmids\": [\"41161376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB6 encodes the β6 subunit of the epithelial integrin αvβ6; as the rate-limiting partner it controls heterodimer expression and availability. Its own transcription is driven by TGFβ1 via direct Smad3/Smad4 binding to a single promoter element (and by ETS1 under acidic conditions), creating an autocrine amplification loop. At the cell surface, αvβ6 binds and activates latent TGFβ1, enabling downstream Smad3 and FAK/PI3K/AKT signaling that drives EMT, invasion, anoikis resistance, and fibroblast/stellate-cell activation; ITGB6 also interacts with binding partners including PD-L1, STC1, and ODAPH-associated LAMC2, and regulates immune microenvironment composition through CX3CL1-mediated macrophage recruitment. Loss-of-function mutations in ITGB6 abolish the cell-matrix interactions required for ameloblast maturation, causing autosomal recessive amelogenesis imperfecta.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB6 encodes the β6 subunit of the epithelial integrin αvβ6, which binds and activates latent TGFβ1 at the cell surface and thereby couples cell-matrix engagement to TGFβ/Smad signaling [#3]. Its own transcription is driven by TGFβ1 through canonical Smad3/Smad4 binding to a single Smad element at promoter position -798, establishing an autocrine amplification loop in which αvβ6-mediated TGFβ1 activation sustains basal ITGB6 expression [#0]; SMAD4-dependent induction is recapitulated in pancreatic cancer, and ETS1 provides an alternative route to ITGB6 transcription in an acidic microenvironment [#14, #16]. Downstream of ligand engagement, ITGB6 activates FAK/PI3K/AKT signaling to confer anoikis resistance and JAK/STAT3 signaling to drive EMT, migration, and invasion, with ITGB6 placed genetically upstream of these cascades by rescue and epistasis experiments [#13, #8, #10]. ITGB6 additionally shapes the tumor microenvironment: it activates fibroblasts and hepatic stellate cells to remodel the ECM and build a pro-metastatic niche [#11, #14], and regulates CX3CL1-mediated recruitment of macrophages that suppress CD8+ T-cell activity and limit immunotherapy response [#12]. The β6 subunit physically engages additional partners including PD-L1 (activating ITGB6/FAK signaling) and STC1 (activating PI3K signaling), and acts downstream of LAMC2 to relay ODAPH-driven TGFβ1/ALP signaling in ameloblast-lineage cells [#2, #4, #15]. Loss-of-function mutations in ITGB6 cause autosomal recessive amelogenesis imperfecta, reflecting a requirement for ITGB6-mediated cell-matrix interactions during ameloblast maturation [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the genomic position of ITGB6 within the integrin gene cluster anchored it physically next to its heterodimer partner ITGAV.\",\n      \"evidence\": \"FISH with GTG-banding and double-labeling FISH on human chromosomes\",\n      \"pmids\": [\"7959743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping alone establishes no function\", \"Does not address regulation or protein partners\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking ITGB6 mutations to a Mendelian disease answered whether ITGB6 has a non-redundant physiological role, showing it is required for ameloblast-driven enamel formation.\",\n      \"evidence\": \"Whole-exome/Sanger sequencing of amelogenesis imperfecta families plus immunohistochemistry of mouse incisors, replicated across two papers\",\n      \"pmids\": [\"24305999\", \"24319098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the matrix ligand engaged during amelogenesis\", \"Mechanism connecting ITGB6 loss to enamel defect not fully resolved at the signaling level\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealing that ITGB6 protein is undetectable in resting muscle despite mRNA presence and is induced post-transcriptionally upon injury established that ITGB6 is a context-induced, not constitutive, protein.\",\n      \"evidence\": \"Matched qRT-PCR, western blot, and IHC in injured vs uninjured mouse skeletal muscle with temporal kinetics\",\n      \"pmids\": [\"24488487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of post-transcriptional control not identified\", \"Functional consequence in muscle repair not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining how ITGB6 transcription is controlled answered whether the integrin's TGFβ-activating output feeds back on its own expression, establishing a Smad3/Smad4 autocrine amplification loop.