{"gene":"ITGA5","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"α5β1 integrin (CD49e/CD29, VLA-5) on neutrophils mediates β2-integrin-independent recruitment to endotoxin-induced lung inflammation; combined blockade of α4β1, α5β1, and β2 integrins with mAbs inhibited PMNL accumulation in the parenchyma by 79% and prevented pulmonary vascular/epithelial permeability.","method":"In vivo antibody blocking (mAb to α5β1, α4β1, β2 integrins) in rat intratracheal LPS model; myeloperoxidase assay and BAL fluid cell counts","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular phenotype, single lab, two readouts (parenchyma and BAL)","pmids":["11254723"],"is_preprint":false},{"year":1998,"finding":"VLA-5 (α5β1; CD49e/CD29) on monocytes mediates migration through synovial fibroblast barriers independently of CD18 and VLA-4; the inhibitory effect required prior blockade of CD11/CD18 to become apparent, and the ligand on synovial fibroblasts is distinct from VCAM-1.","method":"Transwell migration assay with blocking mAbs against α5 (VLA-5), α4 (VLA-4), CD18, and VCAM-1 using HUVEC and human synovial fibroblast barriers; C5a and MCP-1 chemotactic gradients","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional migration assay with multiple blocking antibodies, single lab","pmids":["9552005"],"is_preprint":false},{"year":1995,"finding":"Functional surface expression of α5β1 integrin (CD49e/CD29) correlates with fibronectin adherence and disseminative spread of malignant B-cell lines in SCID mice; lines with non-functional or absent α5β1 did not disseminate.","method":"Immunohistochemistry and flow cytometry for α5β1 expression; fibronectin adhesion assay in vitro; s.c. xenograft dissemination in SCID mice","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft combined with functional adhesion assay, single lab","pmids":["7534750"],"is_preprint":false},{"year":2005,"finding":"ITGA5 (α5 integrin) mRNA and protein are significantly upregulated in rat myometrium during late pregnancy and labor, with expression primarily in myometrial cell membranes; progesterone treatment blocked labor and sustained Itga5 expression, suggesting ITGA5/ITGB1 promotes cellular cohesion to develop a mechanical syncytium for uterine contractions.","method":"qRT-PCR, immunoblot, and immunocytochemistry across pregnancy time-points in rat myometrium; progesterone treatment experiment","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunocytochemistry tied to functional context (labor), with temporal expression and pharmacological manipulation, single lab","pmids":["15635129"],"is_preprint":false},{"year":2010,"finding":"ITGA5 overexpression in MDA-MB-468 breast cancer cells inhibits cell growth, but adhesion to fibronectin reverses this growth inhibition; ITGA5 overexpression enhances cell adhesion and spreading to fibronectin while reducing migration. Knockdown of ITGA5 in MCF-7 cells also inhibits cell growth but has little effect on migration. Downregulation of ITGA5 in MDA-MB-468 is mediated by promoter hypermethylation.","method":"ITGA5 overexpression and siRNA knockdown; cell growth assay, adhesion/spreading assay on fibronectin, migration assay; bisulfite sequencing for methylation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (growth, adhesion, migration), single lab","pmids":["20564209"],"is_preprint":false},{"year":2010,"finding":"RNA interference-mediated knockdown of CD49e (ITGA5) in human thymic epithelial cells modulates expression of >100 genes including genes involved in thymocyte adhesion, integrin signaling, and F-actin stress fiber formation, and decreases adhesion of all CD4/CD8-defined thymocyte subsets to TEC.","method":"siRNA knockdown of CD49e in human TEC line; transcriptomic profiling; thymocyte adhesion assay","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with transcriptomic and functional (adhesion) readouts, single lab","pmids":["21210968"],"is_preprint":false},{"year":2011,"finding":"Alcohol suppresses Nm23, which in turn increases ITGA5 expression, leading to increased breast cancer cell invasion; Nm23 overexpression suppresses ITGA5 upregulation and inhibits alcohol-induced invasion, and ITGA5 knockdown also inhibits alcohol-induced invasion, placing ITGA5 downstream of Nm23 in this pathway.","method":"Ethanol treatment of T47D cells; Boyden chamber invasion assay; qRT-PCR array; Nm23 overexpression and ITGA5 siRNA knockdown; Western blot","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by overexpression and knockdown experiments with defined invasion phenotype, single lab","pmids":["21838876"],"is_preprint":false},{"year":2015,"finding":"Downregulation of ITGA5 by shRNA lentivirus significantly reduces migration capacity of human dental pulp stem cells (hDPSCs) in a transwell assay.","method":"Lentiviral shRNA knockdown of ITGA5 in hDPSCs; transwell migration assay","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (transwell), single lab","pmids":["26823759"],"is_preprint":false},{"year":2016,"finding":"ITGA5 knockdown reduces proliferation and adipogenic differentiation in human adipose-derived stem cells (ASCs), while ITGA5 transgenic overexpression impairs adipogenesis; these effects are distinct from ITGAV, which specifically regulates proliferation via p21/survivin/TAZ, while ITGA5 does not affect proliferation when knocked down.","method":"siRNA knockdown and transgenic overexpression of ITGA5 (and ITGAV) in sorted ASCs; adipogenic differentiation assays; cell proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain-of-function with defined differentiation phenotype, single lab, two orthogonal approaches","pmids":["27363302"],"is_preprint":false},{"year":2017,"finding":"Dioscin directly binds ITGA5 and acts as a potent ITGA5 inhibitor; ITGA5 silencing suppresses collagen synthesis via inhibition of the PI3K/Akt/mTOR pathway, reducing FN, FAK1, p-PI3K, p-Akt, p-mTOR, and collagen proteins in liver fibrosis. ITGA5 DNA transfection reverses dioscin's inhibitory effect on collagen expression through the PI3K/Akt pathway.","method":"SILAC-based proteomics; molecular docking; siRNA and overexpression transfection of ITGA5 in LX-2 cells; Western blot for PI3K/Akt/mTOR pathway proteins; in vivo liver fibrosis model","journal":"Food and chemical toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular docking plus siRNA/overexpression epistasis with pathway readout, single lab, multiple orthogonal methods","pmids":["28689917"],"is_preprint":false},{"year":2019,"finding":"O-GlcNAcylation of ITGA5 protein, mediated by OGT, increases ITGA5 protein stability and expression in colorectal cancer cells; elevated O-GlcNAcylation of ITGA5 promotes CRC cell growth and tumorigenesis.","method":"Immunoprecipitation, in vitro O-GlcNAcylation assay, enzymatic labelling of O-GlcNAc; OGT inhibitor (PUGNAc/GlcN) treatment; CCK-8, flow cytometry, xenotransplantation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical identification of PTM (O-GlcNAcylation) on ITGA5 with functional consequence, single lab","pmids":["31202709"],"is_preprint":false},{"year":2019,"finding":"ITGA5 knockdown in pancreatic stellate cells inhibits their differentiation into activated CAFs and reduces desmoplasia in vivo; a peptidomimetic ITGA5 inhibitor (AV3) reduces desmoplasia, decompresses blood vasculature, enhances tumor perfusion, and potentiates gemcitabine efficacy in pancreatic cancer xenograft and PDX models.","method":"ITGA5 siRNA knockdown in hPSCs; in vivo co-injection and PDX PDAC models; histology; vascular perfusion assay; 3D heterospheroid model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro loss-of-function plus multiple in vivo models with mechanistic readouts (desmoplasia, vascular decompression, perfusion), replicated in PDX","pmids":["31517053"],"is_preprint":false},{"year":2018,"finding":"MRTFA deficiency shifts perivascular progenitor fate from ITGA5+ fibrogenic progenitor cells (FPCs) to adipocyte precursors in adipose tissue during obesity, protecting against fibrosis; ITGA5+ Sca1−Sma+ITGA5+ FPCs are formed in adipose tissue during obesity and the ITGA5-MRTFA pathway governs their identity.","method":"MRTFA knockout mice; flow cytometry and immunofluorescence identifying ITGA5+ FPC subpopulation; high-fat diet obesity model; histological fibrosis assessment","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cell fate phenotype, single lab","pmids":["29768198"],"is_preprint":false},{"year":2022,"finding":"ITGA5 in cervical cancer cells activates downstream PI3K-Akt signaling, increases VEGFA expression and secretion, and promotes endothelial tube formation; fibronectin (FN1) coating modulates ITGA5-mediated angiogenesis, and VEGFA supplementation reverses the decrease in tube formation caused by ITGA5 knockdown.","method":"siRNA knockdown of ITGA5; tube formation assay, 3D spheroid sprout assay; Western blot for p-AKT and VEGFA; ELISA; FN1 coating/siRNA experiments","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway readout and rescue experiment, single lab","pmids":["36999964"],"is_preprint":false},{"year":2022,"finding":"ITGA5 promotes tumor progression in gastric cancer via activation of the FAK/AKT signaling pathway; ITGA5 silencing inhibits proliferation, invasion, migration, and xenograft growth, while overexpression promotes these functions.","method":"ITGA5 siRNA and overexpression in gastric cancer cell lines; Western blot for FAK/AKT; in vitro proliferation/invasion/migration assays; in vivo xenograft model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain-of-function with pathway (FAK/AKT) and in vivo readout, single lab","pmids":["36193075"],"is_preprint":false},{"year":2022,"finding":"ITGA5 and ITGB1 overexpression in HCC cells promotes vasculogenic mimicry (VM) formation, reduces sensitivity to sorafenib, and aggravates hypoxia; VM formation contributes to sorafenib resistance.","method":"Sorafenib-resistant HCC cell line construction; ITGA5/ITGB1 overexpression; CD31/PAS staining for VM; hypoxia probe by flow cytometry","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression only with limited mechanistic resolution","pmids":["35946175"],"is_preprint":false},{"year":2022,"finding":"FN1 drives chemoresistance in TNBC via its receptor ITGA5, activating downstream FAK/Src signaling; miR-326, which is repressed by hypoxia/HIF1A and ECM stiffness, targets ITGA5 to reverse FN1-driven chemoresistance. ITGA5 inhibition overcomes FN1-driven chemotherapy resistance in vitro and potentiates chemotherapy in vivo.","method":"RNA/small RNA sequencing; ChIP for HIF1A; ITGA5 knockdown and miR-326 overexpression; 3D cultures; xenograft models; Western blot for FAK/Src; fibronectin coating","journal":"Breast cancer research and treatment","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transcriptomics, ChIP, RNAi, xenograft), pathway placement, in vivo validation, single lab","pmids":["35338412"],"is_preprint":false},{"year":2022,"finding":"Extracellular vesicle-packaged ITGA5 (together with CDH11) from breast cancer cells with high RUNX2 educates osteoblasts to form an osteogenic premetastatic niche; CDH11high/ITGA5high EVs promote bone colonization by RUNX2-high breast cancer cells.","method":"In vitro and in vivo EV transfer experiments; osteoblast education assay; bone metastasis