{"gene":"ITGA9","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2009,"finding":"ITGA9 protein on mouse and human eggs participates in sperm-egg binding and fusion. RNA interference-mediated knockdown of Itga9 in mouse eggs reduced surface ITGA9 protein and resulted in reduced (but not complete loss of) sperm-egg binding and fusion in IVF assays at specific sperm:egg ratios, demonstrating ITGA9 and its likely beta partner ITGB1 are involved in gamete interactions.","method":"RNAi knockdown of Itga9 in mouse eggs, surface protein detection, IVF binding/fusion assays, function-blocking anti-ITGB1 antibody","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined cellular phenotype, antibody inhibition, two orthogonal approaches in single lab","pmids":["19129508"],"is_preprint":false},{"year":2010,"finding":"ITGA9 forms a heterodimer with ITGB1 as its canonical beta partner, but in RPMI 8866 cells lacking detectable ITGB1, ITGA9 pairs with ITGB7 to form a novel ITGA9-ITGB7 integrin that functions as a binding partner for ADAM2. Anti-ITGA9 antibody and siRNA against ITGB7 both inhibited RPMI 8866 cell adhesion to ADAM2.","method":"Anti-integrin antibody inhibition, siRNA knockdown, cell adhesion assays to ADAM2, integrin subunit expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal antibody and siRNA approaches, single lab, two orthogonal methods establishing novel dimerization","pmids":["21060781"],"is_preprint":false},{"year":2008,"finding":"A recurrent heterozygous missense mutation in the beta-propeller domain of ITGA9 (c.1210G>A, p.G404S) was identified in human fetuses with severe congenital chylothorax who failed to respond to OK-432 pleurodesis treatment, suggesting ITGA9 function in lymphatic development. Computer modeling supported the deleterious nature of this substitution. Family analysis indicated autosomal recessive inheritance.","method":"Genotyping of candidate genes, Sanger sequencing, computer structural modeling, family analysis","journal":"Prenatal diagnosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic mutation identification with structural modeling, single cohort, no direct functional rescue experiment","pmids":["18973153"],"is_preprint":false},{"year":2009,"finding":"An interstitial deletion at 3p21.3 creates an in-frame fusion of MLH1 (exons 1-11) with ITGA9 (exons 17-28). The resulting MLH1*ITGA9 fusion protein lacks DNA mismatch repair capability, as shown by mismatch repair assays. Murine fibroblasts expressing the fusion gene exhibit loss-of-contact inhibition, demonstrating a gain-of-function oncogenic effect from the ITGA9 coding sequences.","method":"PCR, gene cloning, transfection studies, Western blot, mismatch repair functional assays, doxycycline-inducible expression in murine fibroblasts","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional mismatch repair assay, contact inhibition phenotype), single lab","pmids":["19188145"],"is_preprint":false},{"year":2015,"finding":"miR-125b directly targets ITGA9 mRNA to suppress its expression, and ITGA9 upregulation in response to decreased miR-125b promotes melanoma cell migration and invasion. Restoration of miR-125b repressed ITGA9 expression and inhibited malignant phenotypes both in vitro and in vivo, while ITGA9 restoration reversed these effects.","method":"miRNA overexpression, ITGA9 knockdown and overexpression, in vitro invasion/migration assays, in vivo xenograft, luciferase reporter (implied by targeting), Western blot","journal":"Tumour biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, miRNA-target relationship established by functional rescue but abstract does not explicitly confirm direct 3'UTR binding assay","pmids":["26596831"],"is_preprint":false},{"year":2019,"finding":"miR-148a directly targets ITGA9 as confirmed by dual-luciferase reporter gene assay. Overexpression of miR-148a decreased proliferation, migration, and invasiveness of glioblastoma cells and inhibited xenograft tumor growth; restoration of ITGA9 reversed these effects, placing ITGA9 downstream of miR-148a in glioblastoma progression.","method":"Dual-luciferase reporter assay, miRNA overexpression, ITGA9 knockdown and restoration, cell viability/migration/invasion assays, xenograft","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR luciferase reporter confirms target relationship, functional rescue experiment, single lab","pmids":["31489579"],"is_preprint":false},{"year":2023,"finding":"CUL4B in macrophages represses expression of miR-194-5p, which leads to elevated ITGA9, promoting macrophage migration and adhesion, and renal infiltration in diabetic kidney disease. Loss of CUL4B in myeloid cells suppressed macrophage migration, adhesion, and renal infiltration via the CUL4B/miR-194-5p/ITGA9 axis, as demonstrated in two mouse DKD models.","method":"Myeloid-specific CUL4B knockout mouse models, in vitro migration and adhesion assays, miR-194-5p/ITGA9 expression analyses, in vivo/in vitro mechanistic studies","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout in two mouse models, in vitro mechanistic validation, single lab with multiple orthogonal approaches","pmids":["37224018"],"is_preprint":false},{"year":2022,"finding":"ITGA9 functions as a receptor for the chemokine XCL1 in the spinal cord. Intrathecal neutralization of ITGA9 (using YA4 antibody) reversed XCL1-induced hypersensitivity in naive mice and reduced thermal and mechanical hypersensitivity after nerve injury. Neutralization of ITGA9 enhanced morphine and buprenorphine analgesia, demonstrating that XCL1-ITGA9 signaling is pronociceptive in neuropathic pain.","method":"Intrathecal injection of neutralizing antibodies (YA4 anti-ITGA9), von Frey and cold plate behavioral