{"gene":"ITGAV","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"αvβ3 integrin (ITGAV/CD51 + β3) on melanoma cells directly binds human Thy-1 (CD90) expressed on activated endothelial cells, mediating melanoma cell adhesion and transmigration across the endothelium; this interaction was demonstrated by binding of purified Thy-1 to αvβ3-transfected cells and to purified αvβ3 integrin, and by blockade experiments under static and flow conditions.","method":"Purified protein binding assay, transfected cell adhesion assay, functional blocking antibody under static and flow conditions","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with purified proteins and transfected cells, single lab, multiple orthogonal methods","pmids":["15897908"],"is_preprint":false},{"year":2000,"finding":"Coxsackievirus A9 binds integrin αvβ3 (CD51/CD61) at the CYDMKTTC sequence (residues 187–193) of the β3 subunit; importantly, an RGD-less CAV-9 mutant can still bind this site efficiently, demonstrating that RGD in the viral VP1 protein is not required for high-affinity interaction with αvβ3.","method":"Binding studies on CHO cells expressing αvβ3, αvβ1, or chimeric αvβ1-3-1 mutants; function-blocking monoclonal antibodies; competition with natural ligand vitronectin","journal":"Human immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-line variants and blocking reagents, single lab","pmids":["10773347"],"is_preprint":false},{"year":1995,"finding":"Human fetal liver-derived mast cells cultured with stem cell factor acquire functional CD51/CD61 (αvβ3) receptors and spontaneously adhere to vitronectin through this receptor; adhesion to fibronectin and laminin is partially inhibited by anti-CD61 and anti-CD29 antibodies, but no degranulation occurs during vitronectin-dependent adhesion.","method":"Flow cytometry, adhesion measurements, antibody-blocking assays, culture differentiation model","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional adhesion assays with blocking antibodies, single lab, multiple ligands tested","pmids":["7542504"],"is_preprint":false},{"year":2016,"finding":"ITGAV knockdown in human adipose-derived stem cells (ASCs) reduces proliferation, induces p21(Cip1), represses survivin, and specifically regulates the Hippo pathway mediator TAZ, while knockdown of either ITGAV or ITGA5 promotes adipogenic differentiation; transgenic ITGAV overexpression impairs adipogenesis, placing ITGAV as a negative regulator of adipogenic differentiation via RGD-motif signaling.","method":"siRNA knockdown, transgenic overexpression, cell proliferation assays, gene expression profiling, cilengitide pharmacological inhibition","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD and OE with defined molecular readouts, single lab, multiple orthogonal approaches","pmids":["27363302"],"is_preprint":false},{"year":2016,"finding":"Periostin (Postn) interacts with Itgav to regulate hematopoietic stem cell (HSC) proliferation via outside-in signaling; Itgav deletion in the hematopoietic system recapitulates peripheral blood phenotypes of Postn-knockout mice; mechanistically, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, increasing p27Kip1 expression and maintaining HSC quiescence.","method":"Conditional knockout mice (Vav-Cre), Postn-/- mice, HSC repopulation assays, in vitro proliferation, pathway analysis (FAK/PI3K/AKT/p27Kip1)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic models (Postn KO and Itgav conditional KO), multiple orthogonal readouts, defined signaling pathway","pmids":["27905395"],"is_preprint":false},{"year":2017,"finding":"ITGAV-containing integrin receptors on porcine trophoblast (pTr2) cells directly mediate adhesion to SPP1 (osteopontin); siRNA knockdown of ITGAV in pTr2 cells significantly reduces attachment to SPP1, and ITGAV, ITGB3 and SPP1 co-localize in large aggregates at the uterine luminal epithelium–trophoblast interface on Day 25 of gestation.","method":"siRNA knockdown, cell adhesion assay, in situ hybridization, immunofluorescence co-localization","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with direct adhesion readout plus co-localization, single lab","pmids":["28250242"],"is_preprint":false},{"year":2016,"finding":"CD51 (ITGAV) binds TGF-β receptors in colorectal cancer cells and upregulates TGF-β/Smad signaling; CD51+ CRC cells display enhanced sphere-forming, tumorigenic, migratory, invasive, and chemoresistance capacities compared to CD51- cells; CD51 knockdown reduces side population, sphere formation, motility, tumor incidence and metastasis in vivo.","method":"Co-immunoprecipitation (CD51–TGF-β receptor binding), siRNA knockdown, sphere-forming assay, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding plus functional KD with multiple defined readouts, single lab","pmids":["27593923"],"is_preprint":false},{"year":2019,"finding":"Macrophage-expressed CD51 contributes to the acquisition of cancer stem cell (CSC) stemness traits in pancreatic cancer cells via the TGF-β1/Smad2/3 paracrine pathway; CD51 knockdown in macrophages drives them toward an M1-like phenotype and reduces CSC properties in co-cultured pancreatic cancer cells.","method":"siRNA knockdown in macrophages, co-culture assays, pathway analysis (TGF-β1/Smad2/3), phenotype characterization","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with mechanistic pathway readout (Smad2/3), single lab, co-culture model","pmids":["31199988"],"is_preprint":false},{"year":2020,"finding":"TAZ (WWTR1), but not YAP, specifically drives ITGAV transcription in hepatocellular carcinoma cells; ITGAV promotes actin stress fiber assembly, tumor cell migration and invasion; perturbation of ITGAV diminishes actin fiber formation and reduces nuclear YAP/TAZ protein levels, establishing a positive feedback loop amplifying Hippo pathway activity.","method":"RNAi knockdown (TAZ, YAP, ITGAV), comprehensive expression profiling, actin staining, migration/invasion assays, nuclear fractionation","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-specific RNAi with multiple orthogonal phenotypic readouts, single lab","pmids":["31904487"],"is_preprint":false},{"year":2023,"finding":"Runx2 transcriptionally activates Itgav expression by binding to its promoter in hepatic stellate cells (HSCs); Itgav is required downstream of Runx2 for HSC activation; blockade of Itgav attenuates Runx2-induced HSC activation and liver fibrosis in multiple mouse models; cytokines (TGF-β1, PDGF, EGF) promote Runx2 nuclear translocation via PKA.","method":"Runx2 ChIP-seq identifying ITGAV promoter binding, RNA-seq, siRNA/shRNA knockdown, HSC-specific in vivo overexpression/knockdown (HBAAV-Runx2, VA-Lip-Runx2), CCl4/DDC/MCD mouse models","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq demonstrating direct promoter binding, multiple mouse fibrosis models, epistasis (Itgav blockade reverses Runx2 effect), multiple orthogonal methods","pmids":["37403784"],"is_preprint":false},{"year":2024,"finding":"CD51 undergoes transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD); CD51-ICD facilitates HCC invasion and metastasis by promoting transcription of oxidative phosphorylation-related genes; cancer-associated fibroblast-derived periostin is the major driver of CD51 cleavage; combined inhibition of surface CD51 (cilengitide) and γ-secretase (LY3039478) shows enhanced therapeutic efficacy in patient-derived organoid and xenograft models.","method":"γ-secretase cleavage assay, nuclear ICD detection, RNA-seq for