mouse model; EV proteomics","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro EV transfer with specific protein cargo identification, single lab","pmids":["35149589"],"is_preprint":false},{"year":2022,"finding":"Elevated ITGA5 is a downstream effector of hyperactivated mTORC1 in laryngeal squamous cell carcinoma; ITGA5 promotes LSCC progression through upregulation of ephrin-B2 (EFNB2), and inhibition of ITGA5 sensitizes cells to cisplatin in CDX and PDX models.","method":"Raptor knockdown (mTORC1 inhibition); transcriptomic sequencing; ITGA5 functional assays; in vivo CDX and PDX models; Western blot","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (mTORC1→ITGA5→EFNB2) with in vivo validation, single lab","pmids":["36438491"],"is_preprint":false},{"year":2021,"finding":"NEAT1 lncRNA acts as a sponge for miR-128-3p in glioma, relieving miR-128-3p-mediated repression of ITGA5; elevated ITGA5 then activates the FAK signaling pathway to promote cell growth.","method":"Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation; CCK-8, transwell, flow cytometry in U87MG and U251MG cells; ITGA5 siRNA and NEAT1 overexpression/knockdown","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays plus functional rescue experiments, single lab","pmids":["34263426"],"is_preprint":false},{"year":2021,"finding":"Leptin reduces ITGA5 expression in adipocytes, thereby inhibiting activation of the PI3K/AKT signaling pathway, alleviating adipose tissue fibrosis and promoting white fat browning; ITGA5 overexpression with wortmannin (PI3K inhibitor) treatment confirmed ITGA5 acts upstream of PI3K/AKT in fibrosis.","method":"Leptin treatment; proteomics screening; ITGA5 overexpression and siRNA in adipocytes; TGF-β/HFD fibrosis model; qPCR, WB, IHC, immunofluorescence; wortmannin inhibitor","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified target with gain/loss-of-function and pharmacological pathway confirmation, single lab","pmids":["34830238"],"is_preprint":false},{"year":2023,"finding":"AFAP1L1 interacts with VAV2 guanine nucleotide exchange factor to activate Rho GTPase CDC42, which then promotes ITGA5 expression and integrin signaling pathway activation in gastric cancer, driving EMT and metastasis.","method":"Co-immunoprecipitation; cell adhesion assay; in vitro and in vivo GC functional assays; ITGA5 expression analysis after AFAP1L1 manipulation","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP to establish protein interaction, epistasis via signaling pathway, single lab","pmids":["36631800"],"is_preprint":false},{"year":2022,"finding":"FGA (fibrinogen α chain) transcriptionally suppresses ITGA5 expression (confirmed by luciferase and ChIP assays), leading to inhibition of the FAK/ERK pathway and suppression of gastric cancer cell motility, EMT, and autophagy.","method":"Luciferase reporter and ChIP assays confirming FGA transcriptional regulation of ITGA5; Western blot for FAK/ERK; in vivo BALB/c xenograft model","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional regulation confirmed by luciferase and ChIP, pathway readout, in vivo validation, single lab","pmids":["35257941"],"is_preprint":false},{"year":2022,"finding":"ITGA5 knockdown in LSCC cells inhibits expression and secretion of VEGF-C, suppresses lymphatic endothelial cell tube formation and LSCC cell migration/invasion; exogenous VEGF-C supplementation reverses these effects, placing ITGA5 upstream of VEGF-C in lymphangiogenesis.","method":"siRNA knockdown of ITGA5; tube formation assay with HLECs; ELISA for VEGF-C; transwell co-culture; in vivo subcutaneous graft model","journal":"Protoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with VEGF-C rescue, in vitro and in vivo, single lab","pmids":["37338646"],"is_preprint":false},{"year":2023,"finding":"ACTN1 (α-Actinin 1) physically interacts with ITGA5 (confirmed by Co-IP) in HNSCC cells; ACTN1 depletion reduces proliferation, invasion, migration, and EMT, and these effects are reversed by ITGA5 overexpression, demonstrating ACTN1 acts through ITGA5.","method":"Co-immunoprecipitation; CCK8, colony formation, EdU, transwell, wound healing assays; immunofluorescence; xenograft in nude mice; IHC for Ki-67","journal":"Iranian journal of basic medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction plus functional rescue, single lab","pmids":["36742137"],"is_preprint":false},{"year":2023,"finding":"FAPα and ITGA5 form a protein complex in the inflammatory microenvironment of chronic apical periodontitis; silencing either protein decreases osteoclast differentiation; molecular docking shows FAPα binds ITGA5 with -14.5 kcal/mol free energy.","method":"Molecular docking; co-immunoprecipitation; immunofluorescence staining; FAPα/ITGA5 siRNA silencing; osteoclast differentiation assay","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms complex formation, functional consequence by silencing, single lab","pmids":["37979759"],"is_preprint":false},{"year":2024,"finding":"METTL3 stabilizes HOXD8 mRNA in an m6A-dependent manner; HOXD8 then transcriptionally activates ITGA5 (confirmed by ChIP and luciferase), and elevated ITGA5 enhances osteogenic differentiation of CPT periosteum-derived MSCs.","method":"MeRIP assay for m6A modification of HOXD8; luciferase reporter assay; ChIP assay; METTL3/HOXD8/ITGA5 overexpression; Alizarin Red S and ALP assays","journal":"Regenerative therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical assays establishing transcriptional hierarchy, single lab","pmids":["38818480"],"is_preprint":false},{"year":2024,"finding":"FN1 secreted by dental pulp stem cells (DPSCs) promotes endothelial cell proliferation, migration, and tube formation via ITGA5 and downstream PI3K/AKT signaling pathway during dental pulp vascularization.","method":"Co-culture of DPSCs and HUVECs; Western blot for FN1, ITGA5, PI3K/AKT; cell proliferation, scratch, and tube formation assays; siRNA knockdown; in vivo mouse experiments","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments establishing FN1-ITGA5-PI3K/AKT axis, single lab","pmids":["38418738"],"is_preprint":false},{"year":2024,"finding":"Itga5 interacts with PTEN in striatal neurons; Itga5 deficiency in MPTP-induced Parkinson's disease models reduces dendritic spine density, alters synaptic architecture, and impairs motor coordination through reduced AKT signaling; a TAT-Itga5 peptide designed to suppress PTEN activity rescues these deficits.","method":"MPTP mouse model; CRISPR-CasRx knockdown; mass spectrometry; electrophysiology; Western blot; behavioral tests; immunostaining for spine morphology","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockdown with electrophysiological and behavioral readouts plus mass spectrometry-identified PTEN interaction, single lab","pmids":["38993558"],"is_preprint":false},{"year":2024,"finding":"circSDHAF2 promotes N-glycosylation of ITGA5 protein, stabilizing it and facilitating its translocation into exosomes; exosomal ITGA5 is delivered to macrophages and induces SPP1+ MDM formation, which maintains mesenchymal GBM cell status and drives T-cell dysfunction via the SPP1-ITGA5 pathway, promoting immune escape.","method":"Co-immunoprecipitation; RNA immunoprecipitation; pull-down assays; single-cell RNA sequencing; spatial transcriptomics; in vitro and in vivo validation","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pull-down for mechanism, in vivo validation, single lab, multiple methods","pmids":["40084746"],"is_preprint":false},{"year":2024,"finding":"IGFBP2 promotes gefitinib resistance in NSCLC by activating STAT3/CXCL1 axis; ITGA5 is identified as a key player in IGFBP2-mediated resistance but does NOT function as a membrane receptor linking IGFBP2 to intracellular signaling transduction (negative finding for that specific mechanism).","method":"In vitro and in vivo resistance experiments; IGFBP2/ITGA5 knockdown; Western blot for STAT3/CXCL1","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic role of ITGA5 in resistance established but specific receptor function explicitly negated; limited mechanistic detail on ITGA5's actual mechanism","pmids":["38918360"],"is_preprint":false},{"year":2023,"finding":"ITGA5+ synovial fibroblasts (POSTN+, COL3A1+, CCL5+, TGFB1+) are induced to differentiate by TGF-β1 and promote differentiation of naïve CD4+ T cells into CXCL13hiPD-1hi peripheral helper T cells via TGF-β1 secretion; intra-articular injection of ITGA5+ fibroblasts exacerbates collagen-induced arthritis and upregulates TPH cells in mice.","method":"Single-cell and spatial transcriptomics; flow cytometry; co-culture assay; adoptive transfer in CIA mice; bulk RNA sequencing of synovial joints; multiplex immunofluorescence","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer in vivo plus co-culture mechanistic assays, single lab","pmids":["39919897"],"is_preprint":false},{"year":2024,"finding":"Myofibroblast-derived extracellular vesicles transfer ITGA5 protein to HCC cells; ITGA5 delivered to HCC cells directly binds YES1 kinase, activating YES1 and downstream pathways to enhance cancer stem cell-like properties; CRISPR KO of ITGA5 in myofibroblasts impairs this process.","method":"CRISPR Cas9 KO; EV isolation and transfer; Co-IP/mass spectrometry; sphere-forming assay; stemness marker expression; orthotopic HCC mouse model; tissue microarray","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP/MS identifies YES1 as direct ITGA5 binding partner, CRISPR KO, in vivo validation, multiple orthogonal methods, single lab","pmids":["39574133"],"is_preprint":false},{"year":2025,"finding":"ITGA5 on tumor cells binds fibronectin (FN1) in the Schwann cell extracellular matrix, triggering reprogramming of Schwann cells to a reparative phenotype with enhanced NGF secretion; increased NGF suppresses NK cell cytotoxicity by inhibiting IFN-γ, promoting immune evasion and perineural invasion.","method":"Functional assays for SC reprogramming; NGF secretion measurement; NK cell cytotoxicity assay; IFN-γ quantification; cilengitide (ITGA5 inhibitor) treatment with anti-PD-1 therapy","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays establishing ITGA5-FN1-Schwann cell-NGF-NK cell axis, single lab","pmids":["40734271"],"is_preprint":false},{"year":2025,"finding":"13-Methylpalmatine suppresses ITGA5 expression and inhibits activation of the TGF-β/Smad signaling pathway; ITGA5 silencing confirms ITGA5 acts upstream of TGF-β/Smad in pulmonary fibrosis, and ITGA5 overexpression reverses 13-Me-PLT's antifibrotic effect.","method":"Transcriptomic sequencing; molecular docking and SPR for direct binding; ITGA5 silencing and overexpression in MRC5 cells; BLM mouse model; Smad pathway Western blot","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR confirms direct compound-ITGA5 binding, epistasis via siRNA/overexpression, in vivo model, single lab","pmids":["40023972"],"is_preprint":false},{"year":2023,"finding":"TLN1 (Talin-1) overexpression increases ITGA5 expression; ITGA5 knockdown reverses the protective effects of TLN1 on cardiac microvascular endothelial cells under ox-LDL injury, demonstrating TLN1 acts through ITGA5 to regulate CMVEC function.","method":"TLN1 overexpression and ITGA5 siRNA knockdown in ox-LDL-treated CMVECs; proliferation, apoptosis, angiogenesis, inflammation, oxidative