{"gene":"ITGA11","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1999,"finding":"ITGA11 encodes a novel integrin alpha subunit with a large 1120-residue extracellular domain containing a 207-residue I-domain, a transmembrane domain, and a short 24-amino acid cytoplasmic domain. It belongs to the collagen-binding integrin alpha subunit group but differs by an incompletely preserved cytoplasmic GFFKR motif. Transcripts were found predominantly in bone, cartilage, cardiac muscle, and skeletal muscle.","method":"cDNA cloning, sequence analysis, chromosomal localization, tissue expression profiling","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular characterization of the gene product with sequence, structural domain analysis, and chromosomal mapping; foundational characterization paper","pmids":["10486209"],"is_preprint":false},{"year":2002,"finding":"The ITGA11 gene spans 30 exons; a unique inserted region encoding amino acids 804-826 is located at the start of exon 20. A major transcription start site was mapped 30 nucleotides upstream of the translation start. Promoter analysis in fibrosarcoma HT1080 cells identified a core promoter [nt -127 to +25], a silencer region [nt -400 to -127], and an enhancer region [nt -1519 to -400] important for alpha11 transcription in mesenchymal cells.","method":"Genomic PCR, oligo-capping technique for TSS mapping, luciferase promoter reporter assays","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct functional promoter dissection with reporter assays and TSS mapping, single lab","pmids":["12392762"],"is_preprint":false},{"year":2010,"finding":"Progesterone increases ITGA11 expression and phosphorylated focal adhesion kinase (pFAK) in rat cervical stromal cells, and this effect is blocked by the progesterone antagonist mifepristone. Mifepristone conversely increases ITGA2 expression via ERK1/2 signaling, and ERK1/2 inhibition abrogates mifepristone-induced ITGA2 upregulation. ITGA11 expression peaks at mid-gestation (day 18) and declines thereafter.","method":"In vivo rat gestation model, primary rat cervical stromal cell cultures, Western blot, pharmacological inhibitors (mifepristone, ERK1/2 inhibitor)","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with pharmacological manipulation and Western blot, single lab with two orthogonal approaches","pmids":["20959644"],"is_preprint":false},{"year":2015,"finding":"FGF2 overrides TGFβ1-driven ITGA11 expression in human dermal fibroblasts. FGF2-induced downregulation of ITGA11 requires ERK1/2 activity, and in the presence of FGF2, TGFβ1 cannot rescue ITGA11 expression. Loss of ITGA11 is associated with its removal from focal adhesions.","method":"RT-PCR, qRT-PCR, Western blotting, immunocytochemistry, pharmacological ERK1/2 inhibition","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab, functional inhibitor experiments defining pathway dependence","pmids":["26403263"],"is_preprint":false},{"year":2015,"finding":"miR-126a-3p directly targets the 3' UTR of Itga11 mRNA, inhibiting its translation and affecting mRNA stability. Loss of miR-126a-3p function significantly reduced the number of embryo implantation sites in vivo, and miR-126a-3p overexpression promoted cell migratory and invasive capacity in vitro, placing Itga11 downstream of miR-126a-3p in endometrial function during embryo implantation.","method":"Luciferase reporter assay for 3' UTR targeting, in vivo loss-of-function (miR-126a-3p inhibition), Transwell migration/invasion assay","journal":"Reproductive biomedicine online","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3' UTR validation by luciferase assay plus in vivo functional readout, single lab","pmids":["26194885"],"is_preprint":false},{"year":2023,"finding":"Itga11 gene-deleted (Itga11-/-) mice show substantially reduced severity of imiquimod-induced psoriasiform dermatitis, with reduced numbers of fibroblasts, macrophages, T cells, and tissue-resident memory T cells in skin. Differentially expressed genes in Itga11-/- vs. WT mice during inflammation were enriched in extracellular matrix organization, immune system, and lipid metabolism pathways.","method":"Forward genetics (strain comparison), Itga11 knockout mouse model, histopathology, skin transcriptomics, immunofluorescence for immune cells","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and transcriptomic pathway analysis, single lab","pmids":["37565309"],"is_preprint":false},{"year":2024,"finding":"PDGFRα+ITGA11+ cancer-associated fibroblasts (CAFs) promote lymphangiogenesis in early-stage bladder cancer by engaging ITGA11 with its surface receptor SELE (E-selectin) on lymphatic endothelial cells, activating the SRC-p-VEGFR3-MAPK pathway. These CAFs also secrete CHI3L1 to align the surrounding matrix and assist cancer cell intravasation.","method":"Single-cell RNA sequencing, spatial transcriptomics, CAF-specific deficient mouse model, co-culture and signaling assays, multicenter clinical cohort validation","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific knockout mouse model combined with scRNA-seq, spatial transcriptomics, signaling pathway dissection, and large clinical cohort, multiple orthogonal approaches","pmids":["38428409"],"is_preprint":false},{"year":2024,"finding":"Itga11 overexpression in rat bone marrow mesenchymal stem cells (rBMSCs) under hypoxia inhibits proliferation and angiogenesis while enhancing osteogenic differentiation, whereas Itga11 knockdown has the opposite effects. Mechanistically, Itga11 activates the PI3K/Akt signaling pathway in rBMSCs.","method":"siRNA knockdown, pcDNA overexpression, CCK-8 proliferation assay, tube formation assay, alizarin red staining, Western blot, transcriptomic analysis","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal readouts in single lab","pmids":["39566247"],"is_preprint":false},{"year":2025,"finding":"LIPUS upregulates ITGA11 expression in rat BMSCs and promotes osteogenic differentiation by activating the FAK/PI3K/AKT/GSK3β/β-catenin focal adhesion pathway. LIPUS also enhanced implant osseointegration in rats.","method":"In vivo rat implant model (micro-CT, toluidine blue staining), in vitro BMSC assays (ALP staining, alizarin red staining, RT-PCR, Western blot), bioinformatics (GO/KEGG, random forest)","journal":"BMC oral health","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with pathway validation by Western blot, single lab","pmids":["39755586"],"is_preprint":false},{"year":2026,"finding":"ITGA11 promotes lens epithelial-mesenchymal transition (EMT) by driving PTGS2 (COX-2) induction, which mediates arachidonic acid metabolic reprogramming toward pro-inflammatory prostaglandins. ITGA11 knockdown impairs lens epithelial cell migration and suppresses TGFβ2-induced myofibroblast transdifferentiation, reducing α-SMA and fibronectin expression. Pharmacologic inhibition of PTGS2 also suppressed EMT-associated phenotypes.","method":"siRNA knockdown, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence, scratch assay, lipidomic profiling, COX-2 inhibitor (celecoxib) treatment","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts including lipidomics and transcriptomics, single lab","pmids":["42061596"],"is_preprint":false},{"year":2026,"finding":"NAT10, via RNA ac4C modification, stabilizes C/EBPβ mRNA, which transcriptionally upregulates ITGA11, thereby promoting fibroblast activation and extracellular matrix production in pulmonary fibrosis. Rescue experiments confirmed that the pro-fibrotic effects of NAT10 are dependent on the C/EBPβ-ITGA11 axis.","method":"NAT10 inhibitor (Remodelin) in vivo and in vitro, ac4C mRNA modification analysis, rescue experiments, Western blot, gene expression analysis","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis-like rescue experiments defining pathway order (NAT10→C/EBPβ→ITGA11), multiple methods, single lab","pmids":["42090905"],"is_preprint":false},{"year":2026,"finding":"ITGA11 promotes myoblast differentiation via the FAK/Paxillin-Akt-GSK3β pathway. Dexamethasone-induced stress suppresses myogenic differentiation through glucocorticoid receptor (GR)-mediated suppression of the ITGA11-FAK/Paxillin-Akt-GSK3β cascade. ITGA11 overexpression rescued dexamethasone-induced suppression of differentiation.","method":"Transcriptomic analysis, overexpression/siRNA interference, GR antagonist (RU486), Western blot, differentiation assays in sheep fetal myoblasts","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue defining pathway, single lab","pmids":["41720752"],"is_preprint":false}],"current_model":"ITGA11 encodes a collagen-binding integrin alpha subunit (forming the α11β1 heterodimer) expressed predominantly in mesenchymal tissues; it localizes to focal adhesions and signals through FAK/PI3K/Akt and MAPK pathways to regulate fibroblast activation, ECM remodeling, osteogenic differentiation, and myoblast differentiation, while in cancer-associated fibroblasts it interacts with SELE on lymphatic endothelial cells to activate SRC-p-VEGFR3-MAPK signaling and promote lymphangiogenesis; its expression is regulated upstream by progesterone, TGFβ1, FGF2 (via ERK1/2), NAT10-mediated ac4C modification of C/EBPβ mRNA, and by multiple miRNAs targeting its 3' UTR."},"narrative":{"mechanistic_narrative":"ITGA11 encodes a collagen-binding integrin alpha subunit expressed predominantly in mesenchymal tissues including bone, cartilage, cardiac and skeletal muscle, with a large I-domain-containing extracellular region, a transmembrane domain, and a short cytoplasmic tail bearing an incompletely conserved GFFKR motif [PMID:10486209]. As a focal adhesion component, it transduces signals through FAK-anchored cascades: it activates PI3K/Akt to drive osteogenic differentiation of bone marrow mesenchymal stem cells [PMID:39566247], and engages a FAK/Paxillin–Akt–GSK3β axis to promote myoblast differentiation [PMID:41720752]. In cancer-associated fibroblasts, ITGA11 acts as a ligand-engaging receptor that binds SELE (E-selectin) on lymphatic endothelial