{"gene":"ITGA6","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1988,"finding":"ITGA6 (VLA-6, α6β1 integrin) functions as a laminin receptor on platelets. Antibody blockade of the α6 subunit specifically inhibited platelet adhesion to laminin but not to fibrinogen, fibronectin, or collagen. Adhesion was supported by Mn2+, Co2+, and Mg2+ but not Ca2+, Zn2+, or Cu2+.","method":"Monoclonal antibody blocking assay, platelet adhesion assay with extracellular matrix proteins, cation substitution experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal antibody blocking with multiple ligands and controls, replicated across subsequent studies in the corpus","pmids":["2973567"],"is_preprint":false},{"year":1988,"finding":"VLA-6 is a distinct heterodimer on platelets (α6β1) separate from VLA-2 and VLA-5, identified biochemically. The α6 subunit is only loosely or partially associated with the common VLA β subunit, and α5 and α6 subunits have distinct V8 peptide maps and 2D gel migration patterns.","method":"Sequential immunodepletion, V8 protease peptide mapping, 2D O'Farrell gel electrophoresis, anti-α5 and anti-α6 antibody immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods establishing distinct identity of α6 subunit, replicated in subsequent work","pmids":["2967289"],"is_preprint":false},{"year":1990,"finding":"ITGA6 forms two distinct integrin complexes: α6β1 (VLA-6) and α6β4. Monoclonal antibodies against β4 preclear α6β4 but not α6β1 from cell extracts. A substantial fraction of β4 at the cell surface is not associated with α6. The α6 subunit consists of disulfide-linked heavy and light chains with variability in N-linked glycan modification and differential proteolytic cleavage.","method":"Sequential immunoprecipitation, SDS-PAGE, immunoperoxidase staining of tissue sections, anti-β4 monoclonal antibody depletion assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal immunoprecipitation with multiple antibodies, orthogonal biochemical and histological methods","pmids":["1698797"],"is_preprint":false},{"year":1990,"finding":"VLA-6/laminin interaction provides costimulatory signaling to CD3-mediated T cell proliferation. Antibody blockade of the α6 subunit specifically inhibited VLA-6/laminin-dependent costimulation of resting human CD4+ T cells. T cell activation (CD3/TCR crosslinking or PMA) induces rapid but transient VLA-6 binding function; memory T cells express higher VLA-6 than naive T cells.","method":"Monoclonal antibody blocking assay, T cell proliferation assay with co-immobilized CD3 mAb and laminin, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking with proliferation readout, single lab but multiple conditions tested","pmids":["1972721"],"is_preprint":false},{"year":1992,"finding":"CD11/CD18-independent neutrophil (PMN) adherence to laminin is mediated specifically by VLA-6 (α6β1). Anti-α6 antibodies (GoH3 and 450-30) significantly reduced phorbol myristate acetate-stimulated PMN adherence to laminin when CD11/CD18 was blocked, and GoH3 completely inhibited adherence of CD11/CD18-deficient PMNs to laminin.","method":"Monoclonal antibody blocking assay, PMN adhesion assay to laminin-coated surfaces, flow cytometry for VLA-6 expression on PMN","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody blockade with CD11/CD18-deficient cells as genetic confirmation, multiple antibodies used","pmids":["1347710"],"is_preprint":false},{"year":1995,"finding":"CD63 specifically associates with α6β1 (VLA-6) and α3β1 integrins but not α2β1 or α5β1. Large-scale purification using an antibody to the integrin-associated protein yielded CD63. The cytoplasmic domain of α3 was neither required nor sufficient for CD63 association, suggesting the interaction occurs elsewhere in the complex.","method":"Brij 96 detergent co-immunoprecipitation, large-scale purification and N-terminal sequencing, colocalization by immunofluorescence, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-IP with multiple antibodies, protein sequencing, domain mapping, colocalization, replicated across cell lines","pmids":["7629079"],"is_preprint":false},{"year":1997,"finding":"VLA-6 (α6β1) plays an active role in cell migration on laminin beyond initial adhesion. Antibody MA6, which does not inhibit VLA-6-mediated adhesion, still blocked melanoma cell movement on laminin and inhibited in vivo extravasation in liver, without affecting tyrosine phosphorylation of focal adhesion kinase. This demonstrates a distinct epitope on α6 involved in migration but not adhesion.","method":"Cell migration assay on laminin, in vivo videomicroscopy of B16F1 extravasation in liver, FAK phosphorylation assay, two different anti-α6 antibodies with distinct functional effects","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two antibodies with distinct functional effects, in vitro and in vivo validation, FAK signaling analysis","pmids":["9288792"],"is_preprint":false},{"year":1995,"finding":"VLA-5 and VLA-6 together mediate CD18-independent PMNL migration through synovial fibroblast barriers in response to chemotactic factors. Combined blockade of α5 (VLA-5) plus α6 (VLA-6) was required to inhibit CD18-independent migration to the same degree as anti-β1 integrin antibody alone.","method":"Monoclonal antibody blocking assay, PMNL migration through fibroblast barrier on microporous filters, chemotactic gradient assay","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blockade with combined specificity controls, but single lab","pmids":["7541723"],"is_preprint":false},{"year":1995,"finding":"During hypoxia, integrin signaling via α6β1 (VLA-6) engagement on PMNs results in upregulation of CD11b/CD18 expression, dependent on intracellular Ca2+, GPLC activity, and protein tyrosine kinase activity. Cross-linking VLA-6 in fluid-phase PMN progressively increased CD11b/CD18 expression during hypoxia but not normoxia.","method":"Anti-VLA-6 antibody blocking and cross-linking, pharmacological inhibition (genistein, herbimycin A, U73122, cyclopiazonic acid), Ca2+ depletion/restoration, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors targeting distinct pathway components, but single lab","pmids":["7594504"],"is_preprint":false},{"year":1996,"finding":"VLA-6 (α6β1) integrin is expressed and utilized by mouse bone marrow-derived mast cells (BMMC) to adhere to laminin. Using two α6-specific antibodies (MA6 and GoH3), VLA-6 was identified as the laminin receptor on BMMC and long-term mast cell lines.","method":"Mast cell adhesion assay to multiple laminin substrates, flow cytometry, two distinct anti-α6 antibodies (MA6 and GoH3)","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal antibodies with adhesion assay, single lab","pmids":["8899118"],"is_preprint":false},{"year":2000,"finding":"α6β1 integrin (VLA-6) mediates leukocyte tethering and arrest on laminin under physiological shear flow. Antibodies to both α6 and β1 chains abrogated PMN tethering to laminin but not to fibronectin or vitronectin. Antibodies to α2, α3, and β4 showed no significant inhibition, demonstrating specificity of α6β1.","method":"Flow adhesion assay under defined laminar shear flow, monoclonal antibody blocking with chain-specific antibodies","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — flow-based adhesion assay with multiple specificity controls, single lab","pmids":["10698619"],"is_preprint":false},{"year":2010,"finding":"Y-box binding protein-1 (YB-1) directly binds the CD49f (ITGA6) promoter and transcriptionally upregulates its expression. Introduction of wild-type or activated YB-1 stimulated CD49f production; silencing YB-1 decreased CD49f expression and reporter activity.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, YB-1 overexpression, flow cytometry","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter with gain/loss-of-function, single lab","pmids":["20332234"],"is_preprint":false},{"year":2012,"finding":"CD49f (ITGA6) activates PI3K/AKT signaling and suppresses p53, regulating differentiation and pluripotency of mesenchymal stem cells. Forced CD49f expression prolonged PI3K/AKT activation; knockdown in hESCs downregulated PI3K/AKT and upregulated p53, inducing differentiation. OCT4 and SOX2 were found to be recruited to the putative ITGA6 promoter region, placing ITGA6 downstream of pluripotency factors.","method":"ChIP for OCT4/SOX2 at ITGA6 promoter, siRNA knockdown, overexpression, western blot for p-AKT and p53, sphere formation assay","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional knockdown/overexpression with pathway readout, single lab","pmids":["22311737"],"is_preprint":false},{"year":2016,"finding":"ITGA6 is a direct transcriptional target of hypoxia-inducible factors (HIFs). HIF binding to ITGA6 regulatory elements was verified by chromatin immunoprecipitation and luciferase reporter assays. ITGA6 knockdown significantly reduced invasion, and re-expression of ITGA6 in HIF-knockdown cells partially rescued the invasion phenotype.