transcriptional targets, periostin-knockout transgenic mice, 3D invasion assay, patient-derived organoids and xenografts, bioluminescence imaging","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical cleavage demonstration, in vivo genetic model, RNA-seq, patient-derived models, multiple orthogonal methods in single study","pmids":["37604269"],"is_preprint":false},{"year":2023,"finding":"CD51 (ITGAV) intracellular domain (ICD), generated by γ-secretase cleavage, binds transcription factor NR4A3 and acts as a co-activator to promote transcription of NTRK1, NTRK3, and SEMA3E, thereby promoting neurotropism and perineural invasion of colorectal cancer cells; pharmacological inhibition of γ-secretase impedes this process in vitro and in vivo.","method":"γ-secretase cleavage assay, co-immunoprecipitation (CD51-ICD/NR4A3), reporter assays, pharmacological γ-secretase inhibition in vitro and in vivo","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for ICD/NR4A3 interaction plus pharmacological rescue in vivo, single lab","pmids":["37174090"],"is_preprint":false},{"year":2018,"finding":"p53 represses CD51 transcription via Sp1/Sp3 transcription factors in prostate cancer; loss of p53 function leads to elevated CD51 expression, and CD51 is required for prostate cancer stemness and metastasis properties.","method":"Reporter assays, ChIP, siRNA/overexpression, in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays and ChIP for transcriptional mechanism, functional KD/OE with in vivo readout, single lab","pmids":["29743605"],"is_preprint":false},{"year":2024,"finding":"TGFβ type I receptor (TβRI) promotes CRPC cell migration and metastasis via production of thrombospondin 1 (THBS1), which mediates cell migration by interacting with ITGAV and TβRI; deletion of TβRI or THBS1 prevents cancer cell migration and invasion; this axis was confirmed in vivo in xenograft models.","method":"RNA-seq and proteomics of TGFβ-treated CRPC cells, CRISPR-Cas9 and siRNA knockdown of TβRI and THBS1, co-immunoprecipitation of THBS1/ITGAV/TβRI complex, in vivo xenograft assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple complementary genetic approaches (CRISPR + siRNA), Co-IP demonstrating ternary complex, in vivo validation, orthogonal proteomics/RNA-seq","pmids":["39304722"],"is_preprint":false},{"year":2024,"finding":"ITGAV directly interacts with NET-DNA scaffolds in cholangiocarcinoma (CCA) cells; this interaction activates the NFκB signaling pathway, leading to upregulation of VEGF-A expression and promotion of CCA proliferation, migration, invasion, and angiogenesis; NET-DNA pull-down assay coupled with mass spectrometry identified ITGAV as the binding partner.","method":"NET-DNA pull-down + mass spectrometry, chromatin immunoprecipitation (ChIP), RNA sequencing, in vitro and in vivo (organoid and PAD4 KO mouse) models, ELISA","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down/MS identifying binding partner, ChIP for downstream NFκB, in vivo genetic model, single lab","pmids":["38326837"],"is_preprint":false},{"year":2025,"finding":"Cytosolic ITGAV is a principal substrate of the proprotein convertase FURIN; FURIN-mediated maturation of ITGAV is required for lysosomal function and lipophagic flux in astrocytes; an ITGAV mutant that prevents FURIN cleavage diminishes lysosomal puncta and lipophagic processing, and mature (but not mutant) ITGAV rescues lipid droplet accumulation in FURIN-deficient cells.","method":"Immunoprecipitation-mass spectrometry (IP-MS), site-directed mutagenesis of FURIN cleavage site in ITGAV, lipophagic flux assays, lipidomics, FURIN-deficient mouse model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — IP-MS identifying substrate, mutagenesis showing functional consequence, rescue experiment with mature vs. mutant ITGAV, in vivo model","pmids":["41376284"],"is_preprint":false},{"year":2022,"finding":"ITGAV/αv integrin-dependent noncanonical autophagy is specifically induced in germinal center and memory B cell subpopulations in human tonsils and spleens; CRISPR-mediated knockdown of autophagy genes in human B cells shows that ITGAV/αv-dependent autophagy limits activation of specific B cell response pathways while promoting others, providing mechanistic links to immune dysregulation in lupus.","method":"CRISPR-mediated knockdown of autophagy genes, transcriptomic analysis, immunostaining of human tissue sections (tonsil, spleen), flow cytometry of B cell subsets","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KD with transcriptomic pathway readout, human primary cells, single lab","pmids":["36016494"],"is_preprint":false},{"year":2024,"finding":"Human biallelic loss-of-function ITGAV variants cause a previously unknown disease characterized by eye/brain abnormalities, inflammatory bowel disease, and immune dysregulation; mechanistically, reduced functional Integrin αV results in dysregulation of TGF-β-dependent signaling and αVβ3-regulated immune signaling; zebrafish itgav deletion recapitulates patient phenotypes including retinal/brain defects, loss of microglia, and colitis with reduced SMAD3 expression.","method":"Human genetics (biallelic variant identification), patient-derived cell functional studies, RNA sequencing, immunostaining, zebrafish itgav genetic deletion model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cell experiments, zebrafish genetic model recapitulating phenotypes, RNA-seq pathway analysis, multiple families/independent validation","pmids":["39526957"],"is_preprint":false},{"year":2025,"finding":"In SMAD4-positive PDAC cells, ITGAV signals through the TGF-β/SMAD4 pathway to regulate proliferation, migration, and invasion; in SMAD4-negative PDAC cells, ITGAV influences only proliferation and migration via the MAPK/ERK pathway, demonstrating context-dependent SMAD4-dependent vs. SMAD4-independent downstream signaling.","method":"siRNA knockdown of ITGAV in isogenic SMAD4+ and SMAD4- PDAC cell lines, proliferation/migration/invasion assays, pathway analysis (SMAD4, MAPK/ERK)","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic cell-line comparison with defined pathway readouts, single lab","pmids":["40739706"],"is_preprint":false},{"year":2023,"finding":"SOX11 binds the ITGAV gene promoter and transcriptionally regulates ITGAV expression in head and neck squamous cell carcinoma (HNSCC); SOX11 knockdown reduces ITGAV expression, and ITGAV knockdown inhibits migration, invasion, viability, and colony formation of HNSCC cells.","method":"Chromatin immunoprecipitation (ChIP) assay for SOX11 at ITGAV promoter, siRNA knockdown, cell functional assays","journal":"Current oncology (Toronto, Ont.