cells to activate SRC–p-VEGFR3–MAPK signaling and promote lymphangiogenesis [PMID:38428409]. ITGA11 also drives fibrotic and EMT programs, promoting fibroblast activation and ECM production in pulmonary fibrosis [PMID:42090905] and lens epithelial–mesenchymal transition via PTGS2 (COX-2) induction and arachidonic acid reprogramming [PMID:42061596]. Its expression is set by a mesenchymal-selective promoter with defined silencer and enhancer regions [PMID:12392762] and is regulated by progesterone [PMID:20959644], by FGF2 overriding TGFβ1 through ERK1/2 [PMID:26403263], by NAT10/ac4C-stabilized C/EBPβ transcriptional control [PMID:42090905], and by miRNA targeting of its 3' UTR [PMID:26194885]. Loss of Itga11 reduces inflammatory fibroblast and immune cell accumulation in psoriasiform skin disease [PMID:37565309].","teleology":[{"year":1999,"claim":"Established the molecular identity of ITGA11 as a new collagen-binding integrin alpha subunit, defining its domain architecture and mesenchymal expression pattern.","evidence":"cDNA cloning, sequence/domain analysis, chromosomal mapping, and tissue expression profiling","pmids":["10486209"],"confidence":"High","gaps":["No functional ligand-binding or signaling assays in the founding study","Beta partner and heterodimer behavior not addressed here"]},{"year":2002,"claim":"Defined the genomic structure and the cis-regulatory logic controlling mesenchymal-selective alpha11 transcription.","evidence":"Genomic PCR, TSS mapping by oligo-capping, and luciferase promoter reporter dissection in HT1080 cells","pmids":["12392762"],"confidence":"Medium","gaps":["Trans-acting factors binding the silencer/enhancer not identified","Single cell-line promoter context"]},{"year":2010,"claim":"Linked ITGA11 to hormonal control, showing progesterone raises its expression and associated focal adhesion kinase phosphorylation in cervical stroma.","evidence":"Rat gestation model and primary cervical stromal cultures with mifepristone and ERK1/2 inhibitors, Western blot","pmids":["20959644"],"confidence":"Medium","gaps":["Direct transcriptional mechanism of progesterone on ITGA11 not resolved","Correlative pFAK linkage, not causal"]},{"year":2015,"claim":"Established that growth factor inputs converge on ITGA11 expression, with FGF2 dominantly suppressing TGFβ1-driven expression through ERK1/2 and removing alpha11 from focal adhesions.","evidence":"qRT-PCR, Western blot, immunocytochemistry, and ERK1/2 inhibition in human dermal fibroblasts","pmids":["26403263"],"confidence":"Medium","gaps":["Promoter elements mediating FGF2/ERK repression not mapped","Functional consequence of focal adhesion removal not quantified"]},{"year":2015,"claim":"Identified post-transcriptional control of Itga11 by miR-126a-3p and placed it in an endometrial implantation pathway.","evidence":"3' UTR luciferase reporter, in vivo miR-126a-3p inhibition, Transwell migration/invasion assays","pmids":["26194885"],"confidence":"Medium","gaps":["Itga11 contribution to implantation phenotype not isolated from other miR-126a-3p targets","No direct Itga11 rescue"]},{"year":2023,"claim":"Demonstrated a causal role for ITGA11 in inflammatory disease, with knockout reducing fibroblast and immune cell accumulation in psoriasiform dermatitis.","evidence":"Itga11 knockout mouse, histopathology, skin transcriptomics, immunofluorescence","pmids":["37565309"],"confidence":"Medium","gaps":["Molecular signaling driving immune cell recruitment not defined","ECM ligand engaged in skin not identified"]},{"year":2024,"claim":"Revealed an unexpected ligand-receptor role: ITGA11 on CAFs binds SELE on lymphatic endothelium to trigger SRC-p-VEGFR3-MAPK signaling and promote lymphangiogenesis in bladder cancer.","evidence":"scRNA-seq, spatial transcriptomics, CAF-specific knockout mouse, co-culture signaling assays, multicenter clinical cohort","pmids":["38428409"],"confidence":"High","gaps":["Structural basis of ITGA11-SELE engagement not resolved","Whether classical collagen binding contributes to this axis unaddressed"]},{"year":2024,"claim":"Showed ITGA11 promotes osteogenic differentiation while restraining proliferation and angiogenesis in mesenchymal stem cells via PI3K/Akt signaling.","evidence":"siRNA and overexpression in rat BMSCs under hypoxia, proliferation/tube-formation/alizarin red assays, Western blot, transcriptomics","pmids":["39566247"],"confidence":"Medium","gaps":["Upstream ECM ligand activating PI3K/Akt not identified","Single-species in vitro model"]},{"year":2025,"claim":"Connected mechanical stimulation to ITGA11, with LIPUS upregulating it and driving osteogenesis through a FAK/PI3K/AKT/GSK3β/β-catenin focal adhesion pathway.","evidence":"Rat implant model with micro-CT, in vitro BMSC differentiation assays, Western blot, bioinformatics","pmids":["39755586"],"confidence":"Medium","gaps":["Mechanism by which LIPUS induces ITGA11 not defined","Necessity of ITGA11 for LIPUS effect not tested by loss-of-function"]},{"year":2026,"claim":"Defined