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, FACS sorting, invasion assay, HIF KO mouse model","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus luciferase reporter validation plus epistatic rescue experiment, multiple models","pmids":["27001172"],"is_preprint":false},{"year":2016,"finding":"RUNX1 binds to and activates the ITGA6 promoter through a consensus RUNX1 binding motif in myeloid cells, regulating ITGA6 expression. This regulation is distinct from RUNX1's regulation of ITGB4, where RUNX1 activates the ITGB4 promoter without a recognized consensus binding motif.","method":"Chromatin immunoprecipitation (ChIP), promoter-reporter assays, site-directed mutagenesis of RUNX1 binding motif","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays with mutagenesis, single lab","pmids":["28926098"],"is_preprint":false},{"year":2016,"finding":"RFX1 directly activates transcription of Itga6 in Sertoli cells and is required for testis cord integrity. Luciferase and ChIP assays confirmed direct RFX1 binding to the Itga6 promoter. Conditional Rfx1 knockout mice had disrupted testis cords and significantly decreased integrin α6 expression.","method":"Conditional Rfx1 knockout mice (Rfx1flox/flox; Amh-Cre), luciferase reporter assay, chromatin immunoprecipitation (ChIP), immunofluorescence","journal":"Molecular reproduction and development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, ChIP, and reporter assay providing mechanistic chain","pmids":["27228460"],"is_preprint":false},{"year":2017,"finding":"Oncogenic K-RasV12 upregulates ITGA6 expression via the MAPK/ERK/FOSL1 signaling cascade in MDCK cells, promoting anoikis resistance and metastatic capacity. Re-expression of αV-integrin in K-RasV12-transformed cells synergistically upregulated ZEB1 and TWIST1 and triggered EMT.","method":"K-RasV12 expression in MDCK cells, siRNA knockdown, transcriptomic analysis, FOSL1 pathway inhibition, anoikis resistance assay, cyst growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic analysis with functional knockdown validation, single lab","pmids":["28604746"],"is_preprint":false},{"year":2018,"finding":"MYC regulates ITGA6 promoter activity and alternative splicing to favor the pro-proliferative ITGA6A variant in colorectal cancer cells. MYC inhibition or knockdown decreased ITGA6 and ITGA6A levels and reduced the splicing factor ESRP2; ChIP revealed MYC occupancy at both ITGA6 and ESRP2 proximal promoters.","method":"ChIP, luciferase reporter assay, pharmacological MYC inhibitor (10058-F4), shRNA knockdown, RT-PCR for splice variants","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with pharmacological and genetic perturbation, single lab","pmids":["29401653"],"is_preprint":false},{"year":2019,"finding":"METTL3-mediated m6A methylation of ITGA6 mRNA 3'UTR promotes its translation via binding of m6A readers YTHDF1 and YTHDF3 in bladder cancer cells. The eraser ALKBH5 reverses this effect. Overexpression of ITGA6 in METTL3-depleted cells partially restored bladder cancer cell adhesion, migration, and invasion.","method":"Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assay, mutagenesis of m6A sites, METTL3/ALKBH5 knockdown/overexpression, xenograft mouse model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (MeRIP, RIP, luciferase + mutagenesis, epistatic rescue), in vitro and in vivo validation","pmids":["31409574"],"is_preprint":false},{"year":2019,"finding":"ITGA6 interacts with ribosomal protein SA (RPSA) in pancreatic cancer cells, identified by Co-IP combined with mass spectrometry. Although ITGA6 and RPSA interact, they do not mutually regulate each other's expression. ITGA6 promotes invasion via the PI3K/AKT pathway (reducing p-AKT when inhibited), while RPSA acts through MAPK/ERK (reducing p-ERK1/2 when inhibited).","method":"Co-immunoprecipitation combined with mass spectrometry, siRNA knockdown, western blot for p-AKT and p-ERK1/2, invasion and metastasis assays in vitro and in vivo","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS for interaction, siRNA knockdown with pathway readouts, single lab","pmids":["30894280"],"is_preprint":false},{"year":2019,"finding":"miR-143-3p directly targets ITGA6 mRNA (confirmed by dual-luciferase assay) and suppresses gallbladder cancer angiogenesis by downregulating PLGF expression via the ITGA6/PI3K/AKT pathway.","method":"Dual-luciferase reporter assay, antibody array, ELISA, western blot, PLGF rescue analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of direct targeting plus pathway rescue, single lab","pmids":["29416013"],"is_preprint":false},{"year":2019,"finding":"NFAT1 hypermethylation in nasopharyngeal carcinoma leads to its downregulation; NFAT1 overexpression inhibits ITGA6 transcription, thereby suppressing EMT and metastasis. NFAT1 was identified as a transcriptional repressor of ITGA6 in this context.","method":"NFAT1 overexpression, invasion/migration assays, in vivo metastasis model, ChIP/reporter analysis of ITGA6 transcription","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with functional readout and mechanistic link to ITGA6 transcription, single lab","pmids":["30772768"],"is_preprint":false},{"year":2021,"finding":"PSMC2 directly interacts with ITGA6 in hepatocellular carcinoma cells and they mutually regulate each other. Gene microarray identified ITGA6 as downstream of PSMC2; PSMC2 knockdown significantly aggravated HCC inhibition caused by ITGA6 depletion.","method":"Co-immunoprecipitation, gene microarray, ingenuity pathway analysis, siRNA knockdown, cell proliferation and invasion assays, xenograft model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP with functional epistasis data, single lab","pmids":["34413286"],"is_preprint":false},{"year":2021,"finding":"KDM5B demethylates H3K4me3 at the miR-448 promoter, suppressing miR-448 expression. miR-448 targets YTHDF3 and ITGA6 directly; thus the KDM5B/miR-448/YTHDF3/ITGA6 axis promotes HCC progression.","method":"ChIP for H3K4me3, luciferase reporter assay for miR-448 targeting YTHDF3/ITGA6, Pearson correlation, ectopic expression/depletion, xenograft model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for mechanistic chain, in vivo validation, single lab","pmids":["33829656"],"is_preprint":false},{"year":2021,"finding":"BORG lncRNA interacts physically with the E3 SUMO ligase TRIM28, which binds to the Itga6 promoter and drives α6 integrin/CD49f expression in breast cancer stem cells. Genetic inactivation of Itga6 prevented BORG:TRIM28 complexes from inducing BCSC self-renewal, expansion, and lung metastatic outgrowth.","method":"Co-immunoprecipitation (BORG:TRIM28 interaction), ChIP (TRIM28 at Itga6 promoter), Itga6 genetic inactivation, mammosphere assay, xenotransplantation/metastasis models","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and genetic epistasis with in vivo readout, single lab","pmids":["34497119"],"is_preprint":false},{"year":2021,"finding":"Disruption of the SIN3A-PF1 interaction leads to increased occupancy of SIN3A and the transcriptional repressor KLF9 at the promoters of ITGA6 and ITGB1, downregulating their expression and inhibiting invasion in triple-negative breast cancer. KLF9 knockdown restored ITGA6 and ITGB1 expression and the invasive phenotype.","method":"RNA-seq, ChIP for SIN3A and KLF9 at ITGA6/ITGB1 promoters, KLF9 siRNA knockdown, invasion/migration assays, PF1-SID peptide treatment","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and genetic rescue experiment with functional invasion readout, single lab","pmids":["34968869"],"is_preprint":false},{"year":2021,"finding":"ID1/ID3 regulate integrin α6 (Itga6) expression in skin fibroblasts, and this mechanism mediates axon guidance during wound repair. ID1/ID3-overexpressing fibroblasts showed upregulated Itga6 and directly contacted and guided regenerating axons; transplantation of these cells promoted local nerve regeneration in vivo.","method":"RNA-seq, ID1/ID3 overexpression in fibroblasts, transplantation assay, skin excision and sciatic nerve injury models, co-culture with neurons","journal":"Stem cells translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic identification plus gain-of-function in vivo rescue, single lab","pmids":["34520124"],"is_preprint":false},{"year":2024,"finding":"Fucosyltransferase 8 (Fut8) directly interacts with Itga6 and catalyzes core fucosylation of Itga6 in neural stem/progenitor cells. Deletion of Fut8 enhances ubiquitination of Itga6 by promoting binding of ubiquitin ligase Trim21 to Itga6, reducing Itga6 levels and inhibiting PI3K/Akt signaling, thereby impairing adult neurogenesis.","method":"Co-immunoprecipitation (Fut8-Itga6 interaction), core fucosylation biochemical assay, Fut8 conditional knockout, ubiquitination assay, Trim21-Itga6 co-IP, PI3K/Akt pathway readout, Akt agonist rescue experiment","journal":"Science China. Life sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical interaction, post-translational modification assay, genetic KO with mechanistic rescue, multiple orthogonal methods","pmids":["38523237"],"is_preprint":false},{"year":2024,"finding":"ITGA6 