Affinage

ITGA8

Integrin alpha-8 · UniProt P53708

Length
1063 aa
Mass
117.5 kDa
Annotated
2026-06-10
26 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ITGA8 encodes the α8 integrin subunit, an extracellular matrix adhesion and signaling receptor expressed in mesenchymal and smooth-muscle lineages that links matrix engagement to cytoskeletal remodeling, contractile gene programs, and fibrotic responses (PMID:36424917, PMID:41355531). During development it cooperates with the epithelial Fraser-complex protein Fras1 to drive epithelial–mesenchymal interactions, with Itga8 expressed in facial mesenchyme and loss producing pharyngeal pouch and skeletal defects (PMID:27265864). In smooth muscle, Itga8-expressing cells mark vascular and detrusor SMC populations in which YAP/TAZ and SRF/myocardin govern contractile gene expression and tissue contractility (PMID:36424917, PMID:37927241). In fibrotic disease ITGA8 has context-dependent roles: in renal interstitial fibrosis it attenuates TGF-β/SMAD signaling and fibroblast activation (PMID:26938996), whereas in neurogenic bladder it transduces Trem2+ macrophage-derived Fn1 signals through a FAK/RhoA/ROCK axis to activate fibroblasts and drive collagen deposition (PMID:41355531), and in hepatic stellate cells it promotes ECM accumulation through COL11A1 (PMID:40056500). In lung adenocarcinoma ITGA8 acts as a tumor suppressor, dampening FAK/SRC/AKT/MAPK signaling to sensitize cells to EGFR-TKIs (PMID:39809840) and restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition (PMID:41731056). ITGA8 expression is itself regulated epigenetically, being silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer (PMID:32953793).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2016 High

    Established that Itga8 functions in epithelial-mesenchymal interactions during craniofacial development as a partner of the Fraser complex, defining a developmental adhesion role.

    Evidence Forward mutagenesis screen, CRISPR alleles, and double-mutant epistasis with fras1 in zebrafish, with complementary expression domains by in situ hybridization

    PMID:27265864

    Open questions at the time
    • Direct biochemical interaction of Itga8 with Fras1 not demonstrated
    • Mammalian relevance of this developmental role not shown
    • Downstream signaling not defined
  2. 2016 Medium

    Showed that Itga8 restrains rather than promotes fibrosis in the kidney by suppressing TGF-β/SMAD signaling and fibroblast activation, defining an anti-fibrotic function.

    Evidence Itga8-/- mice in the unilateral ureteral obstruction model with IHC for phospho-SMAD2/3, α-SMA, and immune-cell markers

    PMID:26938996

    Open questions at the time
    • Ligand engaging Itga8 in this context not identified
    • Mechanism linking Itga8 to SMAD attenuation unresolved
    • Single lab
  3. 2021 Medium

    Identified ITGA8 as a marker of a functionally distinct Schlemm's-canal-like contractile cell population in the trabecular meshwork, linking expression to aqueous outflow physiology.

    Evidence Magnetic-bead sorting of ITGA8+/- cells from human trabecular meshwork with FISH, flow cytometry, and gel contraction assays

    PMID:33961857

    Open questions at the time
    • Causal role of ITGA8 in the SC phenotype not tested by perturbation
    • Signaling downstream of ITGA8 in these cells unknown
  4. 2022 High

    Validated Itga8 as a vascular smooth-muscle-restricted marker and genetic tool, placing its expression upstream of SRF-dependent contractile gene regulation.

    Evidence Itga8-CreER knock-in mice compared to Myh11-CreER, conditional Srf deletion, blood pressure and contractility assays

    PMID:36424917

    Open questions at the time
    • Whether Itga8 protein itself drives the contractile program not directly tested
    • Defines expression domain, not Itga8 cell-autonomous function
  5. 2023 High

    Used the Itga8-CreER driver to define a YAP/TAZ–myocardin–SRF axis controlling detrusor smooth-muscle contractile identity and bladder function.

    Evidence Itga8-CreER-mediated conditional YAP/TAZ deletion in adult mice with RT-qPCR, Western blot, contraction assays, and YAP gain-of-function in HEK293

    PMID:37927241

    Open questions at the time
    • Result concerns YAP/TAZ biology using Itga8 as a tool, not ITGA8 function per se
    • ITGA8 receptor role in this circuit not addressed
  6. 2024 Low

    Placed ITGA8 downstream of a macrophage exosome-delivered circTMCO3/miR-515-5p axis promoting ovarian cancer malignancy.