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter occupancy plus epistatic knockdown, single lab","pmids":["38534932"],"is_preprint":false},{"year":2023,"finding":"CASZ1 (transcription factor) binds the ITGAV promoter and transcriptionally regulates ITGAV expression in lung cancer cells; CASZ1 overexpression promotes lung cancer cell migration, invasion, and epithelial-mesenchymal transition through ITGAV, while CASZ1 knockdown suppresses these phenotypes and reduces metastasis in vivo.","method":"RNA-seq of CASZ1-silenced cells, ChIP assay for CASZ1 at ITGAV promoter, siRNA/overexpression, in vivo metastasis model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding plus epistatic in vivo validation, single lab","pmids":["36777515"],"is_preprint":false},{"year":2025,"finding":"CCN1 secreted by cardiac fibroblasts binds ITGAV-ITGB1/integrin αvβ1 via its cysteine-knot-containing (CT) domain in cardiomyocytes, activating the PTK2/FAK-MTOR signaling pathway and inhibiting cardiomyocyte autophagy, thereby promoting diabetic cardiomyopathy; fibroblast-specific CCN1 knockout ameliorates cardiac dysfunction and restores autophagic activity in DCM mice.","method":"Proteomic analysis, co-immunoprecipitation (CCN1/ITGAV-ITGB1), molecular dynamics simulation, fibroblast-specific ccn1 knockout mouse, co-culture experiments, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — molecular dynamics + Co-IP defining binding domain, genetic fibroblast-specific KO in vivo, co-culture mechanistic validation, multiple orthogonal methods","pmids":["42056922"],"is_preprint":false},{"year":2025,"finding":"Macrophage ITGAV does not play a significant role in post-infarction cardiac repair and remodeling; myeloid cell-specific and macrophage-specific ITGAV knockout mice show no significant effects on macrophage recruitment, myofibroblast infiltration, collagen deposition, or angiogenesis after myocardial infarction; furthermore, fibronectin-induced changes in macrophage transcriptome (inflammatory, cell cycle, ECM proteolysis genes) are independent of ITGAV.","method":"Myeloid/macrophage-specific ITGAV knockout mice, scRNA-sequencing, immunofluorescence, in vitro RNA-sequencing of ITGAV-KO macrophages treated with fibronectin, cardiac function assessment","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic KO in vivo with comprehensive molecular readouts (scRNA-seq); negative result rigorously established with multiple orthogonal methods","pmids":["41318687"],"is_preprint":false},{"year":2010,"finding":"Mast cell adhesion to bronchial smooth muscle (BSM) specifically depends on CD51 (ITGAV) and CD44 variant 6 (CD44v6); blockade of either CD51 or CD44 significantly decreases mast cell adhesion to BSM; adhesion is mediated primarily through type I collagen of the ECM; CD44v6 expression is increased in asthmatic BSM cells.","method":"3H-thymidine-labeled mast cell adhesion assay, function-blocking antibodies, confocal immunofluorescence, electron microscopy, RT-PCR, western blot, flow cytometry","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with defined ECM substrate, multiple cell imaging methods, single lab","pmids":["20121756"],"is_preprint":false},{"year":2025,"finding":"CD51 (ITGAV) promotes gastric cancer stemness by interacting with Numb, a negative regulator of Notch signaling, diverting Notch1 receptor trafficking from lysosomal degradation to plasma membrane recycling and thereby amplifying Notch pathway activation; pharmacological inhibition with cilengitide suppresses CSC phenotypes in vitro and in patient-derived organoids and xenografts.","method":"Co-immunoprecipitation (CD51/Numb), trafficking assays (lysosomal vs. plasma membrane recycling of Notch1), single-cell RNA sequencing, patient-derived organoids, xenograft models, siRNA/overexpression","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP defining CD51/Numb interaction plus receptor trafficking assays, patient-derived models, single lab","pmids":["40555320"],"is_preprint":false},{"year":2025,"finding":"ADAM9 in macrophages directly binds ITGAV on apoptotic polymorphonuclear leukocytes (PMNs); inhibiting ITGAV expression on PMNs improves ADAM9-mediated macrophage efferocytosis; blocking the ADAM9/ITGAV interaction ameliorates sepsis-induced acute lung injury by promoting macrophage clearance of apoptotic neutrophils.","method":"Co-immunoprecipitation (ADAM9/ITGAV), siRNA knockdown of ITGAV, in vitro efferocytosis assay, LPS-induced ALI mouse model","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct binding, siRNA rescue of efferocytosis, in vivo model, single lab","pmids":["40736047"],"is_preprint":false},{"year":2024,"finding":"Activation of IGF1R signaling in epithelial cutaneous squamous cell carcinoma (cSCC) cells is necessary to induce epithelial-mesenchymal plasticity (EMP) and promotes ITGAV expression; ITGAV knockdown in epithelial plastic cancer cells blocks EMP acquisition, generating epithelial tumors; ITGAV collaborates with IGF1R to drive cSCC progression.","method":"Genetic knockdown (ITGAV siRNA), pharmacological IGF1R inhibition, mouse cSCC progression model, phosphoproteomic analysis, flow cytometry, immunofluorescence","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD plus pharmacological inhibition with defined EMP phenotype, phosphoproteomics, mouse model, single lab","pmids":["39075581"],"is_preprint":false},{"year":2018,"finding":"Demethylation of the ITGAV gene promoter in response to blast-induced shock wave accelerates osteogenic differentiation and mineral deposition in human mesenchymal cells; pharmacological targeting of ITGAV abrogates shock wave-induced mineralization, demonstrating that epigenetic upregulation of ITGAV is required for this process.","method":"Reduced representation bisulfite sequencing (DNA methylation), osteogenic differentiation assays, pharmacological ITGAV inhibition (cilengitide), mineral deposition quantification","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic methylation profiling linked to functional consequence (mineral deposition) with pharmacological rescue, single lab","pmids":["30219480"],"is_preprint":false},{"year":2025,"finding":"LGALS3BP induces ITGAV expression in hepatocellular carcinoma cells by enhancing JunB (JUNB) transcriptional activity; ChIP assays confirmed JunB binding at ITGAV promoter sites; LGALS3BP knockdown suppresses ITGAV expression and reduces cell-to-cell adhesion and invasiveness.","method":"ChIP assay (JunB at ITGAV promoter), recombinant LGALS3BP treatment, siRNA knockdown, qRT-PCR, western blot, cell adhesion and invasion assays","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming promoter binding plus functional KD readout, single lab","pmids":["40578967"],"is_preprint":false},{"year":1993,"finding":"CD51 (ITGAV) is expressed on the basal surface of myoepithelial cells at the myoepithelial-stromal junction in normal breast tissue and co-distributes with TSP1 in invasive lobular carcinoma cells, suggesting a functional receptor-ligand relationship between TSP1 and CD51 at these sites.","method":"Immunohistochemistry, in situ hybridization","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization by IHC/ISH only, no direct binding or functional experiment performed","pmids":["7680285"],"is_preprint":false},{"year":2000,"finding":"The ITGAV gene encodes a 150-kDa mature peptide from a 3,146-bp coding sequence; gene structure characterization revealed the genomic organization enabling mechanistic studies of this integrin subunit.","method":"Gene cloning, cDNA characterization, genomic sequencing","journal":"Cytogenetics and cell genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene cloning without functional assays","pmids":["10965141"],"is_preprint":false},{"year":1993,"finding":"The human ITGAV gene (vitronectin receptor alpha subunit, VNRA) was regionally mapped to chromosome 2q31→q32 by fluorescence in situ hybridization.","method":"Fluorescence in situ hybridization (FISH) with GTG-banding on human-rodent somatic cell hybrids","journal":"Cytogenetics and cell genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — chromosomal localization only, no functional mechanism established","pmids":["7678549"],"is_preprint":false}],"current_model":"ITGAV (integrin αV, CD51) encodes the αV subunit that heterodimerizes with multiple β subunits (β1, β3, β5, β6, β8) to form RGD-binding integrin receptors mediating cell adhesion to extracellular matrix proteins (vitronectin, osteopontin/SPP1, fibronectin, thrombospondin-1); it transduces outside-in signals through FAK/PI3K/AKT, TGF-β/SMAD, MAPK/ERK, NFκB, and Hippo/YAP-TAZ pathways to regulate cell proliferation, migration, invasion, autophagy, stem cell quiescence, and tissue fibrosis; its transcription is directly controlled by Runx2, TAZ, CASZ1, SOX11, and the LGALS3BP-JUNB axis, and repressed by p53 via Sp1/Sp3; FURIN proteolytically matures ITGAV enabling astrocytic lipophagy, while γ-secretase cleavage generates a nuclear intracellular domain (CD51-ICD) that acts as a transcriptional co-activator (partnering with NR4A3 in colorectal cancer and driving oxidative phosphorylation genes in HCC), thereby explaining the failure of surface-targeted inhibitors such as cilengitide; biallelic human loss-of-function variants cause a syndrome of brain/eye malformations, colitis, and immune dysregulation linked to disrupted TGF-β and αVβ3 immune signaling."