engagement in platinum-resistant ovarian cancer activates a positive loop that stimulates IGF production/availability and over-stimulates IGF1R pathway signaling, upregulating Snail expression and promoting epithelial-mesenchymal transition and pre-metastatic niche formation.","method":"Isogenic platinum-resistant cell models, siRNA/genetic knockout, pharmacological inhibition, patient-derived models, western blot for IGF1R pathway and Snail, in vivo xenograft","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic models with genetic and pharmacological perturbation plus in vivo validation, single lab","pmids":["38658801"],"is_preprint":false},{"year":2024,"finding":"ZC3H13 promotes m6A modification of ITGA6 mRNA, enhancing its stability, in bronchial epithelial cells. ZC3H13 knockdown reduced ITGA6 expression and mRNA stability (assessed by actinomycin D assay), and attenuated inflammation and fibrosis in COPD models.","method":"MeRIP-PCR for m6A modification levels, actinomycin D mRNA stability assay, siRNA knockdown, ELISA, flow cytometry, mouse COPD model with HE/Masson staining","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-PCR and mRNA stability assay with functional knockdown, single lab","pmids":["38670474"],"is_preprint":false},{"year":2023,"finding":"Targeted m6A demethylation of ITGA6 mRNA at multiple sites using a dCasRx-ALKBH5 editor significantly reduced ITGA6 protein production and inhibited bladder cancer cell proliferation and migration in vitro and tumor growth in vivo, mechanistically confirming that multi-site m6A modification drives ITGA6 mRNA translation.","method":"CRISPR-based dCasRx-m6A editing platform, MeRIP-seq, polysome profiling, single-base T3 ligase qPCR, xenograft mouse model, luciferase reporter","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific m6A editing with multiple orthogonal readouts (MeRIP-seq, polysome profiling, reporter) and in vivo validation","pmids":["37003532"],"is_preprint":false},{"year":2013,"finding":"ITGA6 gene silencing in human thymic epithelial cells (TEC) decreases cell adhesion to laminin and downregulates expression of other laminin receptor integrin α-chains (ITGA1, ITGA2, ITGA7) while upregulating LAMA1 gene expression. ITGA6 knockdown also modulates chemokine gene expression, indicating ITGA6 participates in a broader cell migration gene network in the thymic epithelium.","method":"RNAi knockdown, flow cytometry for surface expression, cell adhesion assay to laminin, quantitative PCR for downstream gene expression, cytofluorometry","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with multiple downstream readouts including adhesion and gene expression, single lab","pmids":["24564203"],"is_preprint":false},{"year":2024,"finding":"SIMALR lncRNA binds to eEF1A2 and enhances its endogenous GTPase activity; SIMALR-activated eEF1A2 phosphorylation accelerates translation of ITGB4 and ITGA6 mRNA, promoting NPC malignant phenotype.","method":"RNA-protein binding assay (SIMALR:eEF1A2), GTPase activity assay, phosphorylation assay, polysome profiling/translation assay, siRNA knockdown, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical activity assay plus translation assay plus functional rescue, single lab","pmids":["39154122"],"is_preprint":false},{"year":2022,"finding":"In laryngeal squamous cell carcinoma, ITGA6 accelerates Keap1 proteasomal degradation by enhancing TRIM25 expression, leading to increased Nrf2 stability and aberrant activation. ITGA6 also enhances γ-secretase-mediated Notch signaling activation, promoting RBPJ-induced TRIM25 transcription, thus connecting ITGA6 to both Nrf2 and Notch pathways.","method":"siRNA knockdown, western blot for Keap1/Nrf2/TRIM25, γ-secretase inhibitor, ChIP for RBPJ at TRIM25 promoter, co-immunoprecipitation, ubiquitination assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (ChIP, co-IP, ubiquitination) in single lab study","pmids":["38369001"],"is_preprint":false},{"year":2022,"finding":"ITGA6 affects trophoblast cell biological functions (proliferation, invasion, migration, apoptosis) by regulating PI3K/AKT and MAPK signaling pathways. miR-410-5p directly binds to ITGA6 3'UTR (confirmed by dual-luciferase assay) and negatively regulates ITGA6.","method":"Dual-luciferase reporter assay, siRNA knockdown, miRNA mimic/inhibitor transfection, western blot for PI3K/AKT and MAPK pathway components, functional assays","journal":"Journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase confirmation of direct targeting plus pathway readout by western blot, single lab","pmids":["35667342"],"is_preprint":false},{"year":2012,"finding":"ITGA6 knockdown alone or with ITGB1 (CD29) together produces a profound reduction in cancer stem cell migration, while knockdown of either alone has only a slight effect, revealing overlapping yet critical cooperative function of CD49f and CD29 in CSC migration.","method":"shRNA knockdown of CD29 and/or CD49f, cell migration assay, allograft mouse metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown with defined migration readout, single lab","pmids":["24317509"],"is_preprint":false}],"current_model":"ITGA6 (CD49f/VLA-6) encodes the α6 integrin subunit that forms heterodimers with either β1 (α6β1/VLA-6) or β4 (α6β4), functioning primarily as a laminin receptor mediating cell adhesion, migration, and signaling across diverse cell types; its activity is regulated transcriptionally by factors including HIFs, RUNX1, MYC, RFX1, YB-1, NFAT1, and K-Ras/FOSL1, and post-transcriptionally by m6A modifications (written by METTL3/ZC3H13, erased by ALKBH5, and read by YTHDF1/YTHDF3) that promote mRNA translation, as well as by core fucosylation (by FUT8, which prevents ubiquitin-mediated degradation); upon laminin engagement, ITGA6 activates downstream PI3K/AKT, FAK, and IGF1R signaling pathways, and associates with the tetraspanin CD63 in specific complexes, collectively regulating stem cell self-renewal, cancer invasion, immune cell trafficking, and tissue homeostasis."},"narrative":{"mechanistic_narrative":"ITGA6 encodes the α6 integrin subunit, a laminin receptor that pairs with β1 (α6β1/VLA-6) or β4 (α6β4) to mediate cell adhesion, migration, and signaling across hematopoietic, epithelial, and stem cell lineages [PMID:2973567, PMID:2967289, PMID:1698797]. The α6 subunit is a disulfide-linked heavy/light chain protein subject to variable N-glycosylation and proteolytic cleavage, and a substantial pool of β4 exists at the cell surface independent of α6 [PMID:1698797]. α6β1 functions as the dominant laminin receptor on platelets, neutrophils, T cells, and mast cells, where it supports cation-dependent adhesion (Mn2+/Co2+/Mg2+ but not Ca2+), tethering and arrest under shear flow, and CD18-independent leukocyte migration, and provides costimulatory signals to T-cell proliferation [PMID:2973567, PMID:1972721, PMID:1347710, PMID:10698619]. Distinct epitopes of α6 separate its adhesion and migration functions, the latter being required for melanoma movement on laminin and in vivo extravasation [PMID:9288792]; the receptor associates laterally with the tetraspanin CD63 in selective integrin complexes [PMID:7629079]. Upon laminin engagement and cooperation with β1, α6 activates PI3K/AKT signaling that suppresses p53 to sustain stem cell self-renewal and pluripotency, and drives invasion, EMT, and metastasis via IGF1R/Snail and related axes in cancer [PMID:22311737, PMID:38658801, PMID:24317509]. ITGA6 expression is heavily controlled at multiple levels: transcriptionally by activators (HIF, RUNX1, RFX1, YB-1, MYC, TRIM28) and repressors (NFAT1, KLF9/SIN3A) [PMID:20332234, PMID:27001172, PMID:28926098, PMID:27228460, PMID:34497119, PMID:34968869], post-transcriptionally by m6A modification written by METTL3/ZC3H13 and read by YTHDF1/YTHDF3 to promote translation and mRNA stability [PMID:31409574, PMID:38670474, PMID:37003532], and post-translationally by FUT8-mediated core fucosylation that protects α6 from TRIM21-directed ubiquitination and degradation [PMID:38523237]. RFX1-dependent Itga6 expression is required for testis cord integrity, establishing a non-malignant developmental role [PMID:27228460].","teleology":[{"year":1988,"claim":"Established that the α6 subunit constitutes a specific laminin receptor distinct from other VLA integrins, defining the molecular identity and ligand specificity of ITGA6.","evidence":"Antibody blocking of platelet adhesion to ECM proteins with cation substitution; sequential immunodepletion, V8 peptide mapping and 2D gels distinguishing α5 from α6","pmids":["2973567","2967289"],"confidence":"High","gaps":["Did not resolve the binding interface on laminin","β-subunit pairing rules not yet defined"]},{"year":1990,"claim":"Resolved that α6 forms two alternative heterodimers (α6β1 and α6β4) with distinct biochemistry, defining the combinatorial receptor architecture.","evidence":"Sequential immunoprecipitation with anti-β4 depletion, SDS-PAGE, and immunoperoxidase tissue staining","pmids":["1698797"],"confidence":"High","gaps":["Functional