    Evidence Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor and rescue experiments with xenografts

    PMID:38755265

    Open questions at the time
    • Abstract lacks explicit miR-515-5p/ITGA8 binding validation
    • Single lab
    • Oncogenic role here contrasts with tumor-suppressive role in lung adenocarcinoma
  7. 2025 High

    Resolved a pro-fibrotic signaling mechanism in which macrophage-derived Fn1 engages fibroblast ITGA8 to drive cytoskeletal remodeling and collagen deposition via FAK/RhoA/ROCK.

    Evidence scRNA-seq, conditional Col1a2-CreERT;Itga8fl/fl knockout, AAV knockdown, and macrophage depletion in a neurogenic bladder fibrosis model

    PMID:41355531

    Open questions at the time
    • Direct Fn1-ITGA8 binding affinity/specificity not quantified
    • Reconciliation with anti-fibrotic kidney role unresolved
  8. 2025 Medium

    Showed ITGA8 promotes hepatic stellate cell ECM accumulation through COL11A1, defining a pro-fibrotic role in liver.

    Evidence CCl4 fibrosis model with AAV2/6-shItga8 HSC-selective silencing, proteomics, Sirius Red staining, and collagen contraction assays

    PMID:40056500

    Open questions at the time
    • Mechanism by which ITGA8 controls COL11A1 not defined
    • Single lab
  9. 2025 Medium

    Identified ITGA8 as a tumor suppressor in lung adenocarcinoma that dampens FAK/SRC/AKT/MAPK signaling and sensitizes cells to EGFR-TKIs.

    Evidence Genome-wide CRISPR screen, ITGA8 knockdown/overexpression, Western blot, and H1975 xenografts

    PMID:39809840

    Open questions at the time
    • Ligand driving ITGA8 signaling in tumor cells not identified
    • Single lab
  10. 2026 Medium

    Defined ITGA8 as a metabolic gatekeeper restraining aerobic glycolysis via AMPK activation and mTOR/S6K/4EBP1 inhibition in lung adenocarcinoma.

    Evidence ITGA8 overexpression with Seahorse ECAR assays, glucose/lactate measurements, AMPK-inhibitor rescue, and xenografts

    PMID:41731056

    Open questions at the time
    • Mechanistic link from integrin ITGA8 to AMPK not delineated
    • Single lab
  11. 2020 Medium

    Established that ITGA8 is epigenetically silenced by ERα-dependent promoter hypermethylation in ER-positive breast cancer.

    Evidence Methylation-specific PCR, 5-aza-dC demethylation, estradiol treatment, and clinical tissue methylation analysis