},"narrative":{"mechanistic_narrative":"ITGAV (integrin αV, CD51) encodes an αV integrin subunit that pairs with β subunits to form RGD-binding adhesion receptors mediating attachment to extracellular matrix and matricellular ligands including vitronectin, SPP1/osteopontin, periostin, thrombospondin-1, and collagen-associated scaffolds, and it transduces these contacts into intracellular signaling controlling proliferation, migration, invasion, stem-cell behavior, and tissue homeostasis [PMID:7542504, PMID:28250242, PMID:27905395, PMID:39304722, PMID:20121756]. Outside-in signaling through αV integrins engages divergent pathways: periostin–ITGAV ligation suppresses FAK/PI3K/AKT to enforce hematopoietic stem cell quiescence via p27Kip1 [PMID:27905395], CD51 binds TGF-β receptors and amplifies TGF-β/SMAD signaling to confer cancer stem-cell and invasive traits [PMID:27593923, PMID:40739706], and ITGAV feeds a Hippo/YAP-TAZ feedback loop in which TAZ drives ITGAV transcription and ITGAV in turn sustains nuclear YAP/TAZ and actin stress-fiber assembly [PMID:31904487]. ITGAV is also a node in non-adhesive proteolytic signaling: γ-secretase cleaves CD51 to release a nuclear intracellular domain (CD51-ICD) that acts as a transcriptional co-activator, partnering with NR4A3 to drive neurotropic genes in colorectal cancer and inducing oxidative-phosphorylation genes to promote hepatocellular carcinoma invasion, with periostin driving the cleavage event [PMID:37174090, PMID:37604269]. FURIN-mediated maturation of cytosolic ITGAV is required for lysosomal function and lipophagic flux in astrocytes, and αV-dependent noncanonical autophagy operates in germinal-center and memory B cells [PMID:41376284, PMID:36016494]. ITGAV transcription is directly controlled by Runx2, TAZ, SOX11, CASZ1, and a LGALS3BP–JunB axis, and repressed by p53 via Sp1/Sp3 [PMID:37403784, PMID:31904487, PMID:38534932, PMID:36777515, PMID:40578967, PMID:29743605]. Biallelic human loss-of-function ITGAV variants cause a syndrome of eye/brain malformations, inflammatory bowel disease, and immune dysregulation linked to disrupted TGF-β and αVβ3 immune signaling [PMID:39526957].","teleology":[{"year":1993,"claim":"Establishing the gene's chromosomal location and protein product provided the foundation for mechanistic study of the vitronectin-receptor αV subunit.","evidence":"FISH mapping to 2q31→q32 and cDNA/genomic characterization of the 150-kDa subunit","pmids":["7678549","10965141"],"confidence":"Low","gaps":["chromosomal localization alone establishes no function","no signaling or ligand engagement defined"]},{"year":1995,"claim":"Identifying functional αvβ3 on differentiated mast cells and its vitronectin binding defined ITGAV as an adhesion receptor for matrix ligands in immune-lineage cells.","evidence":"Adhesion and antibody-blocking assays in SCF-cultured human fetal mast cells","pmids":["7542504"],"confidence":"Medium","gaps":["downstream signaling not addressed","no in vivo relevance shown"]},{"year":2000,"claim":"Demonstrating that an RGD-less coxsackievirus mutant still binds αvβ3 showed the receptor engages ligands through both RGD-dependent and RGD-independent modes.","evidence":"Binding studies on αvβ3-expressing and chimeric CHO cells with blocking antibodies and vitronectin competition","pmids":["10773347"],"confidence":"Medium","gaps":["the RGD-independent contact residues on ITGAV not mapped","physiological ligands using this mode not enumerated"]},{"year":2005,"claim":"Discovery that αvβ3 binds endothelial Thy-1/CD90 extended ITGAV's ligand repertoire beyond classical matrix proteins to a cell-surface counter-receptor mediating transendothelial migration.","evidence":"Reciprocal purified-protein and transfected-cell binding plus flow/static adhesion blockade in melanoma","pmids":["15897908"],"confidence":"Medium","gaps":["intracellular signaling consequence not defined","single-lab finding"]},{"year":2016,"claim":"Genetic models defined opposing context-dependent ITGAV signaling outputs: periostin–ITGAV suppression of FAK/PI3K/AKT maintains HSC quiescence, while ITGAV restrains adipogenic differentiation via TAZ.","evidence":"Reciprocal Postn-KO and Itgav conditional-KO mice with HSC repopulation assays; siRNA/overexpression in adipose-derived stem cells","pmids":["27905395","27363302"],"confidence":"High","gaps":["how the same receptor selects FAK inhibition versus TAZ regulation is unresolved","ligand-specific signaling thresholds not defined"]},{"year":2016,"claim":"Showing CD51 binds TGF-β receptors and amplifies TGF-β/SMAD signaling linked ITGAV directly to cancer stem-cell and invasive phenotypes.","evidence":"Co-IP of CD51–TGF-β receptor, siRNA knockdown, sphere assays and in vivo tumor models in colorectal cancer","pmids":["27593923"],"confidence":"Medium","gaps":["stoichiometry/structure of the CD51–TGFβR complex unknown","whether engagement requires β-subunit pairing not addressed"]},{"year":2018,"claim":"Identifying p53/Sp1/Sp3 repression and epigenetic demethylation control of ITGAV revealed that its expression is tightly regulated transcriptionally to gate stemness and differentiation programs.","evidence":"Reporter assays and ChIP in prostate cancer; bisulfite sequencing and osteogenic assays in mesenchymal cells","pmids":["29743605","30219480"],"confidence":"Medium","gaps":["interplay of activating versus repressive regulators in a single cell context not integrated","direct p53 occupancy versus indirect Sp-mediated effect not fully separated"]},{"year":2019,"claim":"Showing macrophage CD51 confers stemness on neighboring tumor cells via TGF-β1/Smad2/3 paracrine signaling established a cell-non-autonomous, microenvironmental role for ITGAV.","evidence":"siRNA knockdown in macrophages with co-culture and Smad2/3 pathway readouts in pancreatic cancer","pmids":["31199988"],"confidence":"Medium","gaps":["the ligand engaging macrophage CD51 not identified","single-lab co-culture model"]},{"year":2020,"claim":"Defining a TAZ→ITGAV→nuclear YAP/TAZ positive-feedback loop showed ITGAV both responds to and amplifies Hippo pathway activity through actin remodeling.","evidence":"RNAi of TAZ/YAP/ITGAV, actin staining, migration/invasion and nuclear fractionation in HCC","pmids":["31904487"],"confidence":"Medium","gaps":["mechanism coupling ITGAV adhesion to YAP/TAZ nuclear retention not detailed","TAZ-specific versus YAP selectivity at the promoter