difference between α6β1 and α6β4 signaling not addressed","Regulation of pairing choice unknown"]},{"year":1990,"claim":"Extended α6β1 function from passive adhesion to active immune signaling, showing VLA-6/laminin provides costimulation to T-cell proliferation.","evidence":"Antibody blocking with co-immobilized CD3 mAb and laminin in human CD4+ T cells, flow cytometry","pmids":["1972721"],"confidence":"Medium","gaps":["Intracellular signaling mediators of costimulation not defined","Single-lab antibody-based readout"]},{"year":1992,"claim":"Demonstrated α6β1 mediates CD11/CD18-independent leukocyte adherence to laminin, broadening its role in innate immune trafficking.","evidence":"Anti-α6 antibody blockade with CD11/CD18-deficient neutrophils as genetic confirmation","pmids":["1347710"],"confidence":"High","gaps":["Downstream activation pathway in neutrophils not mapped"]},{"year":1995,"claim":"Identified a lateral partner (CD63) and a hypoxia-linked signaling output, placing α6β1 within tetraspanin-organized membrane complexes and inside-out activation contexts.","evidence":"Brij-96 co-IP, large-scale purification and N-terminal sequencing for CD63; antibody cross-linking with pharmacological inhibitors for hypoxic CD11b/CD18 upregulation","pmids":["7629079","7594504","7541723"],"confidence":"High","gaps":["Functional consequence of CD63 association not established","Direct interaction site within the integrin complex unmapped"]},{"year":1997,"claim":"Separated adhesion from migration functions of α6, showing a distinct epitope drives motility and in vivo extravasation independent of FAK phosphorylation.","evidence":"Two anti-α6 antibodies with differential effects in laminin migration assays and in vivo B16F1 liver extravasation videomicroscopy","pmids":["9288792"],"confidence":"High","gaps":["Molecular signaling distinguishing the migration epitope unknown","Mechanism uncoupled from FAK not explained"]},{"year":2000,"claim":"Established α6β1 functions under physiological shear, mediating leukocyte tethering and arrest on laminin with chain-specific selectivity.","evidence":"Defined laminar shear flow adhesion assay with chain-specific blocking antibodies","pmids":["10698619"],"confidence":"Medium","gaps":["Force-dependent conformational regulation not addressed","Single-lab study"]},{"year":2012,"claim":"Connected α6 to stem cell maintenance, showing it acts downstream of OCT4/SOX2 and drives PI3K/AKT activation that suppresses p53 to sustain pluripotency.","evidence":"ChIP for OCT4/SOX2 at ITGA6 promoter, knockdown/overexpression with p-AKT and p53 readouts, sphere formation; double knockdown with ITGB1 in CSC migration","pmids":["22311737","24317509"],"confidence":"Medium","gaps":["Direct link between α6 engagement and PI3K recruitment not biochemically resolved","Single-lab pathway data"]},{"year":2016,"claim":"Defined a transcriptional regulatory network controlling ITGA6, identifying activators (HIF, RUNX1, RFX1) and linking expression to invasion and tissue integrity.","evidence":"ChIP plus luciferase reporters with epistatic rescue (HIF), motif mutagenesis (RUNX1), and conditional Rfx1 knockout with testis cord phenotype","pmids":["27001172","28926098","27228460"],"confidence":"High","gaps":["Combinatorial logic among transcription factors unresolved","Cell-type specificity of each regulator not systematized"]},{"year":2019,"claim":"Established multilayered post-transcriptional control via m6A, showing METTL3-deposited methylation read by YTHDF1/YTHDF3 promotes ITGA6 mRNA translation and tumor cell invasion, reversibly opposed by ALKBH5.","evidence":"MeRIP, RIP, luciferase + m6A-site mutagenesis, METTL3/ALKBH5 perturbation, and epistatic rescue with xenografts","pmids":["31409574"],"confidence":"High","gaps":["Relative contribution of translation vs stability not fully partitioned","Reader selectivity mechanism unresolved"]},{"year":2021,"claim":"Expanded the regulatory map with additional transcriptional, epigenetic, and physical-interaction inputs (TRIM28, SIN3A/KLF9, KDM5B/miR-448, PSMC2) tying ITGA6 to cancer stemness and progression.","evidence":"Co-IP, ChIP, miRNA luciferase targeting, genetic inactivation, and epistasis with in vivo metastasis models","pmids":["34497119","34968869","33829656","34413286"],"confidence":"Medium","gaps":["Many interactions rest on single Co-IP without reciprocal validation","Convergence of these inputs on a shared output not integrated"]},{"year":2024,"claim":"Defined post-translational stabilization of α6 through FUT8 core fucosylation, which blocks TRIM21-mediated ubiquitination, sustaining PI3K/AKT signaling and adult neurogenesis.","evidence":"Co-IP, core fucosylation biochemistry, Fut8 conditional knockout, ubiquitination assay, Trim21 co-IP, and Akt-agonist rescue","pmids":["38523237"],"confidence":"High","gaps":["Fucosylation site mapping on α6 not detailed","Generalizability beyond neural stem cells untested"]},{"year":2024,"claim":"Linked α6 engagement to a feed-forward IGF1R/Snail loop driving EMT, chemoresistance, and pre-metastatic niche formation, and to additional m6A stabilization in non-malignant airway disease.","evidence":"Isogenic platinum-resistant ovarian models with genetic/pharmacological perturbation and xenografts; MeRIP-PCR and actinomycin D stability assays for ZC3H13 in COPD models","pmids":["38658801","38670474"],"confidence":"Medium","gaps":["Direct biochemical coupling of α6 to IGF production not resolved","Single-lab models"]},{"year":null,"claim":"How the distinct β1 vs β4 heterodimers, lateral partners, and the dense transcriptional/m6A/fucosylation regulatory layers are coordinated to specify adhesion versus migration versus stemness outputs in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of α6 ligand engagement in the corpus","Integration of the multiple regulatory inputs into a unified signaling logic not established","In vivo isoform-specific functions of α6β1 vs α6β4 not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,9,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,12,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5,10]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,6,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,19,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,18,28]}],"complexes":["α6β1 integrin (VLA-6)","α6β4 integrin"],"partners":["ITGB1","ITGB4","CD63","RPSA","PSMC2","FUT8","TRIM21","TRIM28"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23229","full_name":"Integrin alpha-6","aliases":["CD49 antigen-like family member F","VLA-6"],"length_aa":1130,"mass_kda":126.6,"function":"Integrin alpha-6/beta-1 (ITGA6:ITGB1) is a receptor for laminin on platelets (By similarity). 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ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464)","subcellular_location":"Cell membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P23229/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA6","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CD151","stoichiometry":10.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITGA6","total_profiled":1310},"omim":[{"mim_id":"619817","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 6, WITH PYLORIC ATRESIA; JEB6","url":"https://www.omim.org/entry/619817"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"612138","title":"EPIDERMOLYSIS BULLOSA SIMPLEX 5C, WITH PYLORIC ATRESIA; EBS5C","url":"https://www.omim.org/entry/612138"},{"mim_id":"605083","title":"FRIZZLED-RELATED PROTEIN; FRZB","url":"https://www.omim.org/entry/605083"},{"mim_id":"602243","title":"CD151 ANTIGEN; CD151","url":"https://www.omim.org/entry/602243"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGA6"},"hgnc":{"alias_symbol":["CD49f","VLA-6","ITGA6A","ITGA6B"],"prev_symbol":[]},"alphafold":{"accession":"P23229","domains":[{"cath_id":"2.130.10.130","chopping":"27-257_294-504","consensus_level":"medium","plddt":90.8579,"start":27,"end":504},{"cath_id":"2.60.40.1460","chopping":"507-631_642-659","consensus_level":"high","plddt":86.5862,"start":507,"end":659},{"cath_id":"2.60.40.1510","chopping":"676-833","consensus_level":"high","plddt":83.1068,"start":676,"end":833},{"cath_id":"2.60.40.1530","chopping":"837-931_962-1043","consensus_level":"high","plddt":84.1445,"start":837,"end":1043}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23229","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23229-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23229-F1-predicted_aligned_error_v6.png","plddt_mean":80.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA6","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA6"},"sequence":{"accession":"P23229","fasta_url":"https://rest.uniprot.org/uniprotkb/P23229.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23229/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23229"}},"corpus_meta":[{"pmid":"2973567","id":"PMC_2973567","title":"Laminin receptor on platelets is the integrin VLA-6.","date":"1988","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2973567","citation_count":685,"is_preprint":false},{"pmid":"1972721","id":"PMC_1972721","title":"Costimulation of proliferative responses of resting CD4+ T cells by the interaction of VLA-4 and VLA-5 with fibronectin or VLA-6 with laminin.