an epistatic regulatory axis in pulmonary fibrosis where NAT10/ac4C-stabilized C/EBPβ transcriptionally upregulates ITGA11 to drive fibroblast activation and ECM production.","evidence":"NAT10 inhibitor (Remodelin) in vivo/in vitro, ac4C analysis, rescue experiments, Western blot","pmids":["42090905"],"confidence":"Medium","gaps":["Direct C/EBPβ binding at the ITGA11 promoter not shown","Downstream ITGA11 signaling in fibrosis not dissected"]},{"year":2026,"claim":"Showed ITGA11 promotes lens EMT by inducing PTGS2 and arachidonic acid metabolic reprogramming toward prostaglandins.","evidence":"siRNA knockdown, RNA-seq, lipidomics, scratch assay, COX-2 inhibitor (celecoxib) in lens epithelial cells","pmids":["42061596"],"confidence":"Medium","gaps":["Link between integrin signaling and PTGS2 induction not mechanistically defined","TGFβ2 input relationship not fully resolved"]},{"year":2026,"claim":"Established that ITGA11 promotes myoblast differentiation through a FAK/Paxillin-Akt-GSK3β cascade that glucocorticoid signaling suppresses.","evidence":"Overexpression/siRNA, GR antagonist (RU486), Western blot, differentiation assays in sheep fetal myoblasts","pmids":["41720752"],"confidence":"Medium","gaps":["Direct GR regulation of ITGA11 expression not demonstrated","Single-species myoblast model"]},{"year":null,"claim":"The molecular determinants of ITGA11 ligand selectivity (collagen versus SELE) and the structural basis of its focal-adhesion signaling output remain unresolved.","evidence":"No structural or reconstitution study in the available corpus addresses ligand discrimination or cytoplasmic-tail signaling mechanism","pmids":[],"confidence":"Low","gaps":["No structural model of the I-domain bound to ligand","Beta1 partner contribution to downstream signaling not directly tested","Cytoplasmic GFFKR motif function not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,11]}],"complexes":["focal adhesion"],"partners":["SELE","FAK","PXN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKX5","full_name":"Integrin alpha-11","aliases":[],"length_aa":1188,"mass_kda":133.5,"function":"Integrin alpha-11/beta-1 is a receptor for collagen","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UKX5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA11","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA11","total_profiled":1310},"omim":[{"mim_id":"612632","title":"USHER SYNDROME, TYPE IH; USH1H","url":"https://www.omim.org/entry/612632"},{"mim_id":"604789","title":"INTEGRIN, ALPHA-11; ITGA11","url":"https://www.omim.org/entry/604789"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":74.1},{"tissue":"endometrium 1","ntpm":28.8}],"url":"https://www.proteinatlas.org/search/ITGA11"},"hgnc":{"alias_symbol":["HsT18964"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKX5","domains":[{"cath_id":"3.40.50.410","chopping":"164-217_226-233_246-355","consensus_level":"high","plddt":89.9334,"start":164,"end":355},{"cath_id":"2.60.40.1460","chopping":"639-776","consensus_level":"high","plddt":85.8318,"start":639,"end":776},{"cath_id":"2.60.40.1510","chopping":"792-954","consensus_level":"high","plddt":86.4497,"start":792,"end":954},{"cath_id":"2.60.40.1530","chopping":"958-1134","consensus_level":"high","plddt":83.909,"start":958,"end":1134},{"cath_id":"2.40.128","chopping":"29-154","consensus_level":"medium","plddt":90.7382,"start":29,"end":154}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKX5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKX5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKX5-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA11","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA11"},"sequence":{"accession":"Q9UKX5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKX5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKX5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKX5"}},"corpus_meta":[{"pmid":"38428409","id":"PMC_38428409","title":"PDGFRα+ITGA11+ fibroblasts foster early-stage cancer lymphovascular invasion and lymphatic metastasis via ITGA11-SELE interplay.","date":"2024","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/38428409","citation_count":122,"is_preprint":false},{"pmid":"17016581","id":"PMC_17016581","title":"Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer.","date":"2006","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/17016581","citation_count":89,"is_preprint":false},{"pmid":"33174014","id":"PMC_33174014","title":"Long non‑coding RNA FEZF1‑AS1 facilitates non‑small cell lung cancer progression via the ITGA11/miR‑516b‑5p axis.","date":"2020","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33174014","citation_count":41,"is_preprint":false},{"pmid":"34182990","id":"PMC_34182990","title":"CircRNA_100290 promotes GC cell proliferation and invasion via the miR-29b-3p/ITGA11 axis and is regulated by EIF4A3.