tests, RT-qPCR, Western blot, ELISA, immunofluorescence in CCI mouse model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional blockade of ITGA9 with defined behavioral phenotype, multiple readouts, single lab","pmids":["36618360"],"is_preprint":false},{"year":2011,"finding":"ITGA9 expression is epigenetically silenced in breast cancer via CpG island methylation in the first intron of the gene. Treatment with the demethylating agent 5-aza-dC restored ITGA9 expression in ITGA9-negative MCF7 cells; combined treatment with 5-aza-dC and Trichostatin A doubled ITGA9 reactivation, while TSA alone had no effect, identifying CpG methylation as the primary epigenetic mechanism of ITGA9 silencing.","method":"5-aza-dC and Trichostatin A pharmacological treatment, qRT-PCR, methylation analysis of CpG island","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological demethylation with gene reactivation replicated across conditions, single lab, multiple drug treatments","pmids":["21975548"],"is_preprint":false},{"year":2022,"finding":"Overexpression of ITGA9 in human microvascular endothelial cells (HMEC-1) inhibited cell proliferation and migration, while increasing expression of cdc42, ki67, FAK, Src, RAC1, and RhoA. miR-146a-3p targeted ITGA9 to lower its expression, resulting in increased HMEC-1 proliferation and migration, establishing ITGA9 as a negative regulator of endothelial cell proliferation and migration in psoriasis.","method":"ITGA9 overexpression, miR-146a-3p mimic transfection, CCK-8, EdU proliferation, annexin V apoptosis, wound healing, transwell assay, Western blot","journal":"Clinical, cosmetic and investigational dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with downstream signaling markers but no direct mechanistic pathway validation","pmids":["36573168"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated m6A modification negatively regulates ITGA9 expression through translational suppression. High-throughput MeRIP sequencing identified ITGA9 as a critical downstream m6A target. Loss-of-function and gain-of-function experiments showed that ITGA9 delays cellular senescence, and ITGA9 inhibition reversed the anti-senescence effect of METTL3 silencing, while ITGA9 overexpression counteracted METTL3-driven senescence acceleration.","method":"MeRIP sequencing, METTL3 knockdown/overexpression, ITGA9 loss/gain-of-function, METTL3 transgenic mouse model, β-galactosidase assay, p16 expression, cell proliferation assays","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP sequencing identifies m6A modification on ITGA9, genetic rescue/epistasis in vitro and in vivo transgenic model, single lab","pmids":["40153583"],"is_preprint":false},{"year":2026,"finding":"ITGA9 mediates pro-angiogenic signaling via the FAK-ERK1/2 pathway in endothelial cells. A decellularized extracellular matrix/GelMA composite hydrogel upregulated ITGA9 expression in HUVECs, activating FAK-ERK1/2 and enhancing VEGFA expression and angiogenesis. Knockdown of ITGA9 abolished these pro-angiogenic effects, confirming ITGA9-FAK-ERK1/2 as the operative signaling axis.","method":"ITGA9 knockdown, HUVEC viability/migration/tube formation assays, Western blot for FAK/ERK1/2, VEGFA measurement, mouse subcutaneous implantation model","journal":"Materials today. Bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ITGA9 knockdown with defined downstream signaling readouts (FAK-ERK1/2) and in vivo validation, single lab","pmids":["41938137"],"is_preprint":false},{"year":2025,"finding":"ITGA9 in Schlemm's canal (SC) endothelium participates in a mechanosensitive ANGPT2-integrin α9β1 signaling pathway regulating intraocular pressure (IOP). PIEZO1 activation triggers ANGPT2 secretion and promotes cell-surface clustering of integrin α9β1. Deletion of SC-expressed Itga9 in mice caused SC narrowing, impaired flow-mediated SC endothelial proliferation, IOP elevation, and glaucoma.","method":"Endothelial-specific Itga9 conditional knockout mice, IOP measurement, SC morphology analysis, in vitro PIEZO1 activation assays, ANGPT2 blockade","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined structural and functional phenotype, in vitro and in vivo concordance, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.24.683742"],"is_preprint":true},{"year":2025,"finding":"ITGA9 expression identifies human testicular peritubular myoid cells (PTMs): ITGA9+/NGFR+ cells are positive for PTM markers (SMA, CNN1) and negative for Leydig cell markers (HSD3B, STAR), and can form tubular and spheroid structures in vitro. ITGA9−/NGFR+ cells represent adult Leydig cells. This establishes ITGA9 as a cell-surface marker enabling FACS-based isolation of PTMs from human testes.","method":"Single-cell RNA-seq reanalysis, immunofluorescence staining, FACS isolation using ITGA9/NGFR surface markers, in vitro culture and functional characterization","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface marker validated by immunofluorescence and FACS with functional in vitro confirmation, single lab","pmids":["40450328"],"is_preprint":false}],"current_model":"ITGA9 (integrin alpha-9) is a cell-surface adhesion receptor subunit that canonically pairs with ITGB1 (and under compensatory conditions with ITGB7) to mediate cell-ECM and cell-cell interactions; it participates in sperm-egg binding, lymphatic development, macrophage migration and renal infiltration (via CUL4B/miR-194-5p/ITGA9 axis), Schlemm's canal mechanosensitive IOP regulation (via PIEZO1-ANGPT2-ITGA9), pro-angiogenic FAK-ERK1/2 signaling, nociceptive transmission as an XCL1 receptor, and inhibition of cellular senescence downstream of METTL3-mediated m6A translational suppression, with its expression regulated epigenetically by CpG methylation and post-transcriptionally by multiple miRNAs."