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1972721","citation_count":406,"is_preprint":false},{"pmid":"2196219","id":"PMC_2196219","title":"Roles of adhesion molecules in T-cell recognition: fundamental similarities between four integrins on resting human T cells (LFA-1, VLA-4, VLA-5, VLA-6) in expression, binding, and costimulation.","date":"1990","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/2196219","citation_count":366,"is_preprint":false},{"pmid":"1698797","id":"PMC_1698797","title":"The alpha 6 beta 1 (VLA-6) and alpha 6 beta 4 protein complexes: tissue distribution and biochemical properties.","date":"1990","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/1698797","citation_count":233,"is_preprint":false},{"pmid":"31409574","id":"PMC_31409574","title":"N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/31409574","citation_count":174,"is_preprint":false},{"pmid":"2967289","id":"PMC_2967289","title":"Multiple very late antigen (VLA) heterodimers on platelets. 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Antibody blockade of the α6 subunit specifically inhibited platelet adhesion to laminin but not to fibrinogen, fibronectin, or collagen. Adhesion was supported by Mn2+, Co2+, and Mg2+ but not Ca2+, Zn2+, or Cu2+.\",\n      \"method\": \"Monoclonal antibody blocking assay, platelet adhesion assay with extracellular matrix proteins, cation substitution experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal antibody blocking with multiple ligands and controls, replicated across subsequent studies in the corpus\",\n      \"pmids\": [\"2973567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"VLA-6 is a distinct heterodimer on platelets (α6β1) separate from VLA-2 and VLA-5, identified biochemically. The α6 subunit is only loosely or partially associated with the common VLA β subunit, and α5 and α6 subunits have distinct V8 peptide maps and 2D gel migration patterns.\",\n      \"method\": \"Sequential immunodepletion, V8 protease peptide mapping, 2D O'Farrell gel electrophoresis, anti-α5 and anti-α6 antibody immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods establishing distinct identity of α6 subunit, replicated in subsequent work\",\n      \"pmids\": [\"2967289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"ITGA6 forms two distinct integrin complexes: α6β1 (VLA-6) and α6β4. Monoclonal antibodies against β4 preclear α6β4 but not α6β1 from cell extracts. A substantial fraction of β4 at the cell surface is not associated with α6. The α6 subunit consists of disulfide-linked heavy and light chains with variability in N-linked glycan modification and differential proteolytic cleavage.\",\n      \"method\": \"Sequential immunoprecipitation, SDS-PAGE, immunoperoxidase staining of tissue sections, anti-β4 monoclonal antibody depletion assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal immunoprecipitation with multiple antibodies, orthogonal biochemical and histological methods\",\n      \"pmids\": [\"1698797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"VLA-6/laminin interaction provides costimulatory signaling to CD3-mediated T cell proliferation. Antibody blockade of the α6 subunit specifically inhibited VLA-6/laminin-dependent costimulation of resting human CD4+ T cells. T cell activation (CD3/TCR crosslinking or PMA) induces rapid but transient VLA-6 binding function; memory T cells express higher VLA-6 than naive T cells.\",\n      \"method\": \"Monoclonal antibody blocking assay, T cell proliferation assay with co-immobilized CD3 mAb and laminin, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking with proliferation readout, single lab but multiple conditions tested\",\n      \"pmids\": [\"1972721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD11/CD18-independent neutrophil (PMN) adherence to laminin is mediated specifically by VLA-6 (α6β1). Anti-α6 antibodies (GoH3 and 450-30) significantly reduced phorbol myristate acetate-stimulated PMN adherence to laminin when CD11/CD18 was blocked, and GoH3 completely inhibited adherence of CD11/CD18-deficient PMNs to laminin.\",\n      \"method\": \"Monoclonal antibody blocking assay, PMN adhesion assay to laminin-coated surfaces, flow cytometry for VLA-6 expression on PMN\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody blockade with CD11/CD18-deficient cells as genetic confirmation, multiple antibodies used\",\n      \"pmids\": [\"1347710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD63 specifically associates with α6β1 (VLA-6) and α3β1 integrins but not α2β1 or α5β1. Large-scale purification using an antibody to the integrin-associated protein yielded CD63. The cytoplasmic domain of α3 was neither required nor sufficient for CD63 association, suggesting the interaction occurs elsewhere in the complex.\",\n      \"method\": \"Brij 96 detergent co-immunoprecipitation, large-scale purification and N-terminal sequencing, colocalization by immunofluorescence, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-IP with multiple antibodies, protein sequencing, domain mapping, colocalization, replicated across cell lines\",\n      \"pmids\": [\"7629079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"VLA-6 (α6β1) plays an active role in cell migration on laminin beyond initial adhesion. Antibody MA6, which does not inhibit VLA-6-mediated adhesion, still blocked melanoma cell movement on laminin and inhibited in vivo extravasation in liver, without affecting tyrosine phosphorylation of focal adhesion kinase. This demonstrates a distinct epitope on α6 involved in migration but not adhesion.\",\n      \"method\": \"Cell migration assay on laminin, in vivo videomicroscopy of B16F1 extravasation in liver, FAK phosphorylation assay, two different anti-α6 antibodies with distinct functional effects\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two antibodies with distinct functional effects, in vitro and in vivo validation, FAK signaling analysis\",\n      \"pmids\": [\"9288792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VLA-5 and VLA-6 together mediate CD18-independent PMNL migration through synovial fibroblast barriers in response to chemotactic factors. Combined blockade of α5 (VLA-5) plus α6 (VLA-6) was required to inhibit CD18-independent migration to the same degree as anti-β1 integrin antibody alone.\",\n      \"method\": \"Monoclonal antibody blocking assay, PMNL migration through fibroblast barrier on microporous filters, chemotactic gradient assay\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade with combined specificity controls, but single lab\",\n      \"pmids\": [\"7541723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"During hypoxia, integrin signaling via α6β1 (VLA-6) engagement on PMNs results in upregulation of CD11b/CD18 expression, dependent on intracellular Ca2+, GPLC activity, and protein tyrosine kinase activity. Cross-linking VLA-6 in fluid-phase PMN progressively increased CD11b/CD18 expression during hypoxia but not normoxia.\",\n      \"method\": \"Anti-VLA-6 antibody blocking and cross-linking, pharmacological inhibition (genistein, herbimycin A, U73122, cyclopiazonic acid), Ca2+ depletion/restoration, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors targeting distinct pathway components, but single lab\",\n      \"pmids\": [\"7594504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"VLA-6 (α6β1) integrin is expressed and utilized by mouse bone marrow-derived mast cells (BMMC) to adhere to laminin. Using two α6-specific antibodies (MA6 and GoH3), VLA-6 was identified as the laminin receptor on BMMC and long-term mast cell lines.\",\n      \"method\": \"Mast cell adhesion assay to multiple laminin substrates, flow cytometry, two distinct anti-α6 antibodies (MA6 and GoH3)\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal antibodies with adhesion assay, single lab\",\n      \"pmids\": [\"8899118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"α6β1 integrin (VLA-6) mediates leukocyte tethering and arrest on laminin under physiological shear flow. Antibodies to both α6 and β1 chains abrogated PMN tethering to laminin but not to fibronectin or vitronectin. Antibodies to α2, α3, and β4 showed no significant inhibition, demonstrating specificity of α6β1.