stress assays","journal":"Folia morphologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, genetic epistasis without biochemical binding confirmation","pmids":["37144848"],"is_preprint":false},{"year":2015,"finding":"In zebrafish, prdm1a acts upstream of itga5 in posterior pharyngeal arch development; prdm1a mutants show decreased itga5 expression, and injection of itga5 mRNA into prdm1a mutants rescues loss of posterior pharyngeal arch dlx2a expression, ceratobranchial cartilages 2-5, and cell proliferation.","method":"In situ hybridization; double prdm1a;itga5 mutant analysis; mRNA rescue injection; cell proliferation assay","journal":"Genesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis established by double mutant and mRNA rescue in zebrafish (ortholog model), single lab","pmids":["25810090"],"is_preprint":false},{"year":2025,"finding":"ITGA5 drives angiogenesis in diabetic retinopathy by activating the TAK-1/NF-κB signaling pathway; ITGA5 knockdown in vivo reduces neovascularization, decreases FAK, TAK-1, and p65 phosphorylation, and reduces VEGFA, VCAM-1, and ICAM-1 expression.","method":"Streptozotocin-induced diabetic rat model; intravitreal AAV-mediated ITGA5 knockdown; oxygen-induced retinopathy model; Western blot for FAK/TAK-1/NF-κB; tube formation and invasion in high glucose-treated RRMECs","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro KD with pathway readout, single lab","pmids":["40410450"],"is_preprint":false},{"year":2025,"finding":"RPRD1A competes with RPAP2 for binding to RNA Pol II, derepressing ITGA5 transcription via a c-JUN-dependent pathway; upregulated ITGA5 then activates FAK signaling to drive lenvatinib resistance in HCC; combined lenvatinib with ITGA5 inhibitor (volociximab) or FAK inhibitor (defactinib) reverses resistance.","method":"Functional resistance assays; Western blot; transcriptional mechanism assays (RPRD1A-RPAP2-RNA Pol II competition); ITGA5 inhibition and FAK inhibition in preclinical models","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional mechanism established with pathway placement and pharmacological validation, single lab","pmids":["42171939"],"is_preprint":false},{"year":2026,"finding":"DTX1 E3 ubiquitin ligase directly interacts with ITGA5 and promotes its ubiquitination at lysine 137, leading to proteasome-dependent degradation of ITGA5 and maintenance of the contractile VSMC phenotype; DTX1 overexpression reduces ITGA5 levels and attenuates aortic dissection progression in vivo.","method":"Co-immunoprecipitation; protein stability analysis; ubiquitination site identification (K137); gain/loss-of-function in HASMCs; BAPN-induced AD mouse model; Western blot, qPCR, immunofluorescence","journal":"Cardiovascular drugs and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies direct interaction, specific ubiquitination site mapped, in vivo validation, single lab","pmids":["42090073"],"is_preprint":false},{"year":2025,"finding":"ITGA5 directly binds PI3K in vitro (confirmed by binding assay); ITGA5-mediated PI3K/AKT pathway activation promotes EMT and anoikis resistance in bronchial epithelial cells; ITGA5 knockdown reverses TGF-β1-induced EMT and restores anoikis sensitivity.","method":"Quantitative proteomics; ITGA5 knockdown; Western blot for PI3K/AKT; EMT and anoikis assays; molecular docking and dynamics; in vitro PI3K binding assay; in vivo asthma mouse model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro PI3K binding confirmed, functional epistasis with rescue, single lab","pmids":["41772919"],"is_preprint":false},{"year":2025,"finding":"MFAP5, an extracellular matrix component, engages ITGA5 to activate ERK/MAPK signaling in odontoblast-lineage cells, promoting odontoblast differentiation and dentin deposition during tooth mineralization.","method":"10× single-cell RNA sequencing; functional differentiation assays in vitro; ITGA5 and MFAP5 manipulation; Western blot for ERK/MAPK","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays establish pathway axis but limited mechanistic detail on direct binding; single lab","pmids":["41516268"],"is_preprint":false},{"year":2026,"finding":"SPP1-ITGA5 interaction between SPP1+ macrophages and ITGA5+ fibroblasts in HCC triggers secretion of MMP2 by fibroblasts, promoting HCC malignant progression; confirmed by co-immunoprecipitation and cell co-culture assays with in vivo validation.","method":"Co-immunoprecipitation; cell co-culture; in vivo mouse transplantation model; single-cell RNA sequencing; spatial transcriptomics; multiplexed immunofluorescence","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms SPP1-ITGA5 interaction, functional consequence (MMP2) established in vitro and in vivo, single lab","pmids":["41758046"],"is_preprint":false},{"year":2025,"finding":"GBX2 transcription factor binds to the promoter region of ITGA5 and activates its transcription, upregulating ITGA5 expression in bladder cancer cells to promote viability, migration, and invasion.","method":"Chromatin immunoprecipitation (ChIP); luciferase reporter assay for promoter binding; GBX2 knockdown and ITGA5 overexpression rescue experiments","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, rescue experiment, single lab","pmids":["35672622"],"is_preprint":false},{"year":2025,"finding":"ITGA5 promotes GBM cell invasion and migration through SLK (a downstream kinase of the PI3K-Akt pathway); ITGA5 knockdown reduces SLK expression and activity, and this mechanism was identified by proteomics and phosphoproteomics after ITGA5 knockdown.","method":"Proteomics and phosphoproteomics after ITGA5 knockdown; in vitro invasion/migration assays; in vivo GBM model; Western blot; single-cell RNA sequencing","journal":"Neurological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified pathway with functional validation in vitro and in vivo, single lab","pmids":["40544320"],"is_preprint":false},{"year":2026,"finding":"CTHRC1 secreted by cancer-associated fibroblasts directly binds ITGA5 on tumor cells, activating the PI3K/AKT signaling pathway to promote proliferation, EMT, and angiogenesis in HNSCC.","method":"Functional experiments in vitro and in vivo; protein binding confirmation; Western blot for PI3K/AKT; single-cell RNA sequencing; spatial transcriptomics","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding established, pathway readout, in vivo validation, single lab","pmids":["41651176"],"is_preprint":false},{"year":2026,"finding":"ITGA5 interacts with IMP3 (insulin-like growth factor II mRNA binding protein 3), and this interaction regulates IMP3-mediated recruitment of HK2 mRNA, promoting the Warburg effect and cervical cancer progression; HK2 overexpression rescues the effects of ITGA5 knockdown.","method":"Mass spectrometry (Co-IP/MS); Co-immunoprecipitation; RNA immunoprecipitation (RIP); Western blot; xenograft in nude mice; rescue experiment with HK2 overexpression","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifies IMP3 as ITGA5-interacting partner, RIP confirms mRNA recruitment mechanism, rescue experiment, single lab","pmids":["40385029"],"is_preprint":false},{"year":2025,"finding":"Resibufogenin (RBG) activates the ITGA5-VEGF signaling axis in a macrophage-dependent manner to promote reparative angiogenesis in myocardial infarction; RBG upregulates ITGA5 in macrophages via the VAV3/CDC42 signaling pathway; pharmacological ITGA5 inhibition or macrophage depletion completely abolishes RBG-mediated cardioprotection.","method":"Proteomic analysis; macrophage-endothelial co-culture; ITGA5 inhibition; macrophage depletion; MI mouse model; tube formation assay; Western blot for VAV3/CDC42/ITGA5/VEGF","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified axis, pharmacological and cell-depletion epistasis in vivo, single lab","pmids":["42056214"],"is_preprint":false},{"year":2023,"finding":"Nitric oxide (NO) prevents hypoxia-induced ITGA5 CpG promoter hypermethylation by DNMT1 in endothelial progenitor cells; hypoxia suppresses miR-148 levels, increasing DNMT1-mediated ITGA5 promoter methylation and reducing ITGA5 expression and cell-matrix adhesion; NO or miR-148 overexpression restores ITGA5 expression and adhesion.","method":"miScript miRNA qPCR array; DNMT1 inhibitor (5'-azacitidine); miR-148 overexpression; eNOS-GFP transfection; hypoxia model in EPCs; cell-matrix adhesion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism (CpG methylation) confirmed with multiple interventions and functional adhesion readout, single lab","pmids":["36669384"],"is_preprint":false},{"year":2021,"finding":"HIF-1A and NFATC1 transcription factors regulate ITGA5 gene expression in intestinal epithelial cells under hypoxia; chemical activation of HIF signaling (cobalt chloride/oxyquinoline) upregulates ITGA5 expression in Caco-2 cells, confirmed by RNA sequencing and proteomics.","method":"RNA sequencing and proteomics of HIF-activated Caco-2 cells; bioinformatic transcription factor analysis (miRGTF tool); validation in IBD patient RNA-seq datasets","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcription factor assignment is computational with limited direct experimental validation of binding, single lab","pmids":["34858489"],"is_preprint":false},{"year":1991,"finding":"ITGA5 (FNRA, fibronectin receptor alpha subunit) maps to chromosome 12 in humans, confirmed using human-rodent somatic cell hybrids and cDNA probes.","method":"Somatic cell hybrid mapping with cDNA probes","journal":"Annals of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — chromosomal mapping only, no functional mechanism","pmids":["1722386"],"is_preprint":false},{"year":2020,"finding":"CD49e (ITGA5) on Burkitt lymphoma cells mediates cell adhesion-mediated drug resistance (CAM-DR) via NF-κB pathway activation, increasing Bcl-xL and survivin and decreasing Bax, Bim, and PUMA; bortezomib overcomes CAM-DR by inhibiting NF-κB.","method":"CD49e blocking antibodies; NF-κB activity assay; Western blot for apoptosis proteins; bortezomib treatment; adhesion-based drug resistance assay","journal":"Journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with NF-κB pathway readout and pharmacological rescue, single lab","pmids":["33214335"],"is_preprint":false}],"current_model":"ITGA5 (integrin α5, CD49e) encodes the α-subunit of the α5β1 fibronectin receptor and functions as a transmembrane signaling hub that, upon engaging fibronectin or other ligands, activates downstream FAK/AKT, PI3K/AKT/mTOR, FAK/Src, FAK/ERK, and TAK-1/NF-κB signaling cascades to regulate cell adhesion, migration, invasion, EMT, angiogenesis/lymphangiogenesis, and survival; its activity is modulated post-translationally by O-GlcNAcylation (which stabilizes the protein) and ubiquitination by DTX1 (which targets it for proteasomal degradation at K137), and transcriptionally by GBX2, HOXD8 (downstream of METTL3-mediated m6A), HIF-1A/NFATC1, and RPRD1A/c-JUN; ITGA5 forms functional complexes with ACTN1, FAPα, LGMN, IMP3, PTEN, and YES1 kinase, and can be transferred between cells via extracellular vesicles to confer cancer stem cell properties or educate the tumor microenvironment, while its expression is negatively regulated by multiple miRNAs (miR-148b, miR-326, miR-330-5p, miR-128, miR-17, miR-27b, miR-26a, miR-92a, miR-328-3p) and its promoter is subject to methylation-mediated silencing."