},"narrative":{"mechanistic_narrative":"ITGA9 (integrin alpha-9) is a cell-surface adhesion receptor subunit that mediates cell-ECM and cell-cell interactions and transduces these into intracellular signaling that controls cell proliferation, migration, and tissue morphogenesis [PMID:21060781, PMID:41938137]. Its canonical partner is the beta-1 integrin subunit, with which it participates in sperm-egg binding and fusion in mammalian gametes [PMID:19129508]; in cells lacking beta-1, ITGA9 instead pairs with ITGB7 to form a functional ITGA9-ITGB7 heterodimer that binds the sperm protein ADAM2 [PMID:21060781]. As a signaling receptor, ITGA9 drives the FAK-ERK1/2 axis to promote endothelial VEGFA expression and angiogenesis [PMID:41938137], serves as a receptor for the chemokine XCL1 in the spinal cord where XCL1-ITGA9 signaling is pronociceptive in neuropathic pain [PMID:36618360], and participates in a PIEZO1-ANGPT2-integrin alpha9beta1 mechanosensitive pathway in Schlemm's canal endothelium that regulates intraocular pressure, with its loss causing canal narrowing and glaucoma [PMID:bio_10.1101_2025.10.24.683742]. ITGA9 also negatively regulates endothelial proliferation and migration in a context-dependent manner [PMID:36573168] and delays cellular senescence downstream of METTL3-mediated m6A translational suppression [PMID:40153583]. ITGA9 expression is tightly controlled: it is epigenetically silenced in breast cancer through CpG island methylation in its first intron [PMID:21975548] and post-transcriptionally repressed by multiple miRNAs including miR-148a and miR-194-5p, the latter acting in a CUL4B/miR-194-5p/ITGA9 axis that promotes macrophage migration and renal infiltration [PMID:31489579, PMID:37224018]. A recurrent missense mutation in the ITGA9 beta-propeller domain has been linked to severe congenital chylothorax, implicating the gene in lymphatic development [PMID:18973153].","teleology":[{"year":2008,"claim":"Whether ITGA9 contributes to human developmental disease was unknown; identifying a recurrent coding mutation in chylothorax fetuses first linked ITGA9 to lymphatic development.","evidence":"candidate-gene sequencing and structural modeling in fetuses with congenital chylothorax","pmids":["18973153"],"confidence":"Low","gaps":["No functional rescue experiment performed","Inheritance pattern and mechanism of lymphatic defect not established"]},{"year":2009,"claim":"The receptors mediating gamete adhesion were incompletely defined; RNAi knockdown showed egg-surface ITGA9 contributes to sperm-egg binding and fusion.","evidence":"RNAi knockdown in mouse eggs with IVF binding/fusion assays and anti-ITGB1 antibody blockade","pmids":["19129508"],"confidence":"Medium","gaps":["Partial (not complete) loss of fusion leaves redundant receptors unidentified","Direct ligand on sperm not defined in this study"]},{"year":2009,"claim":"Whether ITGA9 coding sequences can drive oncogenic phenotypes was untested; an MLH1-ITGA9 fusion conferred loss of contact inhibition, showing a gain-of-function effect from ITGA9 sequences.","evidence":"cloning and doxycycline-inducible expression of the fusion in murine fibroblasts with mismatch repair and contact-inhibition assays","pmids":["19188145"],"confidence":"Medium","gaps":["Contribution of ITGA9 portion versus loss of MLH1 repair not fully dissected","Relevance to native ITGA9 signaling unclear"]},{"year":2010,"claim":"ITGA9 was assumed to require beta-1; demonstration of an ITGA9-ITGB7 heterodimer binding ADAM2 established beta-subunit plasticity and a defined ligand.","evidence":"anti-integrin antibody inhibition and ITGB7 siRNA in ADAM2 adhesion assays in RPMI 8866 cells","pmids":["21060781"],"confidence":"Medium","gaps":["Physiological contexts where ITGA9-ITGB7 forms in vivo not defined","Single cell line"]},{"year":2011,"claim":"The basis of ITGA9 loss in cancer was unknown; pharmacological demethylation reactivated ITGA9, identifying CpG island methylation as the silencing mechanism.","evidence":"5-aza-dC and Trichostatin A treatment with methylation analysis and qRT-PCR in MCF7 cells","pmids":["21975548"],"confidence":"Medium","gaps":["Functional consequence of reactivated ITGA9 not assessed here","Methylation status across tumor types not surveyed"]},{"year":2019,"claim":"Post-transcriptional control of ITGA9 was poorly defined; multiple miRNAs were shown to directly repress ITGA9 to limit malignant phenotypes, with rescue restoring them.","evidence":"dual-luciferase 3'UTR reporter, miRNA overexpression and ITGA9 restoration with invasion/xenograft assays (miR-125b, miR-148a)","pmids":["26596831","31489579"],"confidence":"Medium","gaps":["Downstream effector pathways of ITGA9 in these tumors not mapped","Whether the same miRNAs operate in normal tissue unclear"]},{"year":2022,"claim":"An immune/neural ligand for ITGA9 was unknown; functional blockade established ITGA9 as a spinal XCL1 receptor driving neuropathic hypersensitivity.","evidence":"intrathecal anti-ITGA9 (YA4) neutralization with behavioral pain testing in a CCI mouse model","pmids":["36618360"],"confidence":"Medium","gaps":["Downstream neuronal signaling from XCL1-ITGA9 not defined","Cell type expressing ITGA9 in spinal cord not pinpointed"]},{"year":2022,"claim":"ITGA9's role in endothelial behavior was ambiguous; overexpression showed it suppresses endothelial proliferation and migration, with miR-146a-3p relieving this restraint.","evidence":"ITGA9 overexpression and miR-146a-3p mimics with proliferation/migration assays and signaling Western blots in HMEC-1","pmids":["36573168"],"confidence":"Low","gaps":["No direct mechanistic validation linking ITGA9 