ITGA11

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).

1. 1999 High

   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

   PMID:10486209

   Open questions at the time

   • No functional ligand-binding or signaling assays in the founding study
   • Beta partner and heterodimer behavior not addressed here
2. 2002 Medium

   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

   PMID:12392762

   Open questions at the time

   • Trans-acting factors binding the silencer/enhancer not identified
   • Single cell-line promoter context
3. 2010 Medium

   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

   PMID:20959644

   Open questions at the time

   • Direct transcriptional mechanism of progesterone on ITGA11 not resolved
   • Correlative pFAK linkage, not causal
4. 2015 Medium

   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

   PMID:26403263

   Open questions at the time

   • Promoter elements mediating FGF2/ERK repression not mapped
   • Functional consequence of focal adhesion removal not quantified
5. 2015 Medium

   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

   PMID:26194885

   Open questions at the time

   • Itga11 contribution to implantation phenotype not isolated from other miR-126a-3p targets
   • No direct Itga11 rescue
6. 2023 Medium

   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

   PMID:37565309

   Open questions at the time

   • Molecular signaling driving immune cell recruitment not defined
   • ECM ligand engaged in skin not identified
7. 2024 High

   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

   PMID:38428409

   Open questions at the time

   • Structural basis of ITGA11-SELE engagement not resolved
   • Whether classical collagen binding contributes to this axis unaddressed
8. 2024 Medium

   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

   PMID:39566247

   Open questions at the time

   • Upstream ECM ligand activating PI3K/Akt not identified
   • Single-species in vitro model
9. 2025 Medium

   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

   PMID:39755586

   Open questions at the time

   • Mechanism by which LIPUS induces ITGA11 not defined
   • Necessity of ITGA11 for LIPUS effect not tested by loss-of-function
10. 2026 Medium

    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

    PMID:42090905

    Open questions at the time

    • Direct C/EBPβ binding at the ITGA11 promoter not shown
    • Downstream ITGA11 signaling in fibrosis not dissected
11. 2026 Medium

    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

    PMID:42061596

    Open questions at the time

    • Link between integrin signaling and PTGS2 induction not mechanistically defined
    • TGFβ2 input relationship not fully resolved
12. 2026 Medium

    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

    PMID:41720752

    Open questions at the time

    • Direct GR regulation of ITGA11 expression not demonstrated
    • Single-species myoblast model

• The molecular determinants of ITGA11 ligand selectivity (collagen versus SELE) and the structural basis of its focal-adhesion signaling output remain unresolved.
• 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