},"narrative":{"mechanistic_narrative":"ITGA5 encodes the α5 subunit (CD49e/VLA-5) of the α5β1 fibronectin receptor, a transmembrane adhesion molecule that engages fibronectin and other extracellular-matrix ligands to couple cell-matrix contact to intracellular signaling and to control adhesion, spreading, migration, invasion, EMT, and angiogenesis across diverse normal and malignant tissues [PMID:7534750, PMID:20564209, PMID:36193075]. Upon ligand engagement, ITGA5 nucleates signaling through FAK-anchored cascades — FAK/AKT in gastric cancer [PMID:36193075], FAK/Src in fibronectin-driven chemoresistant breast cancer [PMID:35338412], FAK/ERK whose suppression blocks gastric-cancer motility [PMID:35257941], and a TAK-1/NF-κB axis driving diabetic-retinopathy neovascularization [PMID:40410450] — and through direct activation of PI3K/AKT, with ITGA5 binding PI3K in vitro to promote EMT and anoikis resistance [PMID:41772919, PMID:36999964, PMID:41651176]. This receptor function repeatedly drives a pro-angiogenic/pro-lymphangiogenic program by elevating VEGFA and VEGF-C secretion [PMID:36999964, PMID:37338646] and operates in fibrogenic contexts upstream of PI3K/Akt/mTOR collagen synthesis and TGF-β/Smad signaling [PMID:28689917, PMID:40023972]. ITGA5 abundance is gated post-translationally — O-GlcNAcylation by OGT and N-glycosylation stabilize the protein [PMID:31202709, PMID:40084746], while the DTX1 E3 ligase ubiquitinates ITGA5 at K137 for proteasomal degradation [PMID:42090073] — and transcriptionally by activators (GBX2, HOXD8 downstream of METTL3 m6A, HIF-1A, RPRD1A/c-JUN) and repressors including promoter hypermethylation and multiple miRNAs such as miR-326 and miR-128-3p [PMID:35672622, PMID:38818480, PMID:35338412, PMID:34263426, PMID:42171939, PMID:36669384]. ITGA5 forms functional complexes with the cytoskeletal adaptor ACTN1, with FAPα, and with YES1 kinase, IMP3, and PTEN, and is transferred between cells in extracellular vesicles to confer cancer stem-cell properties and remodel the tumor microenvironment [PMID:36742137, PMID:37979759, PMID:39574133, PMID:40385029, PMID:38993558, PMID:40084746, PMID:35149589]. Beyond cancer, ITGA5 mediates leukocyte recruitment and adhesion, stem/progenitor differentiation, myometrial contractility, and neuronal synaptic architecture via a PTEN/AKT interaction [PMID:11254723, PMID:27363302, PMID:15635129, PMID:38993558].","teleology":[{"year":1991,"claim":"Establishing the genomic identity of the fibronectin receptor alpha subunit gave the molecular anchor for all subsequent functional study.","evidence":"Somatic cell hybrid mapping with cDNA probes localizing FNRA to chromosome 12","pmids":["1722386"],"confidence":"Low","gaps":["No functional or mechanistic information","Chromosomal localization only"]},{"year":1998,"claim":"Functional blocking assays first showed that α5β1 mediates a distinct, integrin-redundant adhesion/migration program in immune cells, distinguishing it from VLA-4 and β2 integrins.","evidence":"Transwell migration with blocking mAbs across HUVEC and synovial fibroblast barriers (monocytes); in vivo mAb blockade in LPS-induced lung inflammation (neutrophils)","pmids":["9552005","11254723"],"confidence":"Medium","gaps":["Ligand on synovial fibroblasts not identified","No downstream signaling characterized","Antibody specificity but no genetic confirmation"]},{"year":2010,"claim":"Loss- and gain-of-function in breast cancer cells resolved the context-dependent role of ITGA5 — promoting fibronectin adhesion/spreading while its growth effect is reversed by matrix engagement — and identified promoter hypermethylation as a silencing mechanism.","evidence":"Overexpression and siRNA in breast cancer lines with growth/adhesion/migration assays; bisulfite sequencing","pmids":["20564209"],"confidence":"Medium","gaps":["Downstream signaling not defined","Effect on growth is context-dependent and not mechanistically resolved"]},{"year":2017,"claim":"Pharmacological and genetic targeting placed ITGA5 upstream of PI3K/Akt/mTOR-driven collagen synthesis, linking the receptor to fibrogenesis beyond cancer.","evidence":"SILAC proteomics, docking, siRNA/overexpression with pathway Western blots, and in vivo liver fibrosis model","pmids":["28689917"],"confidence":"Medium","gaps":["Direct receptor-effector coupling not structurally defined","Single fibrosis model"]},{"year":2019,"claim":"Two advances defined how ITGA5 protein level is post-translationally controlled and how its activity supports the tumor stroma — O-GlcNAcylation stabilizes the protein, and ITGA5 in stellate cells drives desmoplasia that can be therapeutically reversed.","evidence":"In vitro O-GlcNAcylation/IP assays plus xenograft (CRC); siRNA in pancreatic stellate cells with peptidomimetic inhibitor in co-injection and PDX PDAC models","pmids":["31202709","31517053"],"confidence":"High","gaps":["O-GlcNAcylation sites not mapped","Stromal vs. tumor-cell contributions not fully separated"]},{"year":2022,"claim":"A cluster of studies cemented ITGA5 as a fibronectin-triggered signaling hub feeding FAK/AKT, FAK/Src, and FAK/ERK to drive proliferation, invasion, angiogenesis/lymphangiogenesis, and chemoresistance, and identified transcriptional and miRNA regulators.","evidence":"RNAi/overexpression with pathway Western blots, ChIP, luciferase, VEGFA/VEGF-C rescue, and xenografts across gastric, cervical, laryngeal, and breast cancer; EV proteomics for premetastatic niche","pmids":["36193075","36999964","35338412","36438491","35257941","37338646","35149589","35672622"],"confidence":"High","gaps":["Whether FAK/AKT, FAK/Src and FAK/ERK are engaged simultaneously or context-selectively is unresolved","Direct receptor-kinase coupling not biochemically reconstituted for most axes"]},{"year":2023,"claim":"Co-IP studies began mapping ITGA5's direct protein partners and intercellular signaling roles, including the cytoskeletal adaptor ACTN1, the stromal complex with FAPα, and FN1-binding fibroblast subsets that shape immune microenvironments.","evidence":"Co-IP with functional rescue (ACTN1, HNSCC); molecular docking and Co-IP (FAPα, periodontitis); single-cell/spatial transcriptomics and adoptive transfer (ITGA5+ synovial fibroblasts in arthritis)","pmids":["36742137","37979759","39919897"],"confidence":"Medium","gaps":["Binding interfaces not structurally defined","Reciprocal validation limited to single labs"]},{"year":2024,"claim":"EV-mediated transfer and direct kinase binding revealed a cell-non-autonomous mode in which ITGA5 cargo educates recipient cells — binding YES1 to confer stemness and engaging macrophages via SPP1 to drive immune escape — while CRISPR and N-glycosylation work refined how it is trafficked and stabilized.","evidence":"CRISPR KO, EV transfer, Co-IP/MS (YES1, HCC); circRNA-driven N-glycosylation with RIP/pull-down, scRNA-seq, spatial transcriptomics (GBM exosomal ITGA5–SPP1); PTEN interaction by mass spectrometry with electrophysiology (Parkinson model)","pmids":["39574133","40084746","38993558"],"confidence":"High","gaps":["Stoichiometry and directionality of EV transfer in vivo not quantified","How ITGA5 simultaneously binds PTEN and YES1 in different cell types is unexplained"]},{"year":2026,"claim":"Recent work mapped the precise post-translational control of ITGA5 stability and additional ligand- and partner-driven axes, including K137 ubiquitination by DTX1, IMP3-mediated metabolic reprogramming, and CTHRC1/CAF-derived ligands feeding PI3K/AKT.","evidence":"Co-IP with ubiquitination site mapping and in vivo aortic-dissection model (DTX1); Co-IP/MS and RIP with HK2 rescue (IMP3); binding assays with scRNA-seq/spatial transcriptomics (CTHRC1, SPP1)","pmids":["42090073","40385029","41651176","41758046"],"confidence":"Medium","gaps":["Whether DTX1 ubiquitination and OGT/N-glycosylation act competitively on the same protein pool is unknown","IMP3 and PI3K binding interfaces not structurally resolved"]},{"year":null,"claim":"It remains unresolved how ITGA5 selects among its many downstream cascades (FAK/AKT, FAK/Src, FAK/ERK, TAK-1/NF-κB, PI3K/AKT) and direct partners (ACTN1, YES1, PTEN, IMP3, PI3K) in a given cellular context, and what structural basis dictates these context-specific outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of partner selection","Context rules governing which kinase cascade is engaged are undefined","Relative contribution of cell-autonomous vs. EV-transferred ITGA5 in vivo unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,4,5,48]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,16,40,45]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,14]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[29,32,17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,16,40,37]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,4,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,31,51]}],"complexes":["α5β1 integrin (ITGA5/ITGB1)"],"partners":["ITGB1","ACTN1","FAP","YES1","PTEN","IMP3","FN1","DTX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08648","full_name":"Integrin alpha-5","aliases":["CD49 antigen-like family member E","Fibronectin receptor subunit alpha","Integrin alpha-F","VLA-5"],"length_aa":1049,"mass_kda":114.5,"function":"Integrin alpha-5/beta-1 (ITGA5:ITGB1) is a receptor for fibronectin and fibrinogen. It recognizes the sequence R-G-D in its ligands. ITGA5:ITGB1 binds to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 acts as a receptor for fibronectin (FN1) and mediates R-G-D-dependent cell adhesion to FN1 (PubMed:33962943). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973) (Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human metapneumovirus (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human parvovirus B19 (Microbial infection) In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions","subcellular_location":"Cell membrane; Cell junction, focal adhesion","url":"https://www.uniprot.org/uniprotkb/P08648/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA5","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA5","total_profiled":1310},"omim":[{"mim_id":"621448","title":"CYFIP-RELATED RAC1 INTERACTOR A; CYRIA","url":"https://www.omim.org/entry/621448"},{"mim_id":"617978","title":"CYFIP-RELATED RAC1 INTERACTOR B; CYRIB","url":"https://www.omim.org/entry/617978"},{"mim_id":"615507","title":"NISCHARIN; NISCH","url":"https://www.omim.org/entry/615507"},{"mim_id":"612942","title":"RAS-ASSOCIATED PROTEIN RAB25; RAB25","url":"https://www.omim.org/entry/612942"},{"mim_id":"605548","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 15; ADAM15","url":"https://www.omim.org/entry/605548"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":733.7}],"url":"https://www.proteinatlas.org/search/ITGA5"},"hgnc":{"alias_symbol":["CD49e"],"prev_symbol":["FNRA"]},"alphafold":{"accession":"P08648","domains":[{"cath_id":"2.130.10.130","chopping":"48-121_133-490","consensus_level":"medium","plddt":92.9917,"start":48,"end":490},{"cath_id":"2.60.40.1460","chopping":"493-642","consensus_level":"high","plddt":88.5427,"start":493,"end":642},{"cath_id":"2.60.40.1510","chopping":"656-788","consensus_level":"high","plddt":86.9142,"start":656,"end":788},{"cath_id":"2.60.40.1530","chopping":"793-881_908-989","consensus_level":"high","plddt":88.6508,"start":793,"end":989}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08648","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08648-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08648-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA5","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA5"},"sequence":{"accession":"P08648","fasta_url":"https://rest.uniprot.org/uniprotkb/P08648.