to the listed signaling markers","Apparent opposite (anti-migratory) role versus pro-angiogenic findings unresolved"]},{"year":2023,"claim":"How ITGA9 is regulated in disease-associated macrophages was unclear; a CUL4B/miR-194-5p/ITGA9 axis was shown to drive macrophage migration and renal infiltration.","evidence":"myeloid-specific CUL4B knockout in two diabetic kidney disease mouse models with in vitro migration/adhesion assays","pmids":["37224018"],"confidence":"Medium","gaps":["Direct adhesion ligand engaged by ITGA9 in renal infiltration not identified","Downstream signaling in macrophages not mapped"]},{"year":2025,"claim":"Whether m6A controls ITGA9 and links it to aging was untested; MeRIP-seq and rescue experiments placed ITGA9 downstream of METTL3 as a senescence brake.","evidence":"MeRIP-seq, METTL3 knockdown/overexpression, ITGA9 loss/gain epistasis, and a METTL3 transgenic mouse with senescence assays","pmids":["40153583"],"confidence":"Medium","gaps":["Reader protein mediating translational suppression not identified","Mechanism by which ITGA9 delays senescence not defined"]},{"year":2025,"claim":"Cell-type specificity of ITGA9 in human testis was unknown; ITGA9 was validated as a surface marker distinguishing peritubular myoid cells from Leydig cells.","evidence":"scRNA-seq reanalysis, immunofluorescence, and FACS isolation using ITGA9/NGFR with in vitro culture","pmids":["40450328"],"confidence":"Medium","gaps":["Functional role of ITGA9 within PTMs not tested","Adhesive ligand in the testicular niche not defined"]},{"year":2025,"claim":"How mechanical flow regulates Schlemm's canal was incompletely understood; ITGA9 was placed in a PIEZO1-ANGPT2-integrin alpha9beta1 mechanosensitive pathway controlling IOP and glaucoma.","evidence":"endothelial-specific Itga9 conditional knockout mice with IOP/SC morphology readouts and in vitro PIEZO1 activation (preprint)","pmids":["bio_10.1101_2025.10.24.683742"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Direct integrin alpha9beta1 ligand mediating proliferation not defined"]},{"year":2026,"claim":"The signaling output of ITGA9 in angiogenesis was undefined; knockdown identified ITGA9-FAK-ERK1/2 as the axis driving VEGFA and endothelial angiogenesis.","evidence":"ITGA9 knockdown in HUVECs with tube formation, FAK/ERK1/2 Western blots, VEGFA measurement, and a subcutaneous implantation model","pmids":["41938137"],"confidence":"Medium","gaps":["ECM ligand triggering ITGA9-FAK signaling not isolated","Reconciliation with anti-proliferative endothelial role unresolved"]},{"year":null,"claim":"The native ECM ligands engaged by ITGA9-beta1 across its diverse tissue contexts, and how a single receptor reconciles pro- versus anti-proliferative/migratory outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural/ligand model across endothelial, immune, and reproductive contexts","m6A reader and downstream senescence effectors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,11,12]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10]}],"complexes":["integrin alpha9beta1","integrin alpha9-beta7"],"partners":["ITGB1","ITGB7","ADAM2","XCL1","ANGPT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13797","full_name":"Integrin alpha-9","aliases":["Integrin alpha-RLC"],"length_aa":1035,"mass_kda":114.5,"function":"Integrin alpha-9/beta-1 (ITGA9:ITGB1) is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. ITGA9:ITGB1 may play a crucial role in SVEP1/polydom-mediated myoblast cell adhesion (By similarity). Integrin ITGA9:ITGB1 represses PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells via its interaction with SVEP1, thereby inhibiting vasocontraction (PubMed:35802072)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13797/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA9","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA9","total_profiled":1310},"omim":[{"mim_id":"603963","title":"INTEGRIN, ALPHA-9; ITGA9","url":"https://www.omim.org/entry/603963"},{"mim_id":"188060","title":"THROMBOSPONDIN I; THBS1","url":"https://www.omim.org/entry/188060"},{"mim_id":"135630","title":"INTEGRIN, BETA-1; ITGB1","url":"https://www.omim.org/entry/135630"},{"mim_id":"135600","title":"FIBRONECTIN 1; FN1","url":"https://www.omim.org/entry/135600"},{"mim_id":"130660","title":"ELASTIN MICROFIBRIL INTERFACER 1; EMILIN1","url":"https://www.omim.org/entry/130660"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGA9"},"hgnc":{"alias_symbol":["RLC","ITGA4L","ALPHA-RLC"],"prev_symbol":[]},"alphafold":{"accession":"Q13797","domains":[{"cath_id":"2.130.10.130","chopping":"124-427","consensus_level":"high","plddt":91.7226,"start":124,"end":427},{"cath_id":"2.60.40.1460","chopping":"463-617","consensus_level":"high","plddt":85.8705,"start":463,"end":617},{"cath_id":"2.60.40.1510","chopping":"630-767","consensus_level":"high","plddt":84.2323,"start":630,"end":767},{"cath_id":"2.60.40.1530","chopping":"772-867_883-971","consensus_level":"high","plddt":86.3474,"start":772,"end":971}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13797","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13797-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13797-F1-predicted_aligned_error_v6.png","plddt_mean":85.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA9","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA9"},"sequence":{"accession":"Q13797","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13797.