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34182990","citation_count":37,"is_preprint":false},{"pmid":"10486209","id":"PMC_10486209","title":"Cloning, sequence analysis, and chromosomal localization of the novel human integrin alpha11 subunit (ITGA11).","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10486209","citation_count":27,"is_preprint":false},{"pmid":"26194885","id":"PMC_26194885","title":"Mmu-miR-126a-3p plays a role in murine embryo implantation by regulating Itga11.","date":"2015","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/26194885","citation_count":25,"is_preprint":false},{"pmid":"20959644","id":"PMC_20959644","title":"Progesterone modulates integrin {alpha}2 (ITGA2) and {alpha}11 (ITGA11) in the pregnant cervix.","date":"2010","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/20959644","citation_count":19,"is_preprint":false},{"pmid":"12392762","id":"PMC_12392762","title":"Analysis of the human integrin alpha11 gene (ITGA11) and its promoter.","date":"2002","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/12392762","citation_count":18,"is_preprint":false},{"pmid":"26403263","id":"PMC_26403263","title":"FGF2 Overrides TGFβ1-Driven Integrin ITGA11 Expression in Human Dermal Fibroblasts.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26403263","citation_count":18,"is_preprint":false},{"pmid":"36484486","id":"PMC_36484486","title":"Depletion of circPDSS1 inhibits ITGA11 production to confer cisplatin sensitivity through miR-515-5p in gastric cancer.","date":"2022","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/36484486","citation_count":7,"is_preprint":false},{"pmid":"37565309","id":"PMC_37565309","title":"Forward genetics and functional analysis highlight Itga11 as a modulator of murine psoriasiform dermatitis.","date":"2023","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37565309","citation_count":5,"is_preprint":false},{"pmid":"39791208","id":"PMC_39791208","title":"NGR1 reduces neuronal apoptosis through regulation of ITGA11 following subarachnoid hemorrhage.","date":"2025","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/39791208","citation_count":2,"is_preprint":false},{"pmid":"39755586","id":"PMC_39755586","title":"LIPUS promotes osteogenic differentiation of rat BMSCs and osseointegration of dental implants by regulating ITGA11 and focal adhesion pathway.","date":"2025","source":"BMC oral 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It belongs to the collagen-binding integrin alpha subunit group but differs by an incompletely preserved cytoplasmic GFFKR motif. Transcripts were found predominantly in bone, cartilage, cardiac muscle, and skeletal muscle.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal localization, tissue expression profiling\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular characterization of the gene product with sequence, structural domain analysis, and chromosomal mapping; foundational characterization paper\",\n      \"pmids\": [\"10486209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The ITGA11 gene spans 30 exons; a unique inserted region encoding amino acids 804-826 is located at the start of exon 20. A major transcription start site was mapped 30 nucleotides upstream of the translation start. Promoter analysis in fibrosarcoma HT1080 cells identified a core promoter [nt -127 to +25], a silencer region [nt -400 to -127], and an enhancer region [nt -1519 to -400] important for alpha11 transcription in mesenchymal cells.\",\n      \"method\": \"Genomic PCR, oligo-capping technique for TSS mapping, luciferase promoter reporter assays\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct functional promoter dissection with reporter assays and TSS mapping, single lab\",\n      \"pmids\": [\"12392762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Progesterone increases ITGA11 expression and phosphorylated focal adhesion kinase (pFAK) in rat cervical stromal cells, and this effect is blocked by the progesterone antagonist mifepristone. Mifepristone conversely increases ITGA2 expression via ERK1/2 signaling, and ERK1/2 inhibition abrogates mifepristone-induced ITGA2 upregulation. ITGA11 expression peaks at mid-gestation (day 18) and declines thereafter.\",\n      \"method\": \"In vivo rat gestation model, primary rat cervical stromal cell cultures, Western blot, pharmacological inhibitors (mifepristone, ERK1/2 inhibitor)\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with pharmacological manipulation and Western blot, single lab with two orthogonal approaches\",\n      \"pmids\": [\"20959644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FGF2 overrides TGFβ1-driven ITGA11 expression in human dermal fibroblasts. FGF2-induced downregulation of ITGA11 requires ERK1/2 activity, and in the presence of FGF2, TGFβ1 cannot rescue ITGA11 expression. Loss of ITGA11 is associated with its removal from focal adhesions.