\",\n      \"method\": \"Flow adhesion assay under defined laminar shear flow, monoclonal antibody blocking with chain-specific antibodies\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — flow-based adhesion assay with multiple specificity controls, single lab\",\n      \"pmids\": [\"10698619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Y-box binding protein-1 (YB-1) directly binds the CD49f (ITGA6) promoter and transcriptionally upregulates its expression. Introduction of wild-type or activated YB-1 stimulated CD49f production; silencing YB-1 decreased CD49f expression and reporter activity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, YB-1 overexpression, flow cytometry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter with gain/loss-of-function, single lab\",\n      \"pmids\": [\"20332234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD49f (ITGA6) activates PI3K/AKT signaling and suppresses p53, regulating differentiation and pluripotency of mesenchymal stem cells. Forced CD49f expression prolonged PI3K/AKT activation; knockdown in hESCs downregulated PI3K/AKT and upregulated p53, inducing differentiation. OCT4 and SOX2 were found to be recruited to the putative ITGA6 promoter region, placing ITGA6 downstream of pluripotency factors.\",\n      \"method\": \"ChIP for OCT4/SOX2 at ITGA6 promoter, siRNA knockdown, overexpression, western blot for p-AKT and p53, sphere formation assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional knockdown/overexpression with pathway readout, single lab\",\n      \"pmids\": [\"22311737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ITGA6 is a direct transcriptional target of hypoxia-inducible factors (HIFs). HIF binding to ITGA6 regulatory elements was verified by chromatin immunoprecipitation and luciferase reporter assays. ITGA6 knockdown significantly reduced invasion, and re-expression of ITGA6 in HIF-knockdown cells partially rescued the invasion phenotype.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, FACS sorting, invasion assay, HIF KO mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus luciferase reporter validation plus epistatic rescue experiment, multiple models\",\n      \"pmids\": [\"27001172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RUNX1 binds to and activates the ITGA6 promoter through a consensus RUNX1 binding motif in myeloid cells, regulating ITGA6 expression. This regulation is distinct from RUNX1's regulation of ITGB4, where RUNX1 activates the ITGB4 promoter without a recognized consensus binding motif.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter-reporter assays, site-directed mutagenesis of RUNX1 binding motif\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays with mutagenesis, single lab\",\n      \"pmids\": [\"28926098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RFX1 directly activates transcription of Itga6 in Sertoli cells and is required for testis cord integrity. Luciferase and ChIP assays confirmed direct RFX1 binding to the Itga6 promoter. Conditional Rfx1 knockout mice had disrupted testis cords and significantly decreased integrin α6 expression.\",\n      \"method\": \"Conditional Rfx1 knockout mice (Rfx1flox/flox; Amh-Cre), luciferase reporter assay, chromatin immunoprecipitation (ChIP), immunofluorescence\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, ChIP, and reporter assay providing mechanistic chain\",\n      \"pmids\": [\"27228460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oncogenic K-RasV12 upregulates ITGA6 expression via the MAPK/ERK/FOSL1 signaling cascade in MDCK cells, promoting anoikis resistance and metastatic capacity. Re-expression of αV-integrin in K-RasV12-transformed cells synergistically upregulated ZEB1 and TWIST1 and triggered EMT.\",\n      \"method\": \"K-RasV12 expression in MDCK cells, siRNA knockdown, transcriptomic analysis, FOSL1 pathway inhibition, anoikis resistance assay, cyst growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic analysis with functional knockdown validation, single lab\",\n      \"pmids\": [\"28604746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MYC regulates ITGA6 promoter activity and alternative splicing to favor the pro-proliferative ITGA6A variant in colorectal cancer cells. MYC inhibition or knockdown decreased ITGA6 and ITGA6A levels and reduced the splicing factor ESRP2; ChIP revealed MYC occupancy at both ITGA6 and ESRP2 proximal promoters.\",\n      \"method\": \"ChIP, luciferase reporter assay, pharmacological MYC inhibitor (10058-F4), shRNA knockdown, RT-PCR for splice variants\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"29401653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL3-mediated m6A methylation of ITGA6 mRNA 3'UTR promotes its translation via binding of m6A readers YTHDF1 and YTHDF3 in bladder cancer cells. The eraser ALKBH5 reverses this effect. Overexpression of ITGA6 in METTL3-depleted cells partially restored bladder cancer cell adhesion, migration, and invasion.\",\n      \"method\": \"Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assay, mutagenesis of m6A sites, METTL3/ALKBH5 knockdown/overexpression, xenograft mouse model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (MeRIP, RIP, luciferase + mutagenesis, epistatic rescue), in vitro and in vivo validation\",\n      \"pmids\": [\"31409574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGA6 interacts with ribosomal protein SA (RPSA) in pancreatic cancer cells, identified by Co-IP combined with mass spectrometry. Although ITGA6 and RPSA interact, they do not mutually regulate each other's expression. ITGA6 promotes invasion via the PI3K/AKT pathway (reducing p-AKT when inhibited), while RPSA acts through MAPK/ERK (reducing p-ERK1/2 when inhibited).\",\n      \"method\": \"Co-immunoprecipitation combined with mass spectrometry, siRNA knockdown, western blot for p-AKT and p-ERK1/2, invasion and metastasis assays in vitro and in vivo\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS for interaction, siRNA knockdown with pathway readouts, single lab\",\n      \"pmids\": [\"30894280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-143-3p directly targets ITGA6 mRNA (confirmed by dual-luciferase assay) and suppresses gallbladder cancer angiogenesis by downregulating PLGF expression via the ITGA6/PI3K/AKT pathway.\",\n      \"method\": \"Dual-luciferase reporter assay, antibody array, ELISA, western blot, PLGF rescue analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of direct targeting plus pathway rescue, single lab\",\n      \"pmids\": [\"29416013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NFAT1 hypermethylation in nasopharyngeal carcinoma leads to its downregulation; NFAT1 overexpression inhibits ITGA6 transcription, thereby suppressing EMT and metastasis. NFAT1 was identified as a transcriptional repressor of ITGA6 in this context.\",\n      \"method\": \"NFAT1 overexpression, invasion/migration assays, in vivo metastasis model, ChIP/reporter analysis of ITGA6 transcription\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with functional readout and mechanistic link to ITGA6 transcription, single lab\",\n      \"pmids\": [\"30772768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMC2 directly interacts with ITGA6 in hepatocellular carcinoma cells and they mutually regulate each other. Gene microarray identified ITGA6 as downstream of PSMC2; PSMC2 knockdown significantly aggravated HCC inhibition caused by ITGA6 depletion.\",\n      \"method\": \"Co-immunoprecipitation, gene microarray, ingenuity pathway analysis, siRNA knockdown, cell proliferation and invasion assays, xenograft model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP with functional epistasis data, single lab\",\n      \"pmids\": [\"34413286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5B demethylates H3K4me3 at the miR-448 promoter, suppressing miR-448 expression. miR-448 targets YTHDF3 and ITGA6 directly; thus the KDM5B/miR-448/YTHDF3/ITGA6 axis promotes HCC progression.\",\n      \"method\": \"ChIP for H3K4me3, luciferase reporter assay for miR-448 targeting YTHDF3/ITGA6, Pearson correlation, ectopic expression/depletion, xenograft model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for mechanistic chain, in vivo validation, single lab\",\n      \"pmids\": [\"33829656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BORG lncRNA interacts physically with the E3 SUMO ligase TRIM28, which binds to the Itga6 promoter and drives α6 integrin/CD49f expression in breast cancer stem cells. Genetic inactivation of Itga6 prevented BORG:TRIM28 complexes from inducing BCSC self-renewal, expansion, and lung metastatic outgrowth.\",\n      \"method\": \"Co-immunoprecipitation (BORG:TRIM28 interaction), ChIP (TRIM28 at Itga6 promoter), Itga6 genetic inactivation, mammosphere assay, xenotransplantation/metastasis models\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and genetic epistasis with in vivo readout, single lab\",\n      \"pmids\": [\"34497119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Disruption of the SIN3A-PF1 interaction leads to increased occupancy of SIN3A and the transcriptional repressor KLF9 at the promoters of ITGA6 and ITGB1, downregulating their expression and inhibiting invasion in triple-negative breast cancer. KLF9 knockdown restored ITGA6 and ITGB1 expression and the invasive phenotype.