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13797/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13797"}},"corpus_meta":[{"pmid":"3584239","id":"PMC_3584239","title":"Cloning and characterization of mammalian myosin regulatory light chain (RLC) cDNA: the RLC gene is expressed in smooth, sarcomeric, and nonmuscle tissues.","date":"1987","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/3584239","citation_count":80,"is_preprint":false},{"pmid":"23530050","id":"PMC_23530050","title":"Myosin regulatory light chain (RLC) phosphorylation change as a modulator of cardiac muscle contraction in disease.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23530050","citation_count":72,"is_preprint":false},{"pmid":"19478819","id":"PMC_19478819","title":"A genome-wide association study identifies ITGA9 conferring risk of nasopharyngeal carcinoma.","date":"2009","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19478819","citation_count":67,"is_preprint":false},{"pmid":"16837010","id":"PMC_16837010","title":"Prolonged Ca2+ and force transients in myosin RLC transgenic mouse fibers expressing malignant and benign FHC mutations.","date":"2006","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16837010","citation_count":54,"is_preprint":false},{"pmid":"16076902","id":"PMC_16076902","title":"The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16076902","citation_count":52,"is_preprint":false},{"pmid":"18973153","id":"PMC_18973153","title":"A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy.","date":"2008","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/18973153","citation_count":47,"is_preprint":false},{"pmid":"21696541","id":"PMC_21696541","title":"The effect of myosin RLC phosphorylation in normal and cardiomyopathic mouse hearts.","date":"2012","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21696541","citation_count":44,"is_preprint":false},{"pmid":"4148931","id":"PMC_4148931","title":"Regulation of phosphoenolpyruvate carboxykinase and tyrosine transaminase in hepatoma cell cultures. 3. 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RNA interference-mediated knockdown of Itga9 in mouse eggs reduced surface ITGA9 protein and resulted in reduced (but not complete loss of) sperm-egg binding and fusion in IVF assays at specific sperm:egg ratios, demonstrating ITGA9 and its likely beta partner ITGB1 are involved in gamete interactions.\",\n      \"method\": \"RNAi knockdown of Itga9 in mouse eggs, surface protein detection, IVF binding/fusion assays, function-blocking anti-ITGB1 antibody\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined cellular phenotype, antibody inhibition, two orthogonal approaches in single lab\",\n      \"pmids\": [\"19129508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ITGA9 forms a heterodimer with ITGB1 as its canonical beta partner, but in RPMI 8866 cells lacking detectable ITGB1, ITGA9 pairs with ITGB7 to form a novel ITGA9-ITGB7 integrin that functions as a binding partner for ADAM2. Anti-ITGA9 antibody and siRNA against ITGB7 both inhibited RPMI 8866 cell adhesion to ADAM2.\",\n      \"method\": \"Anti-integrin antibody inhibition, siRNA knockdown, cell adhesion assays to ADAM2, integrin subunit expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal antibody and siRNA approaches, single lab, two orthogonal methods establishing novel dimerization\",\n      \"pmids\": [\"21060781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A recurrent heterozygous missense mutation in the beta-propeller domain of ITGA9 (c.1210G>A, p.G404S) was identified in human fetuses with severe congenital chylothorax who failed to respond to OK-432 pleurodesis treatment, suggesting ITGA9 function in lymphatic development. Computer modeling supported the deleterious nature of this substitution. Family analysis indicated autosomal recessive inheritance.\",\n      \"method\": \"Genotyping of candidate genes, Sanger sequencing, computer structural modeling, family analysis\",\n      \"journal\": \"Prenatal diagnosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic mutation identification with structural modeling, single cohort, no direct functional rescue experiment\",\n      \"pmids\": [\"18973153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"An interstitial deletion at 3p21.3 creates an in-frame fusion of MLH1 (exons 1-11) with ITGA9 (exons 17-28). The resulting MLH1*ITGA9 fusion protein lacks DNA mismatch repair capability, as shown by mismatch repair assays. Murine fibroblasts expressing the fusion gene exhibit loss-of-contact inhibition, demonstrating a gain-of-function oncogenic effect from the ITGA9 coding sequences.\",\n      \"method\": \"PCR, gene cloning, transfection studies, Western blot, mismatch repair functional assays, doxycycline-inducible expression in murine fibroblasts\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional mismatch repair assay, contact inhibition phenotype), single lab\",\n      \"pmids\": [\"19188145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-125b directly targets ITGA9 mRNA to suppress its expression, and ITGA9 upregulation in response to decreased miR-125b promotes melanoma cell migration and invasion. Restoration of miR-125b repressed ITGA9 expression and inhibited malignant phenotypes both in vitro and in vivo, while ITGA9 restoration reversed these effects.\",\n      \"method\": \"miRNA overexpression, ITGA9 knockdown and overexpression, in vitro invasion/migration assays, in vivo xenograft, luciferase reporter (implied by targeting), Western blot\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, miRNA-target relationship established by functional rescue but abstract does not explicitly confirm direct 3'UTR binding assay\",\n      \"pmids\": [\"26596831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-148a directly targets ITGA9 as confirmed by dual-luciferase reporter gene assay. Overexpression of miR-148a decreased proliferation, migration, and invasiveness of glioblastoma cells and inhibited xenograft tumor growth; restoration of ITGA9 reversed these effects, placing ITGA9 downstream of miR-148a in glioblastoma progression.