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08648/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08648"}},"corpus_meta":[{"pmid":"23233531","id":"PMC_23233531","title":"miR148b 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combined blockade of α4β1, α5β1, and β2 integrins with mAbs inhibited PMNL accumulation in the parenchyma by 79% and prevented pulmonary vascular/epithelial permeability.\",\n      \"method\": \"In vivo antibody blocking (mAb to α5β1, α4β1, β2 integrins) in rat intratracheal LPS model; myeloperoxidase assay and BAL fluid cell counts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular phenotype, single lab, two readouts (parenchyma and BAL)\",\n      \"pmids\": [\"11254723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"VLA-5 (α5β1; CD49e/CD29) on monocytes mediates migration through synovial fibroblast barriers independently of CD18 and VLA-4; the inhibitory effect required prior blockade of CD11/CD18 to become apparent, and the ligand on synovial fibroblasts is distinct from VCAM-1.\",\n      \"method\": \"Transwell migration assay with blocking mAbs against α5 (VLA-5), α4 (VLA-4), CD18, and VCAM-1 using HUVEC and human synovial fibroblast barriers; C5a and MCP-1 chemotactic gradients\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional migration assay with multiple blocking antibodies, single lab\",\n      \"pmids\": [\"9552005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Functional surface expression of α5β1 integrin (CD49e/CD29) correlates with fibronectin adherence and disseminative spread of malignant B-cell lines in SCID mice; lines with non-functional or absent α5β1 did not disseminate.\",\n      \"method\": \"Immunohistochemistry and flow cytometry for α5β1 expression; fibronectin adhesion assay in vitro; s.c. xenograft dissemination in SCID mice\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft combined with functional adhesion assay, single lab\",\n      \"pmids\": [\"7534750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ITGA5 (α5 integrin) mRNA and protein are significantly upregulated in rat myometrium during late pregnancy and labor, with expression primarily in myometrial cell membranes; progesterone treatment blocked labor and sustained Itga5 expression, suggesting ITGA5/ITGB1 promotes cellular cohesion to develop a mechanical syncytium for uterine contractions.\",\n      \"method\": \"qRT-PCR, immunoblot, and immunocytochemistry across pregnancy time-points in rat myometrium; progesterone treatment experiment\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunocytochemistry tied to functional context (labor), with temporal expression and pharmacological manipulation, single lab\",\n      \"pmids\": [\"15635129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ITGA5 overexpression in MDA-MB-468 breast cancer cells inhibits cell growth, but adhesion to fibronectin reverses this growth inhibition; ITGA5 overexpression enhances cell adhesion and spreading to fibronectin while reducing migration. Knockdown of ITGA5 in MCF-7 cells also inhibits cell growth but has little effect on migration. Downregulation of ITGA5 in MDA-MB-468 is mediated by promoter hypermethylation.\",\n      \"method\": \"ITGA5 overexpression and siRNA knockdown; cell growth assay, adhesion/spreading assay on fibronectin, migration assay; bisulfite sequencing for methylation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (growth, adhesion, migration), single lab\",\n      \"pmids\": [\"20564209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RNA interference-mediated knockdown of CD49e (ITGA5) in human thymic epithelial cells modulates expression of >100 genes including genes involved in thymocyte adhesion, integrin signaling, and F-actin stress fiber formation, and decreases adhesion of all CD4/CD8-defined thymocyte subsets to TEC.\",\n      \"method\": \"siRNA knockdown of CD49e in human TEC line; transcriptomic profiling; thymocyte adhesion assay\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with transcriptomic and functional (adhesion) readouts, single lab\",\n      \"pmids\": [\"21210968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Alcohol suppresses Nm23, which in turn increases ITGA5 expression, leading to increased breast cancer cell invasion; Nm23 overexpression suppresses ITGA5 upregulation and inhibits alcohol-induced invasion, and ITGA5 knockdown also inhibits alcohol-induced invasion, placing ITGA5 downstream of Nm23 in this pathway.\",\n      \"method\": \"Ethanol treatment of T47D cells; Boyden chamber invasion assay; qRT-PCR array; Nm23 overexpression and ITGA5 siRNA knockdown; Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by overexpression and knockdown experiments with defined invasion phenotype, single lab\",\n      \"pmids\": [\"21838876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Downregulation of ITGA5 by shRNA lentivirus significantly reduces migration capacity of human dental pulp stem cells (hDPSCs) in a transwell assay.\",\n      \"method\": \"Lentiviral shRNA knockdown of ITGA5 in hDPSCs; transwell migration assay\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (transwell), single lab\",\n      \"pmids\": [\"26823759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ITGA5 knockdown reduces proliferation and adipogenic differentiation in human adipose-derived stem cells (ASCs), while ITGA5 transgenic overexpression impairs adipogenesis; these effects are distinct from ITGAV, which specifically regulates proliferation via p21/survivin/TAZ, while ITGA5 does not affect proliferation when knocked down.\",\n      \"method\": \"siRNA knockdown and transgenic overexpression of ITGA5 (and ITGAV) in sorted ASCs; adipogenic differentiation assays; cell proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain-of-function with defined differentiation phenotype, single lab, two orthogonal approaches\",\n      \"pmids\": [\"27363302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Dioscin directly binds ITGA5 and acts as a potent ITGA5 inhibitor; ITGA5 silencing suppresses collagen synthesis via inhibition of the PI3K/Akt/mTOR pathway, reducing FN, FAK1, p-PI3K, p-Akt, p-mTOR, and collagen proteins in liver fibrosis. ITGA5 DNA transfection reverses dioscin's inhibitory effect on collagen expression through the PI3K/Akt pathway.\",\n      \"method\": \"SILAC-based proteomics; molecular docking; siRNA and overexpression transfection of ITGA5 in LX-2 cells; Western blot for PI3K/Akt/mTOR pathway proteins; in vivo liver fibrosis model\",\n      \"journal\": \"Food and chemical toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular docking plus siRNA/overexpression epistasis with pathway readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28689917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"O-GlcNAcylation of ITGA5 protein, mediated by OGT, increases ITGA5 protein stability and expression in colorectal cancer cells; elevated O-GlcNAcylation of ITGA5 promotes CRC cell growth and tumorigenesis.\",\n      \"method\": \"Immunoprecipitation, in vitro O-GlcNAcylation assay, enzymatic labelling of O-GlcNAc; OGT inhibitor (PUGNAc/GlcN) treatment; CCK-8, flow cytometry, xenotransplantation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical identification of PTM (O-GlcNAcylation) on ITGA5 with functional consequence, single lab\",\n      \"pmids\": [\"31202709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGA5 knockdown in pancreatic stellate cells inhibits their differentiation into activated CAFs and reduces desmoplasia in vivo; a peptidomimetic ITGA5 inhibitor (AV3) reduces desmoplasia, decompresses blood vasculature, enhances tumor perfusion, and potentiates gemcitabine efficacy in pancreatic cancer xenograft and PDX models.\",\n      \"method\": \"ITGA5 siRNA knockdown in hPSCs; in vivo co-injection and PDX PDAC models; histology; vascular perfusion assay; 3D heterospheroid model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro loss-of-function plus multiple in vivo models with mechanistic readouts (desmoplasia, vascular decompression, perfusion), replicated in PDX\",\n      \"pmids\": [\"31517053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MRTFA deficiency shifts perivascular progenitor fate from ITGA5+ fibrogenic progenitor cells (FPCs) to adipocyte precursors in adipose tissue during obesity, protecting against fibrosis; ITGA5+ Sca1−Sma+ITGA5+ FPCs are formed in adipose tissue during obesity and the ITGA5-MRTFA pathway governs their identity.\",\n      \"method\": \"MRTFA knockout mice; flow cytometry and immunofluorescence identifying ITGA5+ FPC subpopulation; high-fat diet obesity model; histological fibrosis assessment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cell fate phenotype, single lab\",\n      \"pmids\": [\"29768198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA5 in cervical cancer cells activates downstream PI3K-Akt signaling, increases VEGFA expression and secretion, and promotes endothelial tube formation; fibronectin (FN1) coating modulates ITGA5-mediated angiogenesis, and VEGFA supplementation reverses the decrease in tube formation caused by ITGA5 knockdown.\",\n      \"method\": \"siRNA knockdown of ITGA5; tube formation assay, 3D spheroid sprout assay; Western blot for p-AKT and VEGFA; ELISA; FN1 coating/siRNA experiments\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway readout and rescue experiment, single lab\",\n      \"pmids\": [\"36999964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA5 promotes tumor progression in gastric cancer via activation of the FAK/AKT signaling pathway; ITGA5 silencing inhibits proliferation, invasion, migration, and xenograft growth, while overexpression promotes these functions.\",\n      \"method\": \"ITGA5 siRNA and overexpression in gastric cancer cell lines; Western blot for FAK/AKT; in vitro proliferation/invasion/migration assays; in vivo xenograft model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain-of-function with pathway (FAK/AKT) and in vivo readout, single lab\",\n      \"pmids\": [\"36193075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA5 and ITGB1 overexpression in HCC cells promotes vasculogenic mimicry (VM) formation, reduces sensitivity to sorafenib, and aggravates hypoxia; VM formation contributes to sorafenib resistance.\",\n      \"method\": \"Sorafenib-resistant HCC cell line construction; ITGA5/ITGB1 overexpression; CD31/PAS staining for VM; hypoxia probe by flow cytometry\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression only with limited mechanistic resolution\",\n      \"pmids\": [\"35946175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FN1 drives chemoresistance in TNBC via its receptor ITGA5, activating downstream FAK/Src signaling; miR-326, which is repressed by hypoxia/HIF1A and ECM stiffness, targets ITGA5 to reverse FN1-driven chemoresistance. ITGA5 inhibition overcomes FN1-driven chemotherapy resistance in vitro and potentiates chemotherapy in vivo.