\",\n      \"method\": \"RNA-seq, ChIP for SIN3A and KLF9 at ITGA6/ITGB1 promoters, KLF9 siRNA knockdown, invasion/migration assays, PF1-SID peptide treatment\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and genetic rescue experiment with functional invasion readout, single lab\",\n      \"pmids\": [\"34968869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ID1/ID3 regulate integrin α6 (Itga6) expression in skin fibroblasts, and this mechanism mediates axon guidance during wound repair. ID1/ID3-overexpressing fibroblasts showed upregulated Itga6 and directly contacted and guided regenerating axons; transplantation of these cells promoted local nerve regeneration in vivo.\",\n      \"method\": \"RNA-seq, ID1/ID3 overexpression in fibroblasts, transplantation assay, skin excision and sciatic nerve injury models, co-culture with neurons\",\n      \"journal\": \"Stem cells translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic identification plus gain-of-function in vivo rescue, single lab\",\n      \"pmids\": [\"34520124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fucosyltransferase 8 (Fut8) directly interacts with Itga6 and catalyzes core fucosylation of Itga6 in neural stem/progenitor cells. Deletion of Fut8 enhances ubiquitination of Itga6 by promoting binding of ubiquitin ligase Trim21 to Itga6, reducing Itga6 levels and inhibiting PI3K/Akt signaling, thereby impairing adult neurogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Fut8-Itga6 interaction), core fucosylation biochemical assay, Fut8 conditional knockout, ubiquitination assay, Trim21-Itga6 co-IP, PI3K/Akt pathway readout, Akt agonist rescue experiment\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical interaction, post-translational modification assay, genetic KO with mechanistic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38523237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGA6 engagement in platinum-resistant ovarian cancer activates a positive loop that stimulates IGF production/availability and over-stimulates IGF1R pathway signaling, upregulating Snail expression and promoting epithelial-mesenchymal transition and pre-metastatic niche formation.\",\n      \"method\": \"Isogenic platinum-resistant cell models, siRNA/genetic knockout, pharmacological inhibition, patient-derived models, western blot for IGF1R pathway and Snail, in vivo xenograft\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic models with genetic and pharmacological perturbation plus in vivo validation, single lab\",\n      \"pmids\": [\"38658801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZC3H13 promotes m6A modification of ITGA6 mRNA, enhancing its stability, in bronchial epithelial cells. ZC3H13 knockdown reduced ITGA6 expression and mRNA stability (assessed by actinomycin D assay), and attenuated inflammation and fibrosis in COPD models.\",\n      \"method\": \"MeRIP-PCR for m6A modification levels, actinomycin D mRNA stability assay, siRNA knockdown, ELISA, flow cytometry, mouse COPD model with HE/Masson staining\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-PCR and mRNA stability assay with functional knockdown, single lab\",\n      \"pmids\": [\"38670474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Targeted m6A demethylation of ITGA6 mRNA at multiple sites using a dCasRx-ALKBH5 editor significantly reduced ITGA6 protein production and inhibited bladder cancer cell proliferation and migration in vitro and tumor growth in vivo, mechanistically confirming that multi-site m6A modification drives ITGA6 mRNA translation.\",\n      \"method\": \"CRISPR-based dCasRx-m6A editing platform, MeRIP-seq, polysome profiling, single-base T3 ligase qPCR, xenograft mouse model, luciferase reporter\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific m6A editing with multiple orthogonal readouts (MeRIP-seq, polysome profiling, reporter) and in vivo validation\",\n      \"pmids\": [\"37003532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ITGA6 gene silencing in human thymic epithelial cells (TEC) decreases cell adhesion to laminin and downregulates expression of other laminin receptor integrin α-chains (ITGA1, ITGA2, ITGA7) while upregulating LAMA1 gene expression. ITGA6 knockdown also modulates chemokine gene expression, indicating ITGA6 participates in a broader cell migration gene network in the thymic epithelium.\",\n      \"method\": \"RNAi knockdown, flow cytometry for surface expression, cell adhesion assay to laminin, quantitative PCR for downstream gene expression, cytofluorometry\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with multiple downstream readouts including adhesion and gene expression, single lab\",\n      \"pmids\": [\"24564203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIMALR lncRNA binds to eEF1A2 and enhances its endogenous GTPase activity; SIMALR-activated eEF1A2 phosphorylation accelerates translation of ITGB4 and ITGA6 mRNA, promoting NPC malignant phenotype.\",\n      \"method\": \"RNA-protein binding assay (SIMALR:eEF1A2), GTPase activity assay, phosphorylation assay, polysome profiling/translation assay, siRNA knockdown, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical activity assay plus translation assay plus functional rescue, single lab\",\n      \"pmids\": [\"39154122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In laryngeal squamous cell carcinoma, ITGA6 accelerates Keap1 proteasomal degradation by enhancing TRIM25 expression, leading to increased Nrf2 stability and aberrant activation. ITGA6 also enhances γ-secretase-mediated Notch signaling activation, promoting RBPJ-induced TRIM25 transcription, thus connecting ITGA6 to both Nrf2 and Notch pathways.\",\n      \"method\": \"siRNA knockdown, western blot for Keap1/Nrf2/TRIM25, γ-secretase inhibitor, ChIP for RBPJ at TRIM25 promoter, co-immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (ChIP, co-IP, ubiquitination) in single lab study\",\n      \"pmids\": [\"38369001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA6 affects trophoblast cell biological functions (proliferation, invasion, migration, apoptosis) by regulating PI3K/AKT and MAPK signaling pathways. miR-410-5p directly binds to ITGA6 3'UTR (confirmed by dual-luciferase assay) and negatively regulates ITGA6.\",\n      \"method\": \"Dual-luciferase reporter assay, siRNA knockdown, miRNA mimic/inhibitor transfection, western blot for PI3K/AKT and MAPK pathway components, functional assays\",\n      \"journal\": \"Journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase confirmation of direct targeting plus pathway readout by western blot, single lab\",\n      \"pmids\": [\"35667342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ITGA6 knockdown alone or with ITGB1 (CD29) together produces a profound reduction in cancer stem cell migration, while knockdown of either alone has only a slight effect, revealing overlapping yet critical cooperative function of CD49f and CD29 in CSC migration.\",\n      \"method\": \"shRNA knockdown of CD29 and/or CD49f, cell migration assay, allograft mouse metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown with defined migration readout, single lab\",\n      \"pmids\": [\"24317509\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA6 (CD49f/VLA-6) encodes the α6 integrin subunit that forms heterodimers with either β1 (α6β1/VLA-6) or β4 (α6β4), functioning primarily as a laminin receptor mediating cell adhesion, migration, and signaling across diverse cell types; its activity is regulated transcriptionally by factors including HIFs, RUNX1, MYC, RFX1, YB-1, NFAT1, and K-Ras/FOSL1, and post-transcriptionally by m6A modifications (written by METTL3/ZC3H13, erased by ALKBH5, and read by YTHDF1/YTHDF3) that promote mRNA translation, as well as by core fucosylation (by FUT8, which prevents ubiquitin-mediated degradation); upon laminin engagement, ITGA6 activates downstream PI3K/AKT, FAK, and IGF1R signaling pathways, and associates with the tetraspanin CD63 in specific complexes, collectively regulating stem cell self-renewal, cancer invasion, immune cell trafficking, and tissue homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA6 encodes the α6 integrin subunit, a laminin receptor that pairs with β1 (α6β1/VLA-6) or β4 (α6β4) to mediate cell adhesion, migration, and signaling across hematopoietic, epithelial, and stem cell lineages [#0, #1, #2]. The α6 subunit is a disulfide-linked heavy/light chain protein subject to variable N-glycosylation and proteolytic cleavage, and a substantial pool of β4 exists at the cell surface independent of α6 [#2]. α6β1 functions as the dominant laminin receptor on platelets, neutrophils, T cells, and mast cells, where it supports cation-dependent adhesion (Mn2+/Co2+/Mg2+ but not Ca2+), tethering and arrest under shear flow, and CD18-independent leukocyte migration, and provides costimulatory signals to T-cell proliferation [#0, #3, #4, #10]. Distinct epitopes of α6 separate its adhesion and migration functions, the latter being required for melanoma movement on laminin and in vivo extravasation [#6]; the receptor associates laterally with the tetraspanin CD63 in selective integrin complexes [#5]. Upon laminin engagement and cooperation with β1, α6 activates PI3K/AKT signaling that suppresses p53 to sustain stem cell self-renewal and pluripotency, and drives invasion, EMT, and metastasis via IGF1R/Snail and related axes in cancer [#12, #28, #35]. ITGA6 expression is heavily controlled at multiple levels: transcriptionally by activators (HIF, RUNX1, RFX1, YB-1, MYC, TRIM28) and repressors (NFAT1, KLF9/SIN3A) [#11, #13, #14, #15, #24, #25], post-transcriptionally by m6A modification written by METTL3/ZC3H13 and read by YTHDF1/YTHDF3 to promote translation and mRNA stability [#18, #29, #30], and post-translationally by FUT8-mediated core fucosylation that protects α6 from TRIM21-directed ubiquitination and degradation [#27]. RFX1-dependent Itga6 expression is required for testis cord integrity, establishing a non-malignant developmental role [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established that the α6 subunit constitutes a specific laminin receptor distinct from other VLA integrins, defining the molecular identity and ligand specificity of ITGA6.