not structurally resolved"]},{"year":2023,"claim":"Multiple transcription factors were shown to bind the ITGAV promoter directly, establishing Runx2, SOX11, and CASZ1 as drivers that route ITGAV into fibrosis, EMT, and metastasis programs.","evidence":"ChIP/ChIP-seq plus knockdown and in vivo models (Runx2 in hepatic stellate cell fibrosis; SOX11 in HNSCC; CASZ1 in lung cancer)","pmids":["37403784","38534932","36777515"],"confidence":"High","gaps":["combinatorial control by these factors in a single tissue not addressed","whether they regulate specific αV/β heterodimers unknown"]},{"year":2023,"claim":"Discovery that γ-secretase cleaves CD51 to a nuclear ICD that co-activates NR4A3 redefined ITGAV as a signaling molecule acting in the nucleus, not only at the membrane.","evidence":"γ-secretase cleavage assay, CD51-ICD/NR4A3 Co-IP, reporter assays and pharmacological γ-secretase inhibition in colorectal cancer","pmids":["37174090"],"confidence":"Medium","gaps":["full ICD target gene network beyond NTRK1/NTRK3/SEMA3E not mapped","single-lab interaction"]},{"year":2024,"claim":"The CD51-ICD axis was extended in HCC where periostin drives cleavage and the ICD induces oxidative-phosphorylation genes, explaining why surface-only inhibitors fail and motivating combined γ-secretase blockade.","evidence":"Cleavage and nuclear ICD assays, RNA-seq, periostin-KO mice, patient-derived organoids/xenografts with cilengitide+LY3039478","pmids":["37604269"],"confidence":"High","gaps":["proportion of ITGAV signaling routed through ICD versus surface adhesion not quantified across tissues","regulation of cleavage by β-subunit pairing unknown"]},{"year":2024,"claim":"ITGAV was identified as a node integrating matricellular and innate-immune cues into NF-κB and TGF-β/THBS1 signaling, broadening its pro-tumor signaling beyond canonical FAK/SMAD routes.","evidence":"NET-DNA pull-down/MS and ChIP in cholangiocarcinoma; THBS1/ITGAV/TβRI Co-IP with CRISPR/siRNA and xenografts in CRPC","pmids":["38326837","39304722"],"confidence":"High","gaps":["whether the same heterodimer mediates NET-DNA and THBS1 binding unclear","direct versus scaffold-mediated NF-κB activation not fully separated"]},{"year":2024,"claim":"Biallelic human loss-of-function variants causally linked ITGAV to a multisystem disorder, anchoring its physiological roles in TGF-β and αVβ3 immune signaling in vivo.","evidence":"Human genetics with patient-cell functional studies, RNA-seq, and zebrafish itgav deletion recapitulating retinal/brain, microglial, and colitis phenotypes","pmids":["39526957"],"confidence":"High","gaps":["tissue-specific contributions of distinct αV heterodimers to the syndrome not dissected","genotype–phenotype correlation across variants limited"]},{"year":2025,"claim":"FURIN-dependent maturation of cytosolic ITGAV was shown to be required for lysosomal function and lipophagy, revealing a proteolytic-maturation requirement distinct from surface integrin assembly.","evidence":"IP-MS substrate identification, cleavage-site mutagenesis, lipophagic flux/lipidomics, and rescue with mature versus mutant ITGAV in FURIN-deficient astrocytes/mice","pmids":["41376284"],"confidence":"High","gaps":["how the FURIN-matured form supports lysosomal/lipophagic machinery mechanistically unresolved","relationship to canonical surface ITGAV pool unclear"]},{"year":2025,"claim":"Further mechanisms diversified ITGAV's roles—autophagy regulation in cardiomyocytes, Notch trafficking in gastric cancer stemness, efferocytosis as an apoptotic-cell ligand, and context-dependent SMAD4 versus MAPK/ERK signaling—while a cell-type-specific knockout established that macrophage ITGAV is dispensable for post-infarction repair.","evidence":"Co-IP, trafficking and autophagy-flux assays, fibroblast/macrophage-specific KO mice, isogenic SMAD4+/- PDAC lines, and patient-derived models","pmids":["42056922","40555320","40736047","40739706","41318687"],"confidence":"High","gaps":["unifying determinant of which downstream pathway ITGAV selects per context not defined","negative macrophage-MI result delimits but does not explain tissue-specific requirements"]},{"year":null,"claim":"It remains unresolved how a single αV subunit's β-partner choice, ligand identity, and proteolytic processing (FURIN maturation versus γ-secretase ICD release) are coordinated to select among the many divergent downstream pathways attributed to ITGAV.","evidence":"No single study reconciles surface adhesion, ICD nuclear signaling, and FURIN-dependent maturation within one cellular system","pmids":[],"confidence":"Low","gaps":["no structural model of the CD51-ICD or its cofactor complexes","determinants of β-subunit pairing across the documented functions not established","quantitative balance between membrane and nuclear ITGAV signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,5,23,0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,6,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,8,13]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,5,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,16,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[16,17,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17]}],"complexes":["αvβ3 integrin","αvβ1 integrin","THBS1/ITGAV/TβRI complex"],"partners":["ITGB3","POSTN","THBS1","TGFBR1","NR4A3","FURIN","NUMB","ADAM9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06756","full_name":"Integrin alpha-V","aliases":["Vitronectin receptor","Vitronectin receptor subunit alpha"],"length_aa":1048,"mass_kda":116.0,"function":"The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. ITGAV:ITGB3 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415). ITGAV:ITGB3 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling (PubMed:20682778). ITGAV:ITGB3 binds to FGF1 and this binding is essential for FGF1 signaling (PubMed:18441324). ITGAV:ITGB3 binds to FGF2 and this binding is essential for FGF2 signaling (PubMed:28302677). ITGAV:ITGB3 binds to IGF1 and this binding is essential for IGF1 signaling (PubMed:19578119). ITGAV:ITGB3 binds to IGF2 and this binding is essential for IGF2 signaling (PubMed:28873464). ITGAV:ITGB3 binds to IL1B and this binding is essential for IL1B signaling (PubMed:29030430). ITGAV:ITGB3 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). ITGAV:ITGB3 and ITGAV:ITGB6 act as receptors for fibrillin-1 (FBN1) and mediate R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). Integrin alpha-V/beta-6 or alpha-V/beta-8 (ITGAV:ITGB6 or ITGAV:ITGB8) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation (PubMed:15184403, PubMed:22278742, PubMed:28117447). ITGAV:ITGB3 acts as a receptor for CD40LG (PubMed:31331973). ITGAV:ITGB3 acts as a receptor for IBSP and promotes cell adhesion and migration to IBSP (PubMed:10640428) (Microbial infection) Integrin ITGAV:ITGB5 acts as a receptor for Adenovirus type C (Microbial infection) Integrin ITGAV:ITGB5 and ITGAV:ITGB3 act as receptors for Coxsackievirus A9 and B1 (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Herpes virus 8/HHV-8 (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for herpes simplex 1/HHV-1 (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for Human parechovirus 1 (Microbial infection) Integrin ITGAV:ITGB3 acts as a receptor for West nile virus (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/P06756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGAV","classification":"Not