\",\n      \"evidence\": \"ChIP, promoter reporter with Smad-site mutation, dominant-negative Smad3/4, and adenoviral TGFβ1 mouse model; plus miRNA-driven TGFβR2/SARA epistasis placing ITGB6 downstream of TGFβ/Smad2-3\",\n      \"pmids\": [\"27494713\", \"27508097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single Smad site characterized; other regulatory inputs not mapped\", \"Loop kinetics and thresholds for amplification not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that ITGB6 binds and activates latent TGFβ1 to trigger Smad3-driven EMT connected the integrin's matrix-binding role to a defined invasion-promoting transcriptional program.\",\n      \"evidence\": \"Anti-ITGB6 blocking, dual-luciferase reporter, ELISA, and EMT marker western blots in ovarian cancer 3D spheroids; SMYD3 positive feedback loop\",\n      \"pmids\": [\"34621667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of latent TGFβ1 engagement not resolved\", \"In vivo confirmation limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic and epistasis experiments placed ITGB6 upstream of distinct effector cascades — PODXL2, JAK/STAT3, and STAT1 — and downstream of TGFβ, defining the signaling architecture around the integrin.\",\n      \"evidence\": \"CRISPR KO with RNA-seq (PODXL2) in cholangiocarcinoma; siRNA plus JAK/STAT3 activator rescue in cervical carcinoma; intestinal epithelial ITGB6 transgenic mouse with STAT1 readout in DSS colitis\",\n      \"pmids\": [\"34208313\", \"34268416\", \"33491282\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each link shown in a single tumor/tissue context\", \"Direct physical coupling between ITGB6 and these kinases not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying STC1 as a direct ITGB6 partner activating PI3K, and HAX1-driven translational upregulation of ITGB6, expanded the inputs that elevate ITGB6 activity beyond transcription.\",\n      \"evidence\": \"Co-IP (STC1/ITGB6) with functional assays in ovarian cancer; ribosome profiling and EV transfer with in vivo angiogenesis/metastasis models for HAX1\",\n      \"pmids\": [\"35392966\", \"35524442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of STC1/ITGB6 binding limited\", \"Translational control mechanism by HAX1 not molecularly resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that exosomal ITGB6 transferred to fibroblasts converts them into cancer-associated fibroblasts established a non-cell-autonomous, microenvironment-remodeling function for the integrin.\",\n      \"evidence\": \"Exosome isolation/transfer, recipient fibroblast RNA-seq, exosomal proteomics, and CAF activation assays in lung adenocarcinoma\",\n      \"pmids\": [\"38205211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ITGB6 packaging into exosomes unknown\", \"KLF10 feedback loop dissection incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking ITGB6 to CX3CL1-driven macrophage recruitment and CD8+ T-cell suppression connected the integrin to immune evasion and immunotherapy resistance.\",\n      \"evidence\": \"scRNA-seq, ITGB6 KO immunocompetent mouse models, and CX3CL1-CX3CR1 axis inhibition restoring anti-CD276/anti-PD1 sensitivity\",\n      \"pmids\": [\"39152118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ITGB6 regulates CX3CL1 transcriptionally not defined\", \"Single lab; human relevance from mouse models not confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies consolidated ITGB6's roles in FAK/PI3K/AKT-mediated anoikis resistance, SMAD4-dependent transcription with a stellate-cell pro-fibrotic niche, and as an obligate LAMC2-to-TGFβ1 mediator in ameloblasts.\",\n      \"evidence\": \"RNA-seq/in vivo metastasis models (FAK/PI3K/AKT anoikis); ChIP-qPCR, reporter, and therapeutic monoclonal antibody xenograft (SMAD4/HSC niche); Co-IP and CWHM-12 integrin-inhibitor rescue (LAMC2/ODAPH/TGFβ1/ALP)\",\n      \"pmids\": [\"41022988\", \"41424019\", \"40680053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each mechanism shown in a single model system\", \"Therapeutic antibody efficacy not extended beyond mouse models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the diverse downstream cascades (FAK/PI3K/AKT, JAK/STAT3, STAT1) and physical partners (PD-L1, STC1, LAMC2) reflect a single unified ITGB6 signaling mechanism or context-specific outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ITGB6 partner-binding interfaces\", \"No cross-context comparison of which effectors dominate in which tissue\", \"Mechanism converting matrix engagement into distinct kinase outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 13, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"αvβ6 integrin\"],\n    \"partners\": [\"ITGAV\", \"PD-L1\", \"STC1\", \"LAMC2\", \"TGFB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}