    PMID:32953793

    Open questions at the time
    • Mechanism linking ERα to DNA methylation machinery at the ITGA8 promoter unknown
    • Functional consequence of silencing in breast cancer not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ITGA8 switches between anti-fibrotic and pro-fibrotic, and tumor-suppressive versus oncogenic, outcomes across tissues remains unresolved.
  • No unifying model for context-dependent ITGA8 signaling output
  • β1 partner subunit and exact ECM ligand repertoire not characterized in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
Complex memberships
Fraser protein complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 In zebrafish, Itga8 (expressed in facial mesenchyme) and Fras1 (expressed in epithelia) function together in epithelial-mesenchymal interactions during pharyngeal pouch morphogenesis; itga8 mutants display defective outpocketing of the first pharyngeal pouch and skeletal defects phenotypically similar to fras1 mutants, consistent with both proteins acting within the same Fraser protein complex. Forward mutagenesis screen, CRISPR allele generation, double-mutant analysis, in situ hybridization for expression domains, phenotypic comparison Developmental biology High 27265864
2016 In the unilateral ureteral obstruction model, Itga8 deficiency leads to increased phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive fibroblasts in the tubulointerstitium, as well as enhanced macrophage and T-cell infiltration, indicating that Itga8 attenuates renal interstitial fibrosis by suppressing TGF-β/SMAD signaling and fibroblast activation rather than by regulating cell turnover or apoptosis. Knockout mouse model (Itga8-/-) with UUO, immunohistochemistry for phospho-SMAD2/3, α-SMA, macrophage and T-cell markers; proliferation and apoptosis assays PloS one Medium 26938996
2022 Itga8-CreER knock-in mice drive tamoxifen-dependent recombination preferentially in vascular smooth muscle cells (but not visceral SMCs), and Srf knockout using this driver causes vascular contractile incompetence and failure to mount angiotensin II-induced blood pressure elevation, placing Itga8 expression in vascular SMCs upstream of SRF-dependent contractile gene regulation. Knock-in Cre mouse generation, tamoxifen induction, comparison with Myh11-CreER, conditional Srf knockout, blood pressure measurement, contractility assays Nature cardiovascular research High 36424917
2023 Using the Itga8-CreER model to delete YAP and TAZ in smooth muscle cells, YAP/TAZ were found to regulate myocardin (Myocd) expression and SRF levels in bladder detrusor, which in turn drives contractile gene expression, smooth muscle-specific splicing, and bladder contractility; loss of YAP/TAZ reduced cholinergic receptor expression and impaired carbachol- and myosin phosphatase inhibitor-induced contraction. Itga8-CreER-mediated conditional deletion of YAP/TAZ in adult mice, RT-qPCR, Western blot, gel contraction assay, constitutively active YAP overexpression in HEK293 cells American journal of physiology. Cell physiology High 37927241
2025 In neurogenic bladder fibrosis, Itga8+ fibroblasts coordinate cytoskeletal remodeling via the FAK/RhoA/ROCK signaling axis; Trem2+ macrophage-secreted Fn1 engages Itga8 on fibroblasts to activate them, and conditional deletion (Col1a2-CreERT; Itga8fl/fl) or local Itga8 knockdown attenuates collagen deposition and restores voiding efficiency. Single-cell RNA sequencing, conditional knockout (Col1a2-CreERT; Itga8fl/fl), AAV-mediated knockdown in vivo, macrophage depletion experiments, pathway analysis Advanced science High 41355531
2025 In hepatic stellate cells (HSCs), ITGA8 expression is upregulated during liver fibrosis and promotes ECM accumulation; AAV2/6-mediated silencing of Itga8 in HSCs reduces fibrosis markers (α-SMA, collagen I), decreases inflammatory cytokines, and suppresses COL11A1 expression as identified by proteomics, implicating ITGA8 in ECM cross-linking via COL11A1 regulation and reducing HSC-mediated collagen contraction. CCl4 mouse fibrosis model, AAV2/6-shItga8 selective silencing, in vitro ITGA8 knockdown with proteomic analysis, Sirius Red staining, collagen contraction assay Biochemical and biophysical research communications Medium 40056500
2025 ITGA8 sensitizes lung adenocarcinoma cells to EGFR-TKIs (abivertinib) by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway; ITGA8 knockdown enhanced proliferation, migration, and invasion of H1975 cells and increased tumor growth in xenografts, while overexpression in resistant cells (H1975/ABIR) reduced malignant phenotypes and enhanced drug sensitivity. Genome-wide CRISPR-Cas9 screen, ITGA8 knockdown and overexpression, western blot for FAK/SRC/AKT/MAPK pathway, H1975 xenograft mouse model Acta pharmacologica Sinica Medium 39809840
2026 ITGA8 overexpression in lung adenocarcinoma suppresses aerobic glycolysis (reducing ECAR, glucose uptake, lactate production) by activating the AMPK signaling pathway and inhibiting the mTOR/S6K/4EBP1 axis; AMPK inhibition reversed ITGA8-mediated glycolysis suppression and restoration of malignant phenotypes, establishing ITGA8 as a metabolic gatekeeper. ITGA8 overexpression in LUAD cells, Seahorse metabolic assays (ECAR), glucose/lactate measurements, AMPK inhibitor rescue experiments, in vivo xenograft models, western blot for mTOR/S6K/4EBP1 Scientific reports Medium 41731056
2021 ITGA8-positive cells isolated from human trabecular meshwork display properties of Schlemm's canal (SC) endothelial cells: enhanced expression of SC biomarkers, reduced dexamethasone-inducible myocilin secretion, and stronger endothelin 1-induced contractility compared to ITGA8-negative cells, indicating ITGA8 marks a functionally distinct SC-like population involved in aqueous humor outflow resistance. Fluorescence in situ hybridization, immunofluorescence, magnetic bead-based cell sorting, flow cytometry, RT-PCR, Western blot, gel contraction assay Life sciences Medium 33961857
2025 RAGE regulates cell adhesion through upregulation of ITGA8; the intracellular (cytoplasmic) domain of RAGE is required for modulating cell spreading and for ITGA8 regulation, indicating a signaling link from RAGE's cytoplasmic domain to ITGA8-mediated adhesion to extracellular matrix proteins. RAGE domain deletion constructs, cell adhesion assays, cell spreading assays, protein expression analysis Cells Low 41294858
2020 In ER-positive breast cancer cells, ITGA8 is silenced by promoter hypermethylation; treatment with 5-aza-2'-deoxycytidine restores ITGA8 protein expression, but this restoration is abolished by 17-beta-estradiol (ERα agonist), indicating that ERα-dependent signaling promotes ITGA8 methylation and silencing in ER-positive breast cancer. Methylation-specific PCR, Western blot, 5-aza-dC demethylation treatment, 17-beta-estradiol treatment, clinical tissue methylation analysis Annals of translational medicine Medium 32953793
2024 In ovarian cancer, M2 macrophage-derived exosomes deliver circTMCO3, which acts as a competing endogenous RNA for miR-515-5p, thereby reducing miR-515-5p abundance and upregulating ITGA8; miR-515-5p directly downregulates ITGA8, and ITGA8 overexpression reverses the reduced oncogenic activity caused by circTMCO3 silencing, placing ITGA8 downstream of the circTMCO3/miR-515-5p axis in promoting ovarian cancer malignancy. Exosome isolation, circRNA knockdown, miRNA mimic/inhibitor experiments, luciferase reporter assay (implied by competing endogenous RNA mechanism), in vivo nude mouse xenograft Communications biology Low 38755265