Classified","n_dependent_lines":548,"n_total_lines":1208,"dependency_fraction":0.45364238410596025},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ITGAV","total_profiled":1310},"omim":[{"mim_id":"621375","title":"IMMUNE DYSREGULATION, NEURODEVELOPMENTAL DEFECTS, AND COLITIS; IDNDC","url":"https://www.omim.org/entry/621375"},{"mim_id":"621264","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 1; FMAIT1","url":"https://www.omim.org/entry/621264"},{"mim_id":"620845","title":"TRANSMEMBRANE 4 L6 FAMILY, MEMBER 19; TM4SF19","url":"https://www.omim.org/entry/620845"},{"mim_id":"618926","title":"OSTEOMODULIN; OMD","url":"https://www.omim.org/entry/618926"},{"mim_id":"616506","title":"NEURON-DERIVED NEUROTROPHIC FACTOR; NDNF","url":"https://www.omim.org/entry/616506"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Focal adhesion sites","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGAV"},"hgnc":{"alias_symbol":["CD51"],"prev_symbol":["VNRA","MSK8","VTNR"]},"alphafold":{"accession":"P06756","domains":[{"cath_id":"2.60.40.1460","chopping":"470-621","consensus_level":"high","plddt":91.3974,"start":470,"end":621},{"cath_id":"2.60.40.1510","chopping":"635-766","consensus_level":"high","plddt":90.0256,"start":635,"end":766},{"cath_id":"2.60.40.1530","chopping":"771-863_899-982","consensus_level":"high","plddt":91.6555,"start":771,"end":982}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06756","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06756-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06756-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGAV","jax_strain_url":"https://www.jax.org/strain/search?query=ITGAV"},"sequence":{"accession":"P06756","fasta_url":"https://rest.uniprot.org/uniprotkb/P06756.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06756/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06756"}},"corpus_meta":[{"pmid":"23776077","id":"PMC_23776077","title":"PDGFRα 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blockade experiments under static and flow conditions.\",\n      \"method\": \"Purified protein binding assay, transfected cell adhesion assay, functional blocking antibody under static and flow conditions\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with purified proteins and transfected cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15897908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Coxsackievirus A9 binds integrin αvβ3 (CD51/CD61) at the CYDMKTTC sequence (residues 187–193) of the β3 subunit; importantly, an RGD-less CAV-9 mutant can still bind this site efficiently, demonstrating that RGD in the viral VP1 protein is not required for high-affinity interaction with αvβ3.\",\n      \"method\": \"Binding studies on CHO cells expressing αvβ3, αvβ1, or chimeric αvβ1-3-1 mutants; function-blocking monoclonal antibodies; competition with natural ligand vitronectin\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-line variants and blocking reagents, single lab\",\n      \"pmids\": [\"10773347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human fetal liver-derived mast cells cultured with stem cell factor acquire functional CD51/CD61 (αvβ3) receptors and spontaneously adhere to vitronectin through this receptor; adhesion to fibronectin and laminin is partially inhibited by anti-CD61 and anti-CD29 antibodies, but no degranulation occurs during vitronectin-dependent adhesion.\",\n      \"method\": \"Flow cytometry, adhesion measurements, antibody-blocking assays, culture differentiation model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional adhesion assays with blocking antibodies, single lab, multiple ligands tested\",\n      \"pmids\": [\"7542504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ITGAV knockdown in human adipose-derived stem cells (ASCs) reduces proliferation, induces p21(Cip1), represses survivin, and specifically regulates the Hippo pathway mediator TAZ, while knockdown of either ITGAV or ITGA5 promotes adipogenic differentiation; transgenic ITGAV overexpression impairs adipogenesis, placing ITGAV as a negative regulator of adipogenic differentiation via RGD-motif signaling.\",\n      \"method\": \"siRNA knockdown, transgenic overexpression, cell proliferation assays, gene expression profiling, cilengitide pharmacological inhibition\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD and OE with defined molecular readouts, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"27363302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Periostin (Postn) interacts with Itgav to regulate hematopoietic stem cell (HSC) proliferation via outside-in signaling; Itgav deletion in the hematopoietic system recapitulates peripheral blood phenotypes of Postn-knockout mice; mechanistically, the Postn-Itgav interaction inhibits the FAK/PI3K/AKT pathway in HSCs, increasing p27Kip1 expression and maintaining HSC quiescence.\",\n      \"method\": \"Conditional knockout mice (Vav-Cre), Postn-/- mice, HSC repopulation assays, in vitro proliferation, pathway analysis (FAK/PI3K/AKT/p27Kip1)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic models (Postn KO and Itgav conditional KO), multiple orthogonal readouts, defined signaling pathway\",\n      \"pmids\": [\"27905395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ITGAV-containing integrin receptors on porcine trophoblast (pTr2) cells directly mediate adhesion to SPP1 (osteopontin); siRNA knockdown of ITGAV in pTr2 cells significantly reduces attachment to SPP1, and ITGAV, ITGB3 and SPP1 co-localize in large aggregates at the uterine luminal epithelium–trophoblast interface on Day 25 of gestation.\",\n      \"method\": \"siRNA knockdown, cell adhesion assay, in situ hybridization, immunofluorescence co-localization\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with direct adhesion readout plus co-localization, single lab\",\n      \"pmids\": [\"28250242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD51 (ITGAV) binds TGF-β receptors in colorectal cancer cells and upregulates TGF-β/Smad signaling; CD51+ CRC cells display enhanced sphere-forming, tumorigenic, migratory, invasive, and chemoresistance capacities compared to CD51- cells; CD51 knockdown reduces side population, sphere formation, motility, tumor incidence and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (CD51–TGF-β receptor binding), siRNA knockdown, sphere-forming assay, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding plus functional KD with multiple defined readouts, single lab\",\n      \"pmids\": [\"27593923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Macrophage-expressed CD51 contributes to the acquisition of cancer stem cell (CSC) stemness traits in pancreatic cancer cells via the TGF-β1/Smad2/3 paracrine pathway; CD51 knockdown in macrophages drives them toward an M1-like phenotype and reduces CSC properties in co-cultured pancreatic cancer cells.\",\n      \"method\": \"siRNA knockdown in macrophages, co-culture assays, pathway analysis (TGF-β1/Smad2/3), phenotype characterization\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with mechanistic pathway readout (Smad2/3), single lab, co-culture model\",\n      \"pmids\": [\"31199988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TAZ (WWTR1), but not YAP, specifically drives ITGAV transcription in hepatocellular carcinoma cells; ITGAV promotes actin stress fiber assembly, tumor cell migration and invasion; perturbation of ITGAV diminishes actin fiber formation and reduces nuclear YAP/TAZ protein levels, establishing a positive feedback loop amplifying Hippo pathway activity.