\",\n      \"method\": \"RT-PCR, qRT-PCR, Western blotting, immunocytochemistry, pharmacological ERK1/2 inhibition\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab, functional inhibitor experiments defining pathway dependence\",\n      \"pmids\": [\"26403263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-126a-3p directly targets the 3' UTR of Itga11 mRNA, inhibiting its translation and affecting mRNA stability. Loss of miR-126a-3p function significantly reduced the number of embryo implantation sites in vivo, and miR-126a-3p overexpression promoted cell migratory and invasive capacity in vitro, placing Itga11 downstream of miR-126a-3p in endometrial function during embryo implantation.\",\n      \"method\": \"Luciferase reporter assay for 3' UTR targeting, in vivo loss-of-function (miR-126a-3p inhibition), Transwell migration/invasion assay\",\n      \"journal\": \"Reproductive biomedicine online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3' UTR validation by luciferase assay plus in vivo functional readout, single lab\",\n      \"pmids\": [\"26194885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Itga11 gene-deleted (Itga11-/-) mice show substantially reduced severity of imiquimod-induced psoriasiform dermatitis, with reduced numbers of fibroblasts, macrophages, T cells, and tissue-resident memory T cells in skin. Differentially expressed genes in Itga11-/- vs. WT mice during inflammation were enriched in extracellular matrix organization, immune system, and lipid metabolism pathways.\",\n      \"method\": \"Forward genetics (strain comparison), Itga11 knockout mouse model, histopathology, skin transcriptomics, immunofluorescence for immune cells\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"37565309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDGFRα+ITGA11+ cancer-associated fibroblasts (CAFs) promote lymphangiogenesis in early-stage bladder cancer by engaging ITGA11 with its surface receptor SELE (E-selectin) on lymphatic endothelial cells, activating the SRC-p-VEGFR3-MAPK pathway. These CAFs also secrete CHI3L1 to align the surrounding matrix and assist cancer cell intravasation.\",\n      \"method\": \"Single-cell RNA sequencing, spatial transcriptomics, CAF-specific deficient mouse model, co-culture and signaling assays, multicenter clinical cohort validation\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific knockout mouse model combined with scRNA-seq, spatial transcriptomics, signaling pathway dissection, and large clinical cohort, multiple orthogonal approaches\",\n      \"pmids\": [\"38428409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Itga11 overexpression in rat bone marrow mesenchymal stem cells (rBMSCs) under hypoxia inhibits proliferation and angiogenesis while enhancing osteogenic differentiation, whereas Itga11 knockdown has the opposite effects. Mechanistically, Itga11 activates the PI3K/Akt signaling pathway in rBMSCs.\",\n      \"method\": \"siRNA knockdown, pcDNA overexpression, CCK-8 proliferation assay, tube formation assay, alizarin red staining, Western blot, transcriptomic analysis\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with multiple orthogonal readouts in single lab\",\n      \"pmids\": [\"39566247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LIPUS upregulates ITGA11 expression in rat BMSCs and promotes osteogenic differentiation by activating the FAK/PI3K/AKT/GSK3β/β-catenin focal adhesion pathway. LIPUS also enhanced implant osseointegration in rats.\",\n      \"method\": \"In vivo rat implant model (micro-CT, toluidine blue staining), in vitro BMSC assays (ALP staining, alizarin red staining, RT-PCR, Western blot), bioinformatics (GO/KEGG, random forest)\",\n      \"journal\": \"BMC oral health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with pathway validation by Western blot, single lab\",\n      \"pmids\": [\"39755586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA11 promotes lens epithelial-mesenchymal transition (EMT) by driving PTGS2 (COX-2) induction, which mediates arachidonic acid metabolic reprogramming toward pro-inflammatory prostaglandins. ITGA11 knockdown impairs lens epithelial cell migration and suppresses TGFβ2-induced myofibroblast transdifferentiation, reducing α-SMA and fibronectin expression. Pharmacologic inhibition of PTGS2 also suppressed EMT-associated phenotypes.\",\n      \"method\": \"siRNA knockdown, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence, scratch assay, lipidomic profiling, COX-2 inhibitor (celecoxib) treatment\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts including lipidomics and transcriptomics, single lab\",\n      \"pmids\": [\"42061596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAT10, via RNA ac4C modification, stabilizes C/EBPβ mRNA, which transcriptionally upregulates ITGA11, thereby promoting fibroblast activation and extracellular matrix production in pulmonary fibrosis. Rescue experiments confirmed that the pro-fibrotic effects of NAT10 are dependent on the C/EBPβ-ITGA11 axis.