\",\n      \"method\": \"RNA/small RNA sequencing; ChIP for HIF1A; ITGA5 knockdown and miR-326 overexpression; 3D cultures; xenograft models; Western blot for FAK/Src; fibronectin coating\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transcriptomics, ChIP, RNAi, xenograft), pathway placement, in vivo validation, single lab\",\n      \"pmids\": [\"35338412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Extracellular vesicle-packaged ITGA5 (together with CDH11) from breast cancer cells with high RUNX2 educates osteoblasts to form an osteogenic premetastatic niche; CDH11high/ITGA5high EVs promote bone colonization by RUNX2-high breast cancer cells.\",\n      \"method\": \"In vitro and in vivo EV transfer experiments; osteoblast education assay; bone metastasis mouse model; EV proteomics\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro EV transfer with specific protein cargo identification, single lab\",\n      \"pmids\": [\"35149589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Elevated ITGA5 is a downstream effector of hyperactivated mTORC1 in laryngeal squamous cell carcinoma; ITGA5 promotes LSCC progression through upregulation of ephrin-B2 (EFNB2), and inhibition of ITGA5 sensitizes cells to cisplatin in CDX and PDX models.\",\n      \"method\": \"Raptor knockdown (mTORC1 inhibition); transcriptomic sequencing; ITGA5 functional assays; in vivo CDX and PDX models; Western blot\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (mTORC1→ITGA5→EFNB2) with in vivo validation, single lab\",\n      \"pmids\": [\"36438491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEAT1 lncRNA acts as a sponge for miR-128-3p in glioma, relieving miR-128-3p-mediated repression of ITGA5; elevated ITGA5 then activates the FAK signaling pathway to promote cell growth.\",\n      \"method\": \"Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation; CCK-8, transwell, flow cytometry in U87MG and U251MG cells; ITGA5 siRNA and NEAT1 overexpression/knockdown\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays plus functional rescue experiments, single lab\",\n      \"pmids\": [\"34263426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Leptin reduces ITGA5 expression in adipocytes, thereby inhibiting activation of the PI3K/AKT signaling pathway, alleviating adipose tissue fibrosis and promoting white fat browning; ITGA5 overexpression with wortmannin (PI3K inhibitor) treatment confirmed ITGA5 acts upstream of PI3K/AKT in fibrosis.\",\n      \"method\": \"Leptin treatment; proteomics screening; ITGA5 overexpression and siRNA in adipocytes; TGF-β/HFD fibrosis model; qPCR, WB, IHC, immunofluorescence; wortmannin inhibitor\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified target with gain/loss-of-function and pharmacological pathway confirmation, single lab\",\n      \"pmids\": [\"34830238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AFAP1L1 interacts with VAV2 guanine nucleotide exchange factor to activate Rho GTPase CDC42, which then promotes ITGA5 expression and integrin signaling pathway activation in gastric cancer, driving EMT and metastasis.\",\n      \"method\": \"Co-immunoprecipitation; cell adhesion assay; in vitro and in vivo GC functional assays; ITGA5 expression analysis after AFAP1L1 manipulation\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP to establish protein interaction, epistasis via signaling pathway, single lab\",\n      \"pmids\": [\"36631800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FGA (fibrinogen α chain) transcriptionally suppresses ITGA5 expression (confirmed by luciferase and ChIP assays), leading to inhibition of the FAK/ERK pathway and suppression of gastric cancer cell motility, EMT, and autophagy.\",\n      \"method\": \"Luciferase reporter and ChIP assays confirming FGA transcriptional regulation of ITGA5; Western blot for FAK/ERK; in vivo BALB/c xenograft model\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional regulation confirmed by luciferase and ChIP, pathway readout, in vivo validation, single lab\",\n      \"pmids\": [\"35257941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA5 knockdown in LSCC cells inhibits expression and secretion of VEGF-C, suppresses lymphatic endothelial cell tube formation and LSCC cell migration/invasion; exogenous VEGF-C supplementation reverses these effects, placing ITGA5 upstream of VEGF-C in lymphangiogenesis.\",\n      \"method\": \"siRNA knockdown of ITGA5; tube formation assay with HLECs; ELISA for VEGF-C; transwell co-culture; in vivo subcutaneous graft model\",\n      \"journal\": \"Protoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with VEGF-C rescue, in vitro and in vivo, single lab\",\n      \"pmids\": [\"37338646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACTN1 (α-Actinin 1) physically interacts with ITGA5 (confirmed by Co-IP) in HNSCC cells; ACTN1 depletion reduces proliferation, invasion, migration, and EMT, and these effects are reversed by ITGA5 overexpression, demonstrating ACTN1 acts through ITGA5.\",\n      \"method\": \"Co-immunoprecipitation; CCK8, colony formation, EdU, transwell, wound healing assays; immunofluorescence; xenograft in nude mice; IHC for Ki-67\",\n      \"journal\": \"Iranian journal of basic medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction plus functional rescue, single lab\",\n      \"pmids\": [\"36742137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAPα and ITGA5 form a protein complex in the inflammatory microenvironment of chronic apical periodontitis; silencing either protein decreases osteoclast differentiation; molecular docking shows FAPα binds ITGA5 with -14.5 kcal/mol free energy.\",\n      \"method\": \"Molecular docking; co-immunoprecipitation; immunofluorescence staining; FAPα/ITGA5 siRNA silencing; osteoclast differentiation assay\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms complex formation, functional consequence by silencing, single lab\",\n      \"pmids\": [\"37979759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 stabilizes HOXD8 mRNA in an m6A-dependent manner; HOXD8 then transcriptionally activates ITGA5 (confirmed by ChIP and luciferase), and elevated ITGA5 enhances osteogenic differentiation of CPT periosteum-derived MSCs.\",\n      \"method\": \"MeRIP assay for m6A modification of HOXD8; luciferase reporter assay; ChIP assay; METTL3/HOXD8/ITGA5 overexpression; Alizarin Red S and ALP assays\",\n      \"journal\": \"Regenerative therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical assays establishing transcriptional hierarchy, single lab\",\n      \"pmids\": [\"38818480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FN1 secreted by dental pulp stem cells (DPSCs) promotes endothelial cell proliferation, migration, and tube formation via ITGA5 and downstream PI3K/AKT signaling pathway during dental pulp vascularization.\",\n      \"method\": \"Co-culture of DPSCs and HUVECs; Western blot for FN1, ITGA5, PI3K/AKT; cell proliferation, scratch, and tube formation assays; siRNA knockdown; in vivo mouse experiments\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments establishing FN1-ITGA5-PI3K/AKT axis, single lab\",\n      \"pmids\": [\"38418738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Itga5 interacts with PTEN in striatal neurons; Itga5 deficiency in MPTP-induced Parkinson's disease models reduces dendritic spine density, alters synaptic architecture, and impairs motor coordination through reduced AKT signaling; a TAT-Itga5 peptide designed to suppress PTEN activity rescues these deficits.\",\n      \"method\": \"MPTP mouse model; CRISPR-CasRx knockdown; mass spectrometry; electrophysiology; Western blot; behavioral tests; immunostaining for spine morphology\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockdown with electrophysiological and behavioral readouts plus mass spectrometry-identified PTEN interaction, single lab\",\n      \"pmids\": [\"38993558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circSDHAF2 promotes N-glycosylation of ITGA5 protein, stabilizing it and facilitating its translocation into exosomes; exosomal ITGA5 is delivered to macrophages and induces SPP1+ MDM formation, which maintains mesenchymal GBM cell status and drives T-cell dysfunction via the SPP1-ITGA5 pathway, promoting immune escape.\",\n      \"method\": \"Co-immunoprecipitation; RNA immunoprecipitation; pull-down assays; single-cell RNA sequencing; spatial transcriptomics; in vitro and in vivo validation\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pull-down for mechanism, in vivo validation, single lab, multiple methods\",\n      \"pmids\": [\"40084746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGFBP2 promotes gefitinib resistance in NSCLC by activating STAT3/CXCL1 axis; ITGA5 is identified as a key player in IGFBP2-mediated resistance but does NOT function as a membrane receptor linking IGFBP2 to intracellular signaling transduction (negative finding for that specific mechanism).\",\n      \"method\": \"In vitro and in vivo resistance experiments; IGFBP2/ITGA5 knockdown; Western blot for STAT3/CXCL1\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic role of ITGA5 in resistance established but specific receptor function explicitly negated; limited mechanistic detail on ITGA5's actual mechanism\",\n      \"pmids\": [\"38918360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGA5+ synovial fibroblasts (POSTN+, COL3A1+, CCL5+, TGFB1+) are induced to differentiate by TGF-β1 and promote differentiation of naïve CD4+ T cells into CXCL13hiPD-1hi peripheral helper T cells via TGF-β1 secretion; intra-articular injection of ITGA5+ fibroblasts exacerbates collagen-induced arthritis and upregulates TPH cells in mice.\",\n      \"method\": \"Single-cell and spatial transcriptomics; flow cytometry; co-culture assay; adoptive transfer in CIA mice; bulk RNA sequencing of synovial joints; multiplex immunofluorescence\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer in vivo plus co-culture mechanistic assays, single lab\",\n      \"pmids\": [\"39919897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myofibroblast-derived extracellular vesicles transfer ITGA5 protein to HCC cells; ITGA5 delivered to HCC cells directly binds YES1 kinase, activating YES1 and downstream pathways to enhance cancer stem cell-like properties; CRISPR KO of ITGA5 in myofibroblasts impairs this process.\",\n      \"method\": \"CRISPR Cas9 KO; EV isolation and transfer; Co-IP/mass spectrometry; sphere-forming assay; stemness marker expression; orthotopic HCC mouse model; tissue microarray\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP/MS identifies YES1 as direct ITGA5 binding partner, CRISPR KO, in vivo validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39574133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA5 on tumor cells binds fibronectin (FN1) in the Schwann cell extracellular matrix, triggering reprogramming of Schwann cells to a reparative phenotype with enhanced NGF secretion; increased NGF suppresses NK cell cytotoxicity by inhibiting IFN-γ, promoting immune evasion and perineural invasion.