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Generation and Comparative Analysis of an Itga8-CreER Mouse with Preferential Activity in Vascular Smooth Muscle Cells. Nature cardiovascular research 59 36424917
2007 Identification of PRTFDC1 silencing and aberrant promoter methylation of GPR150, ITGA8 and HOXD11 in ovarian cancers. Life sciences 33 17303177
2017 Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8. Biology of sex differences 28 28572914
2016 Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover. PloS one 24 26938996
2016 Pharyngeal morphogenesis requires fras1-itga8-dependent epithelial-mesenchymal interaction. Developmental biology 23 27265864
2024 M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer. Communications biology 20 38755265
2017 DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population. Neurobiology of aging 19 29290481
2023 LINC01798/miR-17-5p axis regulates ITGA8 and causes changes in tumor microenvironment and stemness in lung adenocarcinoma. Frontiers in immunology 18 36911684
2020 Estrogen receptor α is involved in the regulation of ITGA8 methylation in estrogen receptor-positive breast cancer. Annals of translational medicine 13 32953793
2004 Genomic organization and sequence variation of the human integrin subunit alpha8 gene (ITGA8). Matrix biology : journal of the International Society for Matrix Biology 12 15579315
2012 A missense mutation in the ITGA8 gene, a cell adhesion molecule gene, is associated with schizophrenia in Japanese female patients. Progress in neuro-psychopharmacology & biological psychiatry 11 23153507
2023 Hypermethylated ITGA8 Facilitate Bladder Cancer Cell Proliferation and Metastasis. Applied biochemistry and biotechnology 7 37119505
2016 Analysis of LRRK2, SNCA, and ITGA8 Gene Variants with Sporadic Parkinson's Disease Susceptibility in Chinese Han Population. Parkinson's disease 6 27668119
2025 Genome-wide CRISPR-Cas9 screening identifies ITGA8 responsible for abivertinib sensitivity in lung adenocarcinoma. Acta pharmacologica Sinica 5 39809840
2022 Bi-allelic pathogenic variants in ITGA8 cause slowly progressive renal disease of unknown etiology. Clinical genetics 5 36089563
2021 ITGA8 positive cells in the conventional outflow tissue exhibit Schlemm's canal endothelial cell properties. Life sciences 5 33961857
2023 Itga8-Cre-mediated deletion of YAP and TAZ impairs bladder contractility with minimal inflammation and chondrogenic differentiation. American journal of physiology. Cell physiology 4 37927241
2025 ITGA8 deficiency in hepatic stellate cells attenuates CCl4-Induced liver fibrosis via suppression of COL11A1. Biochemical and biophysical research communications 2 40056500
2016 No Association Between rs7077361 in ITGA8 and Parkinson's Disease in Sweden. The open neurology journal 2 27583043
2025 Targeting Itga8 Mitigates Neurogenic Bladder Fibrosis Driven by Trem2⁺ Macrophage-Derived Fn1 via FAK/RhoA/ROCK Signaling. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41355531
2026 Genetic Control of Tissue Remodeling by a Non-Coding SNP in ITGA8 Explains Carotenoid-Based Color Polymorphism in Marine Mollusks. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41603158
2026 ITGA8 suppresses proliferation and metastasis of lung adenocarcinoma through the inhibition of glycolysis. Scientific reports 0 41731056
2026 Temporal Transcriptomics Leads From Discovery to in Vivo Validation: COL4A3/COL4A6/ COL4A5 and ITGA8 as Novel Arthrofibrosis Biomarkers in Post-traumatic Joint Contracture. Dose-response : a publication of International Hormesis Society 0 41743075
2025 Missense mutation (Ser654Leu) in the ITGA8 gene associated with renal hypodysplasia: A case report. Biomedical reports 0 40017502
2025 The significance of Itga8 and Vangl2 in kidney development: Insights from yotari mice. Acta histochemica 0 40101650
2025 The Receptor for Advanced Glycation End-Products (RAGE) Regulates Cell Adhesion Through Upregulation of ITGA8. Cells 0 41294858

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