\",\n      \"method\": \"NAT10 inhibitor (Remodelin) in vivo and in vitro, ac4C mRNA modification analysis, rescue experiments, Western blot, gene expression analysis\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis-like rescue experiments defining pathway order (NAT10→C/EBPβ→ITGA11), multiple methods, single lab\",\n      \"pmids\": [\"42090905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA11 promotes myoblast differentiation via the FAK/Paxillin-Akt-GSK3β pathway. Dexamethasone-induced stress suppresses myogenic differentiation through glucocorticoid receptor (GR)-mediated suppression of the ITGA11-FAK/Paxillin-Akt-GSK3β cascade. ITGA11 overexpression rescued dexamethasone-induced suppression of differentiation.\",\n      \"method\": \"Transcriptomic analysis, overexpression/siRNA interference, GR antagonist (RU486), Western blot, differentiation assays in sheep fetal myoblasts\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pharmacological rescue defining pathway, single lab\",\n      \"pmids\": [\"41720752\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA11 encodes a collagen-binding integrin alpha subunit (forming the α11β1 heterodimer) expressed predominantly in mesenchymal tissues; it localizes to focal adhesions and signals through FAK/PI3K/Akt and MAPK pathways to regulate fibroblast activation, ECM remodeling, osteogenic differentiation, and myoblast differentiation, while in cancer-associated fibroblasts it interacts with SELE on lymphatic endothelial cells to activate SRC-p-VEGFR3-MAPK signaling and promote lymphangiogenesis; its expression is regulated upstream by progesterone, TGFβ1, FGF2 (via ERK1/2), NAT10-mediated ac4C modification of C/EBPβ mRNA, and by multiple miRNAs targeting its 3' UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA11 encodes a collagen-binding integrin alpha subunit expressed predominantly in mesenchymal tissues including bone, cartilage, cardiac and skeletal muscle, with a large I-domain-containing extracellular region, a transmembrane domain, and a short cytoplasmic tail bearing an incompletely conserved GFFKR motif [#0]. As a focal adhesion component, it transduces signals through FAK-anchored cascades: it activates PI3K/Akt to drive osteogenic differentiation of bone marrow mesenchymal stem cells [#7], and engages a FAK/Paxillin–Akt–GSK3\\u03b2 axis to promote myoblast differentiation [#11]. In cancer-associated fibroblasts, ITGA11 acts as a ligand-engaging receptor that binds SELE (E-selectin) on lymphatic endothelial cells to activate SRC–p-VEGFR3–MAPK signaling and promote lymphangiogenesis [#6]. ITGA11 also drives fibrotic and EMT programs, promoting fibroblast activation and ECM production in pulmonary fibrosis [#10] and lens epithelial–mesenchymal transition via PTGS2 (COX-2) induction and arachidonic acid reprogramming [#9]. Its expression is set by a mesenchymal-selective promoter with defined silencer and enhancer regions [#1] and is regulated by progesterone [#2], by FGF2 overriding TGF\\u03b21 through ERK1/2 [#3], by NAT10/ac4C-stabilized C/EBP\\u03b2 transcriptional control [#10], and by miRNA targeting of its 3' UTR [#4]. Loss of Itga11 reduces inflammatory fibroblast and immune cell accumulation in psoriasiform skin disease [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the molecular identity of ITGA11 as a new collagen-binding integrin alpha subunit, defining its domain architecture and mesenchymal expression pattern.\",\n      \"evidence\": \"cDNA cloning, sequence/domain analysis, chromosomal mapping, and tissue expression profiling\",\n      \"pmids\": [\"10486209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional ligand-binding or signaling assays in the founding study\", \"Beta partner and heterodimer behavior not addressed here\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the genomic structure and the cis-regulatory logic controlling mesenchymal-selective alpha11 transcription.\",\n      \"evidence\": \"Genomic PCR, TSS mapping by oligo-capping, and luciferase promoter reporter dissection in HT1080 cells\",\n      \"pmids\": [\"12392762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors binding the silencer/enhancer not identified\", \"Single cell-line promoter context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked ITGA11 to hormonal control, showing progesterone raises its expression and associated focal adhesion kinase phosphorylation in cervical stroma.\",\n      \"evidence\": \"Rat gestation model and primary cervical stromal cultures with mifepristone and ERK1/2 inhibitors, Western blot\",\n      \"pmids\": [\"20959644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism of progesterone on ITGA11 not resolved\", \"Correlative pFAK linkage, not causal\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that growth factor inputs converge on ITGA11 expression, with FGF2 dominantly suppressing TGF\\u03b21-driven expression through ERK1/2 and removing alpha11 from focal adhesions.