ITGA11

ITGA11 encodes integrin alpha-11, a collagen-binding integrin alpha subunit that heterodimerizes with beta-1 to mediate cell-matrix and cell-cell adhesion, fibroblast-driven extracellular matrix remodeling, and downstream intracellular signaling through the FAK/PI3K/AKT and SRC/MAPK pathways. The alpha-11 subunit contains a 207-residue I-domain critical for collagen recognition, a transmembrane segment, and a short cytoplasmic tail with a variant GFFKR motif, and its transcription in mesenchymal cells is driven by a defined core promoter with distinct silencer and enhancer elements (PMID:10486209, PMID:12392762). ITGA11 expression is post-transcriptionally regulated by multiple miRNA–ceRNA axes (miR-516b-5p, miR-29b-3p, miR-515-5p, miR-126a-3p), and at the signaling level it activates FAK/Paxillin–AKT–GSK3β to promote osteogenic and myogenic differentiation, while on cancer-associated fibroblasts it directly engages E-selectin (SELE) on lymphatic endothelial cells to activate SRC–pVEGFR3–MAPK-dependent lymphangiogenesis (PMID:33174014, PMID:38428409, PMID:39755586, PMID:41720752). Genetic deletion of Itga11 in mice markedly attenuates psoriasiform skin inflammation by reducing fibroblast and immune cell infiltration and altering ECM-organization and immune transcriptional programs (PMID:37565309).

1. 1999 High

   Cloning of ITGA11 established it as a new collagen-receptor integrin alpha subunit, resolving its domain architecture (I-domain, transmembrane, short cytoplasmic tail with variant GFFKR motif) and chromosomal location (15q22.3-q23).

   Evidence cDNA cloning, sequence analysis, and FISH/mapping in human cells

   PMID:10486209

   Open questions at the time

   • No ligand-binding specificity data at this stage
   • Beta-subunit pairing not experimentally confirmed here
   • No functional assays performed
2. 2002 High

   Promoter dissection revealed a modular transcriptional architecture (core promoter, silencer, enhancer) governing ITGA11 expression in mesenchymal cells, explaining its tissue-restricted expression pattern.

   Evidence Luciferase reporter constructs and oligo-capping in HT1080 fibrosarcoma cells

   PMID:12392762

   Open questions at the time

   • Trans-acting transcription factors binding these elements not identified
   • Regulation in non-mesenchymal contexts not tested
3. 2010 Medium

   Hormonal regulation of ITGA11 was demonstrated: progesterone upregulates ITGA11 and pFAK in cervical stromal cells, linking integrin alpha-11 to reproductive tissue remodeling.

   Evidence Western blot on primary rat cervical stromal cells with progesterone/mifepristone treatment

   PMID:20959644

   Open questions at the time

   • Mechanism of progesterone-mediated transcriptional or post-transcriptional upregulation not defined
   • Not confirmed in human tissue
4. 2015 Medium

   Two independent regulatory inputs were resolved: FGF2/ERK1/2 signaling dominantly suppresses ITGA11 even in the presence of TGFβ1 in dermal fibroblasts, while miR-126a-3p directly targets the ITGA11 3′ UTR to control endometrial cell migration during embryo implantation.

   Evidence RT-PCR, Western blot, ERK1/2 inhibition in fibroblasts; luciferase reporter and in vivo miR-126a-3p inhibition in mice

   PMID:26194885 PMID:26403263

   Open questions at the time

   • Whether FGF2 acts at the ITGA11 promoter or post-transcriptionally not resolved
   • In vivo implantation phenotype not rescued by ITGA11 re-expression
5. 2020 Medium

   A ceRNA regulatory paradigm was established: multiple non-coding RNAs (FEZF1-AS1/miR-516b-5p, circRNA_100290/miR-29b-3p, circPDSS1/miR-515-5p) converge on ITGA11 to modulate its expression in cancer contexts, controlling proliferation, migration, EMT, and chemoresistance.

   Evidence Dual-luciferase reporter, RNA immunoprecipitation, knockdown/overexpression, and xenograft models in NSCLC and gastric cancer cells

   PMID:33174014 PMID:34182990 PMID:36484486

   Open questions at the time

   • Functional contribution of ITGA11 itself versus other miRNA targets not individually dissected
   • ceRNA axes not validated across independent labs
   • Endogenous stoichiometry of ceRNA competition not assessed
6. 2023 High

   Genetic loss-of-function in Itga11-knockout mice demonstrated a non-redundant role in skin inflammation, with Itga11 deletion substantially reducing psoriasiform dermatitis severity, fibroblast numbers, and immune cell infiltration.

   Evidence Itga11−/− knockout mice with imiquimod-induced psoriasis, skin transcriptomics, immunohistochemistry, forward genetics across 13 inbred strains

   PMID:37565309

   Open questions at the time

   • Whether the phenotype is fibroblast-intrinsic or involves immune cell-expressed ITGA11 not resolved
   • Downstream signaling pathway mediating immune recruitment not defined
7. 2024 High

   ITGA11 on PDGFRα+ cancer-associated fibroblasts was shown to directly bind E-selectin (SELE) on lymphatic endothelial cells, activating SRC–pVEGFR3–MAPK signaling to drive lymphangiogenesis and facilitate cancer cell intravasation — establishing a cell-cell adhesion function beyond classical collagen binding.

   Evidence Single-cell RNA-seq, spatial transcriptomics, PDGFRα+ITGA11+ CAF-specific deficient mouse model, 910-case clinical cohort

   PMID:38428409

   Open questions at the time

   • Structural basis of ITGA11–SELE interaction not determined
   • Whether beta-1 subunit is required for SELE binding not tested
8. 2024 Medium

   ITGA11 was positioned as a key effector of the FAK/PI3K/AKT pathway in osteogenic differentiation: overexpression in bone marrow MSCs under hypoxia promoted osteogenesis while inhibiting proliferation and angiogenesis, and LIPUS-mediated ITGA11 upregulation enhanced osseointegration in vivo.

   Evidence Gain- and loss-of-function in rat BMSCs, in vivo rat femur implant model with micro-CT and signaling pathway analysis

   PMID:39566247 PMID:39755586

   Open questions at the time

   • Direct collagen-binding requirement for osteogenic signaling not tested
   • Pathway specificity relative to other integrins not established
9. 2026 Medium

   ITGA11 was shown to promote myoblast differentiation through FAK/Paxillin–Akt–GSK3β signaling, and glucocorticoid receptor-mediated transcriptional suppression of ITGA11 was identified as the mechanism of dexamethasone-induced differentiation arrest.

   Evidence Overexpression/siRNA, Western blot, GR antagonist RU486, sheep fetal myoblasts

   PMID:41720752

   Open questions at the time

   • Whether GR directly binds the ITGA11 promoter not demonstrated
   • Applicability to human myogenesis not tested

• The structural basis of ITGA11's dual ligand recognition (collagen I and E-selectin), the identity of transcription factors acting on its promoter elements, and the fibroblast-intrinsic versus immune cell-mediated contributions to its inflammatory phenotype remain unresolved.
• No crystal structure of ITGA11 I-domain with collagen or SELE
• Trans-acting factors for the defined promoter silencer/enhancer unknown
• Conditional cell-type-specific knockouts in inflammation not reported