\",\n      \"evidence\": \"Antibody blocking of platelet adhesion to ECM proteins with cation substitution; sequential immunodepletion, V8 peptide mapping and 2D gels distinguishing α5 from α6\",\n      \"pmids\": [\"2973567\", \"2967289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the binding interface on laminin\", \"β-subunit pairing rules not yet defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Resolved that α6 forms two alternative heterodimers (α6β1 and α6β4) with distinct biochemistry, defining the combinatorial receptor architecture.\",\n      \"evidence\": \"Sequential immunoprecipitation with anti-β4 depletion, SDS-PAGE, and immunoperoxidase tissue staining\",\n      \"pmids\": [\"1698797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional difference between α6β1 and α6β4 signaling not addressed\", \"Regulation of pairing choice unknown\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Extended α6β1 function from passive adhesion to active immune signaling, showing VLA-6/laminin provides costimulation to T-cell proliferation.\",\n      \"evidence\": \"Antibody blocking with co-immobilized CD3 mAb and laminin in human CD4+ T cells, flow cytometry\",\n      \"pmids\": [\"1972721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling mediators of costimulation not defined\", \"Single-lab antibody-based readout\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstrated α6β1 mediates CD11/CD18-independent leukocyte adherence to laminin, broadening its role in innate immune trafficking.\",\n      \"evidence\": \"Anti-α6 antibody blockade with CD11/CD18-deficient neutrophils as genetic confirmation\",\n      \"pmids\": [\"1347710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream activation pathway in neutrophils not mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified a lateral partner (CD63) and a hypoxia-linked signaling output, placing α6β1 within tetraspanin-organized membrane complexes and inside-out activation contexts.\",\n      \"evidence\": \"Brij-96 co-IP, large-scale purification and N-terminal sequencing for CD63; antibody cross-linking with pharmacological inhibitors for hypoxic CD11b/CD18 upregulation\",\n      \"pmids\": [\"7629079\", \"7594504\", \"7541723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CD63 association not established\", \"Direct interaction site within the integrin complex unmapped\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Separated adhesion from migration functions of α6, showing a distinct epitope drives motility and in vivo extravasation independent of FAK phosphorylation.\",\n      \"evidence\": \"Two anti-α6 antibodies with differential effects in laminin migration assays and in vivo B16F1 liver extravasation videomicroscopy\",\n      \"pmids\": [\"9288792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling distinguishing the migration epitope unknown\", \"Mechanism uncoupled from FAK not explained\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Established α6β1 functions under physiological shear, mediating leukocyte tethering and arrest on laminin with chain-specific selectivity.\",\n      \"evidence\": \"Defined laminar shear flow adhesion assay with chain-specific blocking antibodies\",\n      \"pmids\": [\"10698619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Force-dependent conformational regulation not addressed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected α6 to stem cell maintenance, showing it acts downstream of OCT4/SOX2 and drives PI3K/AKT activation that suppresses p53 to sustain pluripotency.\",\n      \"evidence\": \"ChIP for OCT4/SOX2 at ITGA6 promoter, knockdown/overexpression with p-AKT and p53 readouts, sphere formation; double knockdown with ITGB1 in CSC migration\",\n      \"pmids\": [\"22311737\", \"24317509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between α6 engagement and PI3K recruitment not biochemically resolved\", \"Single-lab pathway data\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a transcriptional regulatory network controlling ITGA6, identifying activators (HIF, RUNX1, RFX1) and linking expression to invasion and tissue integrity.\",\n      \"evidence\": \"ChIP plus luciferase reporters with epistatic rescue (HIF), motif mutagenesis (RUNX1), and conditional Rfx1 knockout with testis cord phenotype\",\n      \"pmids\": [\"27001172\", \"28926098\", \"27228460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic among transcription factors unresolved\", \"Cell-type specificity of each regulator not systematized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established multilayered post-transcriptional control via m6A, showing METTL3-deposited methylation read by YTHDF1/YTHDF3 promotes ITGA6 mRNA translation and tumor cell invasion, reversibly opposed by ALKBH5.\",\n      \"evidence\": \"MeRIP, RIP, luciferase + m6A-site mutagenesis, METTL3/ALKBH5 perturbation, and epistatic rescue with xenografts\",\n      \"pmids\": [\"31409574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of translation vs stability not fully partitioned\", \"Reader selectivity mechanism unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the regulatory map with additional transcriptional, epigenetic, and physical-interaction inputs (TRIM28, SIN3A/KLF9, KDM5B/miR-448, PSMC2) tying ITGA6 to cancer stemness and progression.\",\n      \"evidence\": \"Co-IP, ChIP, miRNA luciferase targeting, genetic inactivation, and epistasis with in vivo metastasis models\",\n      \"pmids\": [\"34497119\", \"34968869\", \"33829656\", \"34413286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many interactions rest on single Co-IP without reciprocal validation\", \"Convergence of these inputs on a shared output not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational stabilization of α6 through FUT8 core fucosylation, which blocks TRIM21-mediated ubiquitination, sustaining PI3K/AKT signaling and adult neurogenesis.\",\n      \"evidence\": \"Co-IP, core fucosylation biochemistry, Fut8 conditional knockout, ubiquitination assay, Trim21 co-IP, and Akt-agonist rescue\",\n      \"pmids\": [\"38523237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fucosylation site mapping on α6 not detailed\", \"Generalizability beyond neural stem cells untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked α6 engagement to a feed-forward IGF1R/Snail loop driving EMT, chemoresistance, and pre-metastatic niche formation, and to additional m6A stabilization in non-malignant airway disease.\",\n      \"evidence\": \"Isogenic platinum-resistant ovarian models with genetic/pharmacological perturbation and xenografts; MeRIP-PCR and actinomycin D stability assays for ZC3H13 in COPD models\",\n      \"pmids\": [\"38658801\", \"38670474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical coupling of α6 to IGF production not resolved\", \"Single-lab models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct β1 vs β4 heterodimers, lateral partners, and the dense transcriptional/m6A/fucosylation regulatory layers are coordinated to specify adhesion versus migration versus stemness outputs in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of α6 ligand engagement in the corpus\", \"Integration of the multiple regulatory inputs into a unified signaling logic not established\", \"In vivo isoform-specific functions of α6β1 vs α6β4 not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 9, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 12, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 6, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 19, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 18, 28]}\n    ],\n    \"complexes\": [\n      \"α6β1 integrin (VLA-6)\",\n      \"α6β4 integrin\"\n    ],\n    \"partners\": [\n      \"ITGB1\",\n      \"ITGB4\",\n      \"CD63\",\n      \"RPSA\",\n      \"PSMC2\",\n      \"FUT8\",\n      \"TRIM21\",\n      \"TRIM28\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}