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA overexpression, ITGA9 knockdown and restoration, cell viability/migration/invasion assays, xenograft\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR luciferase reporter confirms target relationship, functional rescue experiment, single lab\",\n      \"pmids\": [\"31489579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CUL4B in macrophages represses expression of miR-194-5p, which leads to elevated ITGA9, promoting macrophage migration and adhesion, and renal infiltration in diabetic kidney disease. Loss of CUL4B in myeloid cells suppressed macrophage migration, adhesion, and renal infiltration via the CUL4B/miR-194-5p/ITGA9 axis, as demonstrated in two mouse DKD models.\",\n      \"method\": \"Myeloid-specific CUL4B knockout mouse models, in vitro migration and adhesion assays, miR-194-5p/ITGA9 expression analyses, in vivo/in vitro mechanistic studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout in two mouse models, in vitro mechanistic validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37224018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA9 functions as a receptor for the chemokine XCL1 in the spinal cord. Intrathecal neutralization of ITGA9 (using YA4 antibody) reversed XCL1-induced hypersensitivity in naive mice and reduced thermal and mechanical hypersensitivity after nerve injury. Neutralization of ITGA9 enhanced morphine and buprenorphine analgesia, demonstrating that XCL1-ITGA9 signaling is pronociceptive in neuropathic pain.\",\n      \"method\": \"Intrathecal injection of neutralizing antibodies (YA4 anti-ITGA9), von Frey and cold plate behavioral tests, RT-qPCR, Western blot, ELISA, immunofluorescence in CCI mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional blockade of ITGA9 with defined behavioral phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"36618360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ITGA9 expression is epigenetically silenced in breast cancer via CpG island methylation in the first intron of the gene. Treatment with the demethylating agent 5-aza-dC restored ITGA9 expression in ITGA9-negative MCF7 cells; combined treatment with 5-aza-dC and Trichostatin A doubled ITGA9 reactivation, while TSA alone had no effect, identifying CpG methylation as the primary epigenetic mechanism of ITGA9 silencing.\",\n      \"method\": \"5-aza-dC and Trichostatin A pharmacological treatment, qRT-PCR, methylation analysis of CpG island\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological demethylation with gene reactivation replicated across conditions, single lab, multiple drug treatments\",\n      \"pmids\": [\"21975548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of ITGA9 in human microvascular endothelial cells (HMEC-1) inhibited cell proliferation and migration, while increasing expression of cdc42, ki67, FAK, Src, RAC1, and RhoA. miR-146a-3p targeted ITGA9 to lower its expression, resulting in increased HMEC-1 proliferation and migration, establishing ITGA9 as a negative regulator of endothelial cell proliferation and migration in psoriasis.\",\n      \"method\": \"ITGA9 overexpression, miR-146a-3p mimic transfection, CCK-8, EdU proliferation, annexin V apoptosis, wound healing, transwell assay, Western blot\",\n      \"journal\": \"Clinical, cosmetic and investigational dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with downstream signaling markers but no direct mechanistic pathway validation\",\n      \"pmids\": [\"36573168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated m6A modification negatively regulates ITGA9 expression through translational suppression. High-throughput MeRIP sequencing identified ITGA9 as a critical downstream m6A target. Loss-of-function and gain-of-function experiments showed that ITGA9 delays cellular senescence, and ITGA9 inhibition reversed the anti-senescence effect of METTL3 silencing, while ITGA9 overexpression counteracted METTL3-driven senescence acceleration.\",\n      \"method\": \"MeRIP sequencing, METTL3 knockdown/overexpression, ITGA9 loss/gain-of-function, METTL3 transgenic mouse model, β-galactosidase assay, p16 expression, cell proliferation assays\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP sequencing identifies m6A modification on ITGA9, genetic rescue/epistasis in vitro and in vivo transgenic model, single lab\",\n      \"pmids\": [\"40153583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA9 mediates pro-angiogenic signaling via the FAK-ERK1/2 pathway in endothelial cells. A decellularized extracellular matrix/GelMA composite hydrogel upregulated ITGA9 expression in HUVECs, activating FAK-ERK1/2 and enhancing VEGFA expression and angiogenesis. Knockdown of ITGA9 abolished these pro-angiogenic effects, confirming ITGA9-FAK-ERK1/2 as the operative signaling axis.\",\n      \"method\": \"ITGA9 knockdown, HUVEC viability/migration/tube formation assays, Western blot for FAK/ERK1/2, VEGFA measurement, mouse subcutaneous implantation model\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ITGA9 knockdown with defined downstream signaling readouts (FAK-ERK1/2) and in vivo validation, single lab\",\n      \"pmids\": [\"41938137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA9 in Schlemm's canal (SC) endothelium participates in a mechanosensitive ANGPT2-integrin α9β1 signaling pathway regulating intraocular pressure (IOP). PIEZO1 activation triggers ANGPT2 secretion and promotes cell-surface clustering of integrin α9β1. Deletion of SC-expressed Itga9 in mice caused SC narrowing, impaired flow-mediated SC endothelial proliferation, IOP elevation, and glaucoma.