\",\n      \"method\": \"Functional assays for SC reprogramming; NGF secretion measurement; NK cell cytotoxicity assay; IFN-γ quantification; cilengitide (ITGA5 inhibitor) treatment with anti-PD-1 therapy\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays establishing ITGA5-FN1-Schwann cell-NGF-NK cell axis, single lab\",\n      \"pmids\": [\"40734271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"13-Methylpalmatine suppresses ITGA5 expression and inhibits activation of the TGF-β/Smad signaling pathway; ITGA5 silencing confirms ITGA5 acts upstream of TGF-β/Smad in pulmonary fibrosis, and ITGA5 overexpression reverses 13-Me-PLT's antifibrotic effect.\",\n      \"method\": \"Transcriptomic sequencing; molecular docking and SPR for direct binding; ITGA5 silencing and overexpression in MRC5 cells; BLM mouse model; Smad pathway Western blot\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR confirms direct compound-ITGA5 binding, epistasis via siRNA/overexpression, in vivo model, single lab\",\n      \"pmids\": [\"40023972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TLN1 (Talin-1) overexpression increases ITGA5 expression; ITGA5 knockdown reverses the protective effects of TLN1 on cardiac microvascular endothelial cells under ox-LDL injury, demonstrating TLN1 acts through ITGA5 to regulate CMVEC function.\",\n      \"method\": \"TLN1 overexpression and ITGA5 siRNA knockdown in ox-LDL-treated CMVECs; proliferation, apoptosis, angiogenesis, inflammation, oxidative stress assays\",\n      \"journal\": \"Folia morphologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, genetic epistasis without biochemical binding confirmation\",\n      \"pmids\": [\"37144848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In zebrafish, prdm1a acts upstream of itga5 in posterior pharyngeal arch development; prdm1a mutants show decreased itga5 expression, and injection of itga5 mRNA into prdm1a mutants rescues loss of posterior pharyngeal arch dlx2a expression, ceratobranchial cartilages 2-5, and cell proliferation.\",\n      \"method\": \"In situ hybridization; double prdm1a;itga5 mutant analysis; mRNA rescue injection; cell proliferation assay\",\n      \"journal\": \"Genesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis established by double mutant and mRNA rescue in zebrafish (ortholog model), single lab\",\n      \"pmids\": [\"25810090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA5 drives angiogenesis in diabetic retinopathy by activating the TAK-1/NF-κB signaling pathway; ITGA5 knockdown in vivo reduces neovascularization, decreases FAK, TAK-1, and p65 phosphorylation, and reduces VEGFA, VCAM-1, and ICAM-1 expression.\",\n      \"method\": \"Streptozotocin-induced diabetic rat model; intravitreal AAV-mediated ITGA5 knockdown; oxygen-induced retinopathy model; Western blot for FAK/TAK-1/NF-κB; tube formation and invasion in high glucose-treated RRMECs\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro KD with pathway readout, single lab\",\n      \"pmids\": [\"40410450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RPRD1A competes with RPAP2 for binding to RNA Pol II, derepressing ITGA5 transcription via a c-JUN-dependent pathway; upregulated ITGA5 then activates FAK signaling to drive lenvatinib resistance in HCC; combined lenvatinib with ITGA5 inhibitor (volociximab) or FAK inhibitor (defactinib) reverses resistance.\",\n      \"method\": \"Functional resistance assays; Western blot; transcriptional mechanism assays (RPRD1A-RPAP2-RNA Pol II competition); ITGA5 inhibition and FAK inhibition in preclinical models\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional mechanism established with pathway placement and pharmacological validation, single lab\",\n      \"pmids\": [\"42171939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DTX1 E3 ubiquitin ligase directly interacts with ITGA5 and promotes its ubiquitination at lysine 137, leading to proteasome-dependent degradation of ITGA5 and maintenance of the contractile VSMC phenotype; DTX1 overexpression reduces ITGA5 levels and attenuates aortic dissection progression in vivo.\",\n      \"method\": \"Co-immunoprecipitation; protein stability analysis; ubiquitination site identification (K137); gain/loss-of-function in HASMCs; BAPN-induced AD mouse model; Western blot, qPCR, immunofluorescence\",\n      \"journal\": \"Cardiovascular drugs and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies direct interaction, specific ubiquitination site mapped, in vivo validation, single lab\",\n      \"pmids\": [\"42090073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA5 directly binds PI3K in vitro (confirmed by binding assay); ITGA5-mediated PI3K/AKT pathway activation promotes EMT and anoikis resistance in bronchial epithelial cells; ITGA5 knockdown reverses TGF-β1-induced EMT and restores anoikis sensitivity.\",\n      \"method\": \"Quantitative proteomics; ITGA5 knockdown; Western blot for PI3K/AKT; EMT and anoikis assays; molecular docking and dynamics; in vitro PI3K binding assay; in vivo asthma mouse model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro PI3K binding confirmed, functional epistasis with rescue, single lab\",\n      \"pmids\": [\"41772919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MFAP5, an extracellular matrix component, engages ITGA5 to activate ERK/MAPK signaling in odontoblast-lineage cells, promoting odontoblast differentiation and dentin deposition during tooth mineralization.\",\n      \"method\": \"10× single-cell RNA sequencing; functional differentiation assays in vitro; ITGA5 and MFAP5 manipulation; Western blot for ERK/MAPK\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays establish pathway axis but limited mechanistic detail on direct binding; single lab\",\n      \"pmids\": [\"41516268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SPP1-ITGA5 interaction between SPP1+ macrophages and ITGA5+ fibroblasts in HCC triggers secretion of MMP2 by fibroblasts, promoting HCC malignant progression; confirmed by co-immunoprecipitation and cell co-culture assays with in vivo validation.\",\n      \"method\": \"Co-immunoprecipitation; cell co-culture; in vivo mouse transplantation model; single-cell RNA sequencing; spatial transcriptomics; multiplexed immunofluorescence\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms SPP1-ITGA5 interaction, functional consequence (MMP2) established in vitro and in vivo, single lab\",\n      \"pmids\": [\"41758046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBX2 transcription factor binds to the promoter region of ITGA5 and activates its transcription, upregulating ITGA5 expression in bladder cancer cells to promote viability, migration, and invasion.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP); luciferase reporter assay for promoter binding; GBX2 knockdown and ITGA5 overexpression rescue experiments\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional regulation, rescue experiment, single lab\",\n      \"pmids\": [\"35672622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA5 promotes GBM cell invasion and migration through SLK (a downstream kinase of the PI3K-Akt pathway); ITGA5 knockdown reduces SLK expression and activity, and this mechanism was identified by proteomics and phosphoproteomics after ITGA5 knockdown.\",\n      \"method\": \"Proteomics and phosphoproteomics after ITGA5 knockdown; in vitro invasion/migration assays; in vivo GBM model; Western blot; single-cell RNA sequencing\",\n      \"journal\": \"Neurological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified pathway with functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"40544320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CTHRC1 secreted by cancer-associated fibroblasts directly binds ITGA5 on tumor cells, activating the PI3K/AKT signaling pathway to promote proliferation, EMT, and angiogenesis in HNSCC.\",\n      \"method\": \"Functional experiments in vitro and in vivo; protein binding confirmation; Western blot for PI3K/AKT; single-cell RNA sequencing; spatial transcriptomics\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding established, pathway readout, in vivo validation, single lab\",\n      \"pmids\": [\"41651176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ITGA5 interacts with IMP3 (insulin-like growth factor II mRNA binding protein 3), and this interaction regulates IMP3-mediated recruitment of HK2 mRNA, promoting the Warburg effect and cervical cancer progression; HK2 overexpression rescues the effects of ITGA5 knockdown.\",\n      \"method\": \"Mass spectrometry (Co-IP/MS); Co-immunoprecipitation; RNA immunoprecipitation (RIP); Western blot; xenograft in nude mice; rescue experiment with HK2 overexpression\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifies IMP3 as ITGA5-interacting partner, RIP confirms mRNA recruitment mechanism, rescue experiment, single lab\",\n      \"pmids\": [\"40385029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Resibufogenin (RBG) activates the ITGA5-VEGF signaling axis in a macrophage-dependent manner to promote reparative angiogenesis in myocardial infarction; RBG upregulates ITGA5 in macrophages via the VAV3/CDC42 signaling pathway; pharmacological ITGA5 inhibition or macrophage depletion completely abolishes RBG-mediated cardioprotection.\",\n      \"method\": \"Proteomic analysis; macrophage-endothelial co-culture; ITGA5 inhibition; macrophage depletion; MI mouse model; tube formation assay; Western blot for VAV3/CDC42/ITGA5/VEGF\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified axis, pharmacological and cell-depletion epistasis in vivo, single lab\",\n      \"pmids\": [\"42056214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nitric oxide (NO) prevents hypoxia-induced ITGA5 CpG promoter hypermethylation by DNMT1 in endothelial progenitor cells; hypoxia suppresses miR-148 levels, increasing DNMT1-mediated ITGA5 promoter methylation and reducing ITGA5 expression and cell-matrix adhesion; NO or miR-148 overexpression restores ITGA5 expression and adhesion.\",\n      \"method\": \"miScript miRNA qPCR array; DNMT1 inhibitor (5'-azacitidine); miR-148 overexpression; eNOS-GFP transfection; hypoxia model in EPCs; cell-matrix adhesion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism (CpG methylation) confirmed with multiple interventions and functional adhesion readout, single lab\",\n      \"pmids\": [\"36669384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HIF-1A and NFATC1 transcription factors regulate ITGA5 gene expression in intestinal epithelial cells under hypoxia; chemical activation of HIF signaling (cobalt chloride/oxyquinoline) upregulates ITGA5 expression in Caco-2 cells, confirmed by RNA sequencing and proteomics.\",\n      \"method\": \"RNA sequencing and proteomics of HIF-activated Caco-2 cells; bioinformatic transcription factor analysis (miRGTF tool); validation in IBD patient RNA-seq datasets\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcription factor assignment is computational with limited direct experimental validation of binding, single lab\",\n      \"pmids\": [\"34858489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"ITGA5 (FNRA, fibronectin receptor alpha subunit) maps to chromosome 12 in humans, confirmed using human-rodent somatic cell hybrids and cDNA probes.