\",\n      \"method\": \"RNAi knockdown (TAZ, YAP, ITGAV), comprehensive expression profiling, actin staining, migration/invasion assays, nuclear fractionation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-specific RNAi with multiple orthogonal phenotypic readouts, single lab\",\n      \"pmids\": [\"31904487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Runx2 transcriptionally activates Itgav expression by binding to its promoter in hepatic stellate cells (HSCs); Itgav is required downstream of Runx2 for HSC activation; blockade of Itgav attenuates Runx2-induced HSC activation and liver fibrosis in multiple mouse models; cytokines (TGF-β1, PDGF, EGF) promote Runx2 nuclear translocation via PKA.\",\n      \"method\": \"Runx2 ChIP-seq identifying ITGAV promoter binding, RNA-seq, siRNA/shRNA knockdown, HSC-specific in vivo overexpression/knockdown (HBAAV-Runx2, VA-Lip-Runx2), CCl4/DDC/MCD mouse models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq demonstrating direct promoter binding, multiple mouse fibrosis models, epistasis (Itgav blockade reverses Runx2 effect), multiple orthogonal methods\",\n      \"pmids\": [\"37403784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD51 undergoes transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD); CD51-ICD facilitates HCC invasion and metastasis by promoting transcription of oxidative phosphorylation-related genes; cancer-associated fibroblast-derived periostin is the major driver of CD51 cleavage; combined inhibition of surface CD51 (cilengitide) and γ-secretase (LY3039478) shows enhanced therapeutic efficacy in patient-derived organoid and xenograft models.\",\n      \"method\": \"γ-secretase cleavage assay, nuclear ICD detection, RNA-seq for transcriptional targets, periostin-knockout transgenic mice, 3D invasion assay, patient-derived organoids and xenografts, bioluminescence imaging\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical cleavage demonstration, in vivo genetic model, RNA-seq, patient-derived models, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37604269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD51 (ITGAV) intracellular domain (ICD), generated by γ-secretase cleavage, binds transcription factor NR4A3 and acts as a co-activator to promote transcription of NTRK1, NTRK3, and SEMA3E, thereby promoting neurotropism and perineural invasion of colorectal cancer cells; pharmacological inhibition of γ-secretase impedes this process in vitro and in vivo.\",\n      \"method\": \"γ-secretase cleavage assay, co-immunoprecipitation (CD51-ICD/NR4A3), reporter assays, pharmacological γ-secretase inhibition in vitro and in vivo\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for ICD/NR4A3 interaction plus pharmacological rescue in vivo, single lab\",\n      \"pmids\": [\"37174090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p53 represses CD51 transcription via Sp1/Sp3 transcription factors in prostate cancer; loss of p53 function leads to elevated CD51 expression, and CD51 is required for prostate cancer stemness and metastasis properties.\",\n      \"method\": \"Reporter assays, ChIP, siRNA/overexpression, in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays and ChIP for transcriptional mechanism, functional KD/OE with in vivo readout, single lab\",\n      \"pmids\": [\"29743605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TGFβ type I receptor (TβRI) promotes CRPC cell migration and metastasis via production of thrombospondin 1 (THBS1), which mediates cell migration by interacting with ITGAV and TβRI; deletion of TβRI or THBS1 prevents cancer cell migration and invasion; this axis was confirmed in vivo in xenograft models.\",\n      \"method\": \"RNA-seq and proteomics of TGFβ-treated CRPC cells, CRISPR-Cas9 and siRNA knockdown of TβRI and THBS1, co-immunoprecipitation of THBS1/ITGAV/TβRI complex, in vivo xenograft assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple complementary genetic approaches (CRISPR + siRNA), Co-IP demonstrating ternary complex, in vivo validation, orthogonal proteomics/RNA-seq\",\n      \"pmids\": [\"39304722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGAV directly interacts with NET-DNA scaffolds in cholangiocarcinoma (CCA) cells; this interaction activates the NFκB signaling pathway, leading to upregulation of VEGF-A expression and promotion of CCA proliferation, migration, invasion, and angiogenesis; NET-DNA pull-down assay coupled with mass spectrometry identified ITGAV as the binding partner.\",\n      \"method\": \"NET-DNA pull-down + mass spectrometry, chromatin immunoprecipitation (ChIP), RNA sequencing, in vitro and in vivo (organoid and PAD4 KO mouse) models, ELISA\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down/MS identifying binding partner, ChIP for downstream NFκB, in vivo genetic model, single lab\",\n      \"pmids\": [\"38326837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cytosolic ITGAV is a principal substrate of the proprotein convertase FURIN; FURIN-mediated maturation of ITGAV is required for lysosomal function and lipophagic flux in astrocytes; an ITGAV mutant that prevents FURIN cleavage diminishes lysosomal puncta and lipophagic processing, and mature (but not mutant) ITGAV rescues lipid droplet accumulation in FURIN-deficient cells.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (IP-MS), site-directed mutagenesis of FURIN cleavage site in ITGAV, lipophagic flux assays, lipidomics, FURIN-deficient mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — IP-MS identifying substrate, mutagenesis showing functional consequence, rescue experiment with mature vs. mutant ITGAV, in vivo model\",\n      \"pmids\": [\"41376284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGAV/αv integrin-dependent noncanonical autophagy is specifically induced in germinal center and memory B cell subpopulations in human tonsils and spleens; CRISPR-mediated knockdown of autophagy genes in human B cells shows that ITGAV/αv-dependent autophagy limits activation of specific B cell response pathways while promoting others, providing mechanistic links to immune dysregulation in lupus.\",\n      \"method\": \"CRISPR-mediated knockdown of autophagy genes, transcriptomic analysis, immunostaining of human tissue sections (tonsil, spleen), flow cytometry of B cell subsets\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KD with transcriptomic pathway readout, human primary cells, single lab\",\n      \"pmids\": [\"36016494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Human biallelic loss-of-function ITGAV variants cause a previously unknown disease characterized by eye/brain abnormalities, inflammatory bowel disease, and immune dysregulation; mechanistically, reduced functional Integrin αV results in dysregulation of TGF-β-dependent signaling and αVβ3-regulated immune signaling; zebrafish itgav deletion recapitulates patient phenotypes including retinal/brain defects, loss of microglia, and colitis with reduced SMAD3 expression.\",\n      \"method\": \"Human genetics (biallelic variant identification), patient-derived cell functional studies, RNA sequencing, immunostaining, zebrafish itgav genetic deletion model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cell experiments, zebrafish genetic model recapitulating phenotypes, RNA-seq pathway analysis, multiple families/independent validation\",\n      \"pmids\": [\"39526957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In SMAD4-positive PDAC cells, ITGAV signals through the TGF-β/SMAD4 pathway to regulate proliferation, migration, and invasion; in SMAD4-negative PDAC cells, ITGAV influences only proliferation and migration via the MAPK/ERK pathway, demonstrating context-dependent SMAD4-dependent vs. SMAD4-independent downstream signaling.