\",\n      \"evidence\": \"qRT-PCR, Western blot, immunocytochemistry, and ERK1/2 inhibition in human dermal fibroblasts\",\n      \"pmids\": [\"26403263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter elements mediating FGF2/ERK repression not mapped\", \"Functional consequence of focal adhesion removal not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified post-transcriptional control of Itga11 by miR-126a-3p and placed it in an endometrial implantation pathway.\",\n      \"evidence\": \"3' UTR luciferase reporter, in vivo miR-126a-3p inhibition, Transwell migration/invasion assays\",\n      \"pmids\": [\"26194885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Itga11 contribution to implantation phenotype not isolated from other miR-126a-3p targets\", \"No direct Itga11 rescue\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a causal role for ITGA11 in inflammatory disease, with knockout reducing fibroblast and immune cell accumulation in psoriasiform dermatitis.\",\n      \"evidence\": \"Itga11 knockout mouse, histopathology, skin transcriptomics, immunofluorescence\",\n      \"pmids\": [\"37565309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signaling driving immune cell recruitment not defined\", \"ECM ligand engaged in skin not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an unexpected ligand-receptor role: ITGA11 on CAFs binds SELE on lymphatic endothelium to trigger SRC-p-VEGFR3-MAPK signaling and promote lymphangiogenesis in bladder cancer.\",\n      \"evidence\": \"scRNA-seq, spatial transcriptomics, CAF-specific knockout mouse, co-culture signaling assays, multicenter clinical cohort\",\n      \"pmids\": [\"38428409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ITGA11-SELE engagement not resolved\", \"Whether classical collagen binding contributes to this axis unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ITGA11 promotes osteogenic differentiation while restraining proliferation and angiogenesis in mesenchymal stem cells via PI3K/Akt signaling.\",\n      \"evidence\": \"siRNA and overexpression in rat BMSCs under hypoxia, proliferation/tube-formation/alizarin red assays, Western blot, transcriptomics\",\n      \"pmids\": [\"39566247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream ECM ligand activating PI3K/Akt not identified\", \"Single-species in vitro model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected mechanical stimulation to ITGA11, with LIPUS upregulating it and driving osteogenesis through a FAK/PI3K/AKT/GSK3\\u03b2/\\u03b2-catenin focal adhesion pathway.\",\n      \"evidence\": \"Rat implant model with micro-CT, in vitro BMSC differentiation assays, Western blot, bioinformatics\",\n      \"pmids\": [\"39755586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LIPUS induces ITGA11 not defined\", \"Necessity of ITGA11 for LIPUS effect not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an epistatic regulatory axis in pulmonary fibrosis where NAT10/ac4C-stabilized C/EBP\\u03b2 transcriptionally upregulates ITGA11 to drive fibroblast activation and ECM production.\",\n      \"evidence\": \"NAT10 inhibitor (Remodelin) in vivo/in vitro, ac4C analysis, rescue experiments, Western blot\",\n      \"pmids\": [\"42090905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct C/EBP\\u03b2 binding at the ITGA11 promoter not shown\", \"Downstream ITGA11 signaling in fibrosis not dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed ITGA11 promotes lens EMT by inducing PTGS2 and arachidonic acid metabolic reprogramming toward prostaglandins.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, lipidomics, scratch assay, COX-2 inhibitor (celecoxib) in lens epithelial cells\",\n      \"pmids\": [\"42061596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between integrin signaling and PTGS2 induction not mechanistically defined\", \"TGF\\u03b22 input relationship not fully resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established that ITGA11 promotes myoblast differentiation through a FAK/Paxillin-Akt-GSK3\\u03b2 cascade that glucocorticoid signaling suppresses.\",\n      \"evidence\": \"Overexpression/siRNA, GR antagonist (RU486), Western blot, differentiation assays in sheep fetal myoblasts\",\n      \"pmids\": [\"41720752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GR regulation of ITGA11 expression not demonstrated\", \"Single-species myoblast model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular determinants of ITGA11 ligand selectivity (collagen versus SELE) and the structural basis of its focal-adhesion signaling output remain unresolved.\",\n      \"evidence\": \"No structural or reconstitution study in the available corpus addresses ligand discrimination or cytoplasmic-tail signaling mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the I-domain bound to ligand\", \"Beta1 partner contribution to downstream signaling not directly tested\", \"Cytoplasmic GFFKR motif function not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005925\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"complexes\": [\"focal adhesion\"],\n    \"partners\": [\"SELE\", \"FAK\", \"PXN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}