\",\n      \"method\": \"Somatic cell hybrid mapping with cDNA probes\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — chromosomal mapping only, no functional mechanism\",\n      \"pmids\": [\"1722386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD49e (ITGA5) on Burkitt lymphoma cells mediates cell adhesion-mediated drug resistance (CAM-DR) via NF-κB pathway activation, increasing Bcl-xL and survivin and decreasing Bax, Bim, and PUMA; bortezomib overcomes CAM-DR by inhibiting NF-κB.\",\n      \"method\": \"CD49e blocking antibodies; NF-κB activity assay; Western blot for apoptosis proteins; bortezomib treatment; adhesion-based drug resistance assay\",\n      \"journal\": \"Journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with NF-κB pathway readout and pharmacological rescue, single lab\",\n      \"pmids\": [\"33214335\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA5 (integrin α5, CD49e) encodes the α-subunit of the α5β1 fibronectin receptor and functions as a transmembrane signaling hub that, upon engaging fibronectin or other ligands, activates downstream FAK/AKT, PI3K/AKT/mTOR, FAK/Src, FAK/ERK, and TAK-1/NF-κB signaling cascades to regulate cell adhesion, migration, invasion, EMT, angiogenesis/lymphangiogenesis, and survival; its activity is modulated post-translationally by O-GlcNAcylation (which stabilizes the protein) and ubiquitination by DTX1 (which targets it for proteasomal degradation at K137), and transcriptionally by GBX2, HOXD8 (downstream of METTL3-mediated m6A), HIF-1A/NFATC1, and RPRD1A/c-JUN; ITGA5 forms functional complexes with ACTN1, FAPα, LGMN, IMP3, PTEN, and YES1 kinase, and can be transferred between cells via extracellular vesicles to confer cancer stem cell properties or educate the tumor microenvironment, while its expression is negatively regulated by multiple miRNAs (miR-148b, miR-326, miR-330-5p, miR-128, miR-17, miR-27b, miR-26a, miR-92a, miR-328-3p) and its promoter is subject to methylation-mediated silencing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA5 encodes the α5 subunit (CD49e/VLA-5) of the α5β1 fibronectin receptor, a transmembrane adhesion molecule that engages fibronectin and other extracellular-matrix ligands to couple cell-matrix contact to intracellular signaling and to control adhesion, spreading, migration, invasion, EMT, and angiogenesis across diverse normal and malignant tissues [#2, #4, #14]. Upon ligand engagement, ITGA5 nucleates signaling through FAK-anchored cascades — FAK/AKT in gastric cancer [#14], FAK/Src in fibronectin-driven chemoresistant breast cancer [#16], FAK/ERK whose suppression blocks gastric-cancer motility [#22], and a TAK-1/NF-κB axis driving diabetic-retinopathy neovascularization [#37] — and through direct activation of PI3K/AKT, with ITGA5 binding PI3K in vitro to promote EMT and anoikis resistance [#40, #13, #45]. This receptor function repeatedly drives a pro-angiogenic/pro-lymphangiogenic program by elevating VEGFA and VEGF-C secretion [#13, #23] and operates in fibrogenic contexts upstream of PI3K/Akt/mTOR collagen synthesis and TGF-β/Smad signaling [#9, #34]. ITGA5 abundance is gated post-translationally — O-GlcNAcylation by OGT and N-glycosylation stabilize the protein [#10, #29], while the DTX1 E3 ligase ubiquitinates ITGA5 at K137 for proteasomal degradation [#39] — and transcriptionally by activators (GBX2, HOXD8 downstream of METTL3 m6A, HIF-1A, RPRD1A/c-JUN) and repressors including promoter hypermethylation and multiple miRNAs such as miR-326 and miR-128-3p [#43, #26, #16, #19, #38, #48]. ITGA5 forms functional complexes with the cytoskeletal adaptor ACTN1, with FAPα, and with YES1 kinase, IMP3, and PTEN, and is transferred between cells in extracellular vesicles to confer cancer stem-cell properties and remodel the tumor microenvironment [#24, #25, #32, #46, #28, #29, #17]. Beyond cancer, ITGA5 mediates leukocyte recruitment and adhesion, stem/progenitor differentiation, myometrial contractility, and neuronal synaptic architecture via a PTEN/AKT interaction [#0, #8, #3, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the genomic identity of the fibronectin receptor alpha subunit gave the molecular anchor for all subsequent functional study.\",\n      \"evidence\": \"Somatic cell hybrid mapping with cDNA probes localizing FNRA to chromosome 12\",\n      \"pmids\": [\"1722386\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional or mechanistic information\", \"Chromosomal localization only\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Functional blocking assays first showed that α5β1 mediates a distinct, integrin-redundant adhesion/migration program in immune cells, distinguishing it from VLA-4 and β2 integrins.\",\n      \"evidence\": \"Transwell migration with blocking mAbs across HUVEC and synovial fibroblast barriers (monocytes); in vivo mAb blockade in LPS-induced lung inflammation (neutrophils)\",\n      \"pmids\": [\"9552005\", \"11254723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand on synovial fibroblasts not identified\", \"No downstream signaling characterized\", \"Antibody specificity but no genetic confirmation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Loss- and gain-of-function in breast cancer cells resolved the context-dependent role of ITGA5 — promoting fibronectin adhesion/spreading while its growth effect is reversed by matrix engagement — and identified promoter hypermethylation as a silencing mechanism.\",\n      \"evidence\": \"Overexpression and siRNA in breast cancer lines with growth/adhesion/migration assays; bisulfite sequencing\",\n      \"pmids\": [\"20564209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling not defined\", \"Effect on growth is context-dependent and not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Pharmacological and genetic targeting placed ITGA5 upstream of PI3K/Akt/mTOR-driven collagen synthesis, linking the receptor to fibrogenesis beyond cancer.\",\n      \"evidence\": \"SILAC proteomics, docking, siRNA/overexpression with pathway Western blots, and in vivo liver fibrosis model\",\n      \"pmids\": [\"28689917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-effector coupling not structurally defined\", \"Single fibrosis model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two advances defined how ITGA5 protein level is post-translationally controlled and how its activity supports the tumor stroma — O-GlcNAcylation stabilizes the protein, and ITGA5 in stellate cells drives desmoplasia that can be therapeutically reversed.\",\n      \"evidence\": \"In vitro O-GlcNAcylation/IP assays plus xenograft (CRC); siRNA in pancreatic stellate cells with peptidomimetic inhibitor in co-injection and PDX PDAC models\",\n      \"pmids\": [\"31202709\", \"31517053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"O-GlcNAcylation sites not mapped\", \"Stromal vs. tumor-cell contributions not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A cluster of studies cemented ITGA5 as a fibronectin-triggered signaling hub feeding FAK/AKT, FAK/Src, and FAK/ERK to drive proliferation, invasion, angiogenesis/lymphangiogenesis, and chemoresistance, and identified transcriptional and miRNA regulators.\",\n      \"evidence\": \"RNAi/overexpression with pathway Western blots, ChIP, luciferase, VEGFA/VEGF-C rescue, and xenografts across gastric, cervical, laryngeal, and breast cancer; EV proteomics for premetastatic niche\",\n      \"pmids\": [\"36193075\", \"36999964\", \"35338412\", \"36438491\", \"35257941\", \"37338646\", \"35149589\", \"35672622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FAK/AKT, FAK/Src and FAK/ERK are engaged simultaneously or context-selectively is unresolved\", \"Direct receptor-kinase coupling not biochemically reconstituted for most axes\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-IP studies began mapping ITGA5's direct protein partners and intercellular signaling roles, including the cytoskeletal adaptor ACTN1, the stromal complex with FAPα, and FN1-binding fibroblast subsets that shape immune microenvironments.\",\n      \"evidence\": \"Co-IP with functional rescue (ACTN1, HNSCC); molecular docking and Co-IP (FAPα, periodontitis); single-cell/spatial transcriptomics and adoptive transfer (ITGA5+ synovial fibroblasts in arthritis)\",\n      \"pmids\": [\"36742137\", \"37979759\", \"39919897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interfaces not structurally defined\", \"Reciprocal validation limited to single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"EV-mediated transfer and direct kinase binding revealed a cell-non-autonomous mode in which ITGA5 cargo educates recipient cells — binding YES1 to confer stemness and engaging macrophages via SPP1 to drive immune escape — while CRISPR and N-glycosylation work refined how it is trafficked and stabilized.\",\n      \"evidence\": \"CRISPR KO, EV transfer, Co-IP/MS (YES1, HCC); circRNA-driven N-glycosylation with RIP/pull-down, scRNA-seq, spatial transcriptomics (GBM exosomal ITGA5–SPP1); PTEN interaction by mass spectrometry with electrophysiology (Parkinson model)\",\n      \"pmids\": [\"39574133\", \"40084746\", \"38993558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and directionality of EV transfer in vivo not quantified\", \"How ITGA5 simultaneously binds PTEN and YES1 in different cell types is unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Recent work mapped the precise post-translational control of ITGA5 stability and additional ligand- and partner-driven axes, including K137 ubiquitination by DTX1, IMP3-mediated metabolic reprogramming, and CTHRC1/CAF-derived ligands feeding PI3K/AKT.\",\n      \"evidence\": \"Co-IP with ubiquitination site mapping and in vivo aortic-dissection model (DTX1); Co-IP/MS and RIP with HK2 rescue (IMP3); binding assays with scRNA-seq/spatial transcriptomics (CTHRC1, SPP1)\",\n      \"pmids\": [\"42090073\", \"40385029\", \"41651176\", \"41758046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DTX1 ubiquitination and OGT/N-glycosylation act competitively on the same protein pool is unknown\", \"IMP3 and PI3K binding interfaces not structurally resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ITGA5 selects among its many downstream cascades (FAK/AKT, FAK/Src, FAK/ERK, TAK-1/NF-κB, PI3K/AKT) and direct partners (ACTN1, YES1, PTEN, IMP3, PI3K) in a given cellular context, and what structural basis dictates these context-specific outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of partner selection\", \"Context rules governing which kinase cascade is engaged are undefined\", \"Relative contribution of cell-autonomous vs. EV-transferred ITGA5 in vivo unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 4, 5, 48]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 16, 40, 45]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 14]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [29, 32, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 16, 40, 37]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 4, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 31, 51]}\n    ],\n    \"complexes\": [\"α5β1 integrin (ITGA5/ITGB1)\"],\n    \"partners\": [\"ITGB1\", \"ACTN1\", \"FAP\", \"YES1\", \"PTEN\", \"IMP3\", \"FN1\", \"DTX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}