\",\n      \"method\": \"siRNA knockdown of ITGAV in isogenic SMAD4+ and SMAD4- PDAC cell lines, proliferation/migration/invasion assays, pathway analysis (SMAD4, MAPK/ERK)\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic cell-line comparison with defined pathway readouts, single lab\",\n      \"pmids\": [\"40739706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SOX11 binds the ITGAV gene promoter and transcriptionally regulates ITGAV expression in head and neck squamous cell carcinoma (HNSCC); SOX11 knockdown reduces ITGAV expression, and ITGAV knockdown inhibits migration, invasion, viability, and colony formation of HNSCC cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) assay for SOX11 at ITGAV promoter, siRNA knockdown, cell functional assays\",\n      \"journal\": \"Current oncology (Toronto, Ont.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter occupancy plus epistatic knockdown, single lab\",\n      \"pmids\": [\"38534932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CASZ1 (transcription factor) binds the ITGAV promoter and transcriptionally regulates ITGAV expression in lung cancer cells; CASZ1 overexpression promotes lung cancer cell migration, invasion, and epithelial-mesenchymal transition through ITGAV, while CASZ1 knockdown suppresses these phenotypes and reduces metastasis in vivo.\",\n      \"method\": \"RNA-seq of CASZ1-silenced cells, ChIP assay for CASZ1 at ITGAV promoter, siRNA/overexpression, in vivo metastasis model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding plus epistatic in vivo validation, single lab\",\n      \"pmids\": [\"36777515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCN1 secreted by cardiac fibroblasts binds ITGAV-ITGB1/integrin αvβ1 via its cysteine-knot-containing (CT) domain in cardiomyocytes, activating the PTK2/FAK-MTOR signaling pathway and inhibiting cardiomyocyte autophagy, thereby promoting diabetic cardiomyopathy; fibroblast-specific CCN1 knockout ameliorates cardiac dysfunction and restores autophagic activity in DCM mice.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation (CCN1/ITGAV-ITGB1), molecular dynamics simulation, fibroblast-specific ccn1 knockout mouse, co-culture experiments, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — molecular dynamics + Co-IP defining binding domain, genetic fibroblast-specific KO in vivo, co-culture mechanistic validation, multiple orthogonal methods\",\n      \"pmids\": [\"42056922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage ITGAV does not play a significant role in post-infarction cardiac repair and remodeling; myeloid cell-specific and macrophage-specific ITGAV knockout mice show no significant effects on macrophage recruitment, myofibroblast infiltration, collagen deposition, or angiogenesis after myocardial infarction; furthermore, fibronectin-induced changes in macrophage transcriptome (inflammatory, cell cycle, ECM proteolysis genes) are independent of ITGAV.\",\n      \"method\": \"Myeloid/macrophage-specific ITGAV knockout mice, scRNA-sequencing, immunofluorescence, in vitro RNA-sequencing of ITGAV-KO macrophages treated with fibronectin, cardiac function assessment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic KO in vivo with comprehensive molecular readouts (scRNA-seq); negative result rigorously established with multiple orthogonal methods\",\n      \"pmids\": [\"41318687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mast cell adhesion to bronchial smooth muscle (BSM) specifically depends on CD51 (ITGAV) and CD44 variant 6 (CD44v6); blockade of either CD51 or CD44 significantly decreases mast cell adhesion to BSM; adhesion is mediated primarily through type I collagen of the ECM; CD44v6 expression is increased in asthmatic BSM cells.\",\n      \"method\": \"3H-thymidine-labeled mast cell adhesion assay, function-blocking antibodies, confocal immunofluorescence, electron microscopy, RT-PCR, western blot, flow cytometry\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with defined ECM substrate, multiple cell imaging methods, single lab\",\n      \"pmids\": [\"20121756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD51 (ITGAV) promotes gastric cancer stemness by interacting with Numb, a negative regulator of Notch signaling, diverting Notch1 receptor trafficking from lysosomal degradation to plasma membrane recycling and thereby amplifying Notch pathway activation; pharmacological inhibition with cilengitide suppresses CSC phenotypes in vitro and in patient-derived organoids and xenografts.\",\n      \"method\": \"Co-immunoprecipitation (CD51/Numb), trafficking assays (lysosomal vs. plasma membrane recycling of Notch1), single-cell RNA sequencing, patient-derived organoids, xenograft models, siRNA/overexpression\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining CD51/Numb interaction plus receptor trafficking assays, patient-derived models, single lab\",\n      \"pmids\": [\"40555320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADAM9 in macrophages directly binds ITGAV on apoptotic polymorphonuclear leukocytes (PMNs); inhibiting ITGAV expression on PMNs improves ADAM9-mediated macrophage efferocytosis; blocking the ADAM9/ITGAV interaction ameliorates sepsis-induced acute lung injury by promoting macrophage clearance of apoptotic neutrophils.\",\n      \"method\": \"Co-immunoprecipitation (ADAM9/ITGAV), siRNA knockdown of ITGAV, in vitro efferocytosis assay, LPS-induced ALI mouse model\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct binding, siRNA rescue of efferocytosis, in vivo model, single lab\",\n      \"pmids\": [\"40736047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Activation of IGF1R signaling in epithelial cutaneous squamous cell carcinoma (cSCC) cells is necessary to induce epithelial-mesenchymal plasticity (EMP) and promotes ITGAV expression; ITGAV knockdown in epithelial plastic cancer cells blocks EMP acquisition, generating epithelial tumors; ITGAV collaborates with IGF1R to drive cSCC progression.\",\n      \"method\": \"Genetic knockdown (ITGAV siRNA), pharmacological IGF1R inhibition, mouse cSCC progression model, phosphoproteomic analysis, flow cytometry, immunofluorescence\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD plus pharmacological inhibition with defined EMP phenotype, phosphoproteomics, mouse model, single lab\",\n      \"pmids\": [\"39075581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Demethylation of the ITGAV gene promoter in response to blast-induced shock wave accelerates osteogenic differentiation and mineral deposition in human mesenchymal cells; pharmacological targeting of ITGAV abrogates shock wave-induced mineralization, demonstrating that epigenetic upregulation of ITGAV is required for this process.\",\n      \"method\": \"Reduced representation bisulfite sequencing (DNA methylation), osteogenic differentiation assays, pharmacological ITGAV inhibition (cilengitide), mineral deposition quantification\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic methylation profiling linked to functional consequence (mineral deposition) with pharmacological rescue, single lab\",\n      \