\",\n      \"method\": \"Endothelial-specific Itga9 conditional knockout mice, IOP measurement, SC morphology analysis, in vitro PIEZO1 activation assays, ANGPT2 blockade\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined structural and functional phenotype, in vitro and in vivo concordance, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.24.683742\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA9 expression identifies human testicular peritubular myoid cells (PTMs): ITGA9+/NGFR+ cells are positive for PTM markers (SMA, CNN1) and negative for Leydig cell markers (HSD3B, STAR), and can form tubular and spheroid structures in vitro. ITGA9−/NGFR+ cells represent adult Leydig cells. This establishes ITGA9 as a cell-surface marker enabling FACS-based isolation of PTMs from human testes.\",\n      \"method\": \"Single-cell RNA-seq reanalysis, immunofluorescence staining, FACS isolation using ITGA9/NGFR surface markers, in vitro culture and functional characterization\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface marker validated by immunofluorescence and FACS with functional in vitro confirmation, single lab\",\n      \"pmids\": [\"40450328\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA9 (integrin alpha-9) is a cell-surface adhesion receptor subunit that canonically pairs with ITGB1 (and under compensatory conditions with ITGB7) to mediate cell-ECM and cell-cell interactions; it participates in sperm-egg binding, lymphatic development, macrophage migration and renal infiltration (via CUL4B/miR-194-5p/ITGA9 axis), Schlemm's canal mechanosensitive IOP regulation (via PIEZO1-ANGPT2-ITGA9), pro-angiogenic FAK-ERK1/2 signaling, nociceptive transmission as an XCL1 receptor, and inhibition of cellular senescence downstream of METTL3-mediated m6A translational suppression, with its expression regulated epigenetically by CpG methylation and post-transcriptionally by multiple miRNAs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA9 (integrin alpha-9) is a cell-surface adhesion receptor subunit that mediates cell-ECM and cell-cell interactions and transduces these into intracellular signaling that controls cell proliferation, migration, and tissue morphogenesis [#1, #11]. Its canonical partner is the beta-1 integrin subunit, with which it participates in sperm-egg binding and fusion in mammalian gametes [#0]; in cells lacking beta-1, ITGA9 instead pairs with ITGB7 to form a functional ITGA9-ITGB7 heterodimer that binds the sperm protein ADAM2 [#1]. As a signaling receptor, ITGA9 drives the FAK-ERK1/2 axis to promote endothelial VEGFA expression and angiogenesis [#11], serves as a receptor for the chemokine XCL1 in the spinal cord where XCL1-ITGA9 signaling is pronociceptive in neuropathic pain [#7], and participates in a PIEZO1-ANGPT2-integrin alpha9beta1 mechanosensitive pathway in Schlemm's canal endothelium that regulates intraocular pressure, with its loss causing canal narrowing and glaucoma [#12]. ITGA9 also negatively regulates endothelial proliferation and migration in a context-dependent manner [#9] and delays cellular senescence downstream of METTL3-mediated m6A translational suppression [#10]. ITGA9 expression is tightly controlled: it is epigenetically silenced in breast cancer through CpG island methylation in its first intron [#8] and post-transcriptionally repressed by multiple miRNAs including miR-148a and miR-194-5p, the latter acting in a CUL4B/miR-194-5p/ITGA9 axis that promotes macrophage migration and renal infiltration [#5, #6]. A recurrent missense mutation in the ITGA9 beta-propeller domain has been linked to severe congenital chylothorax, implicating the gene in lymphatic development [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Whether ITGA9 contributes to human developmental disease was unknown; identifying a recurrent coding mutation in chylothorax fetuses first linked ITGA9 to lymphatic development.\",\n      \"evidence\": \"candidate-gene sequencing and structural modeling in fetuses with congenital chylothorax\",\n      \"pmids\": [\"18973153\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional rescue experiment performed\", \"Inheritance pattern and mechanism of lymphatic defect not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The receptors mediating gamete adhesion were incompletely defined; RNAi knockdown showed egg-surface ITGA9 contributes to sperm-egg binding and fusion.\",\n      \"evidence\": \"RNAi knockdown in mouse eggs with IVF binding/fusion assays and anti-ITGB1 antibody blockade\",\n      \"pmids\": [\"19129508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial (not complete) loss of fusion leaves redundant receptors unidentified\", \"Direct ligand on sperm not defined in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether ITGA9 coding sequences can drive oncogenic phenotypes was untested; an MLH1-ITGA9 fusion conferred loss of contact inhibition, showing a gain-of-function effect from ITGA9 sequences.\",\n      \"evidence\": \"cloning and doxycycline-inducible expression of the fusion in murine fibroblasts with mismatch repair and contact-inhibition assays\",\n      \"pmids\": [\"19188145\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of ITGA9 portion versus loss of MLH1 repair not fully dissected\", \"Relevance to native ITGA9 signaling unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"ITGA9 was assumed to require beta-1; demonstration of an ITGA9-ITGB7 heterodimer binding ADAM2 established beta-subunit plasticity and a defined ligand.\",\n      \"evidence\": \"anti-integrin antibody inhibition and ITGB7 siRNA in ADAM2 adhesion assays in RPMI 8866 cells\",\n      \"pmids\": [\"21060781\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts where ITGA9-ITGB7 forms in vivo not defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The basis of ITGA9 loss in cancer was unknown; pharmacological demethylation reactivated ITGA9, identifying CpG island methylation as the silencing mechanism.\",\n      \"evidence\": \"5-aza-dC and Trichostatin A treatment with methylation analysis and qRT-PCR in MCF7 cells\",\n      \"pmids\": [\"21975548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of reactivated ITGA9 not assessed here\", \"Methylation status across tumor types not surveyed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Post-transcriptional control of ITGA9 was poorly defined; multiple miRNAs were shown to directly repress ITGA9 to limit malignant phenotypes, with rescue restoring them.\",\n      \"evidence\": \"dual-luciferase 3'UTR reporter, miRNA overexpression and ITGA9 restoration with invasion/xenograft assays (miR-125b, miR-148a)\",\n      \"pmids\": [\"26596831\", \"31489579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathways of ITGA9 in these tumors not mapped\", \"Whether the same miRNAs operate in normal tissue unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An immune/neural ligand for ITGA9 was unknown; functional blockade established ITGA9 as a spinal XCL1 receptor driving neuropathic hypersensitivity.\",\n      \"evidence\": \"intrathecal anti-ITGA9 (YA4) neutralization with behavioral pain testing in a CCI mouse model\",\n      \"pmids\": [\"36618360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neuronal signaling from XCL1-ITGA9 not defined\", \"Cell type expressing ITGA9 in spinal cord not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ITGA9's role in endothelial behavior was ambiguous; overexpression showed it suppresses endothelial proliferation and migration, with miR-146a-3p relieving this restraint.\",\n      \"evidence\": \"ITGA9 overexpression and miR-146a-3p mimics with proliferation/migration assays and signaling Western blots in HMEC-1\",\n      \"pmids\": [\"36573168\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic validation linking ITGA9 to the listed signaling markers\", \"Apparent opposite (anti-migratory) role versus pro-angiogenic findings unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How ITGA9 is regulated in disease-associated macrophages was unclear; a CUL4B/miR-194-5p/ITGA9 axis was shown to drive macrophage migration and renal infiltration.\",\n      \"evidence\": \"myeloid-specific CUL4B knockout in two diabetic kidney disease mouse models with in vitro migration/adhesion assays\",\n      \"pmids\": [\"37224018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct adhesion ligand engaged by ITGA9 in renal infiltration not identified\", \"Downstream signaling in macrophages not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether m6A controls ITGA9 and links it to aging was untested; MeRIP-seq and rescue experiments placed ITGA9 downstream of METTL3 as a senescence brake.\",\n      \"evidence\": \"MeRIP-seq, METTL3 knockdown/overexpression, ITGA9 loss/gain epistasis, and a METTL3 transgenic mouse with senescence assays\",\n      \"pmids\": [\"40153583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reader protein mediating translational suppression not identified\", \"Mechanism by which ITGA9 delays senescence not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cell-type specificity of ITGA9 in human testis was unknown; ITGA9 was validated as a surface marker distinguishing peritubular myoid cells from Leydig cells.\",\n      \"evidence\": \"scRNA-seq reanalysis, immunofluorescence, and FACS isolation using ITGA9/NGFR with in vitro culture\",\n      \"pmids\": [\"40450328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of ITGA9 within PTMs not tested\", \"Adhesive ligand in the testicular niche not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How mechanical flow regulates Schlemm's canal was incompletely understood; ITGA9 was placed in a PIEZO1-ANGPT2-integrin alpha9beta1 mechanosensitive pathway controlling IOP and glaucoma.\",\n      \"evidence\": \"endothelial-specific Itga9 conditional knockout mice with IOP/SC morphology readouts and in vitro PIEZO1 activation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.24.683742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Direct integrin alpha9beta1 ligand mediating proliferation not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The signaling output of ITGA9 in angiogenesis was undefined; knockdown identified ITGA9-FAK-ERK1/2 as the axis driving VEGFA and endothelial angiogenesis.\",\n      \"evidence\": \"ITGA9 knockdown in HUVECs with tube formation, FAK/ERK1/2 Western blots, VEGFA measurement, and a subcutaneous implantation model\",\n      \"pmids\": [\"41938137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ECM ligand triggering ITGA9-FAK signaling not isolated\", \"Reconciliation with anti-proliferative endothelial role unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The native ECM ligands engaged by ITGA9-beta1 across its diverse tissue contexts, and how a single receptor reconciles pro- versus anti-proliferative/migratory outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural/ligand model across endothelial, immune, and reproductive contexts\", \"m6A reader and downstream senescence effectors unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 11, 12]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"integrin alpha9beta1\", \"integrin alpha9-beta7\"],\n    \"partners\": [\"ITGB1\", \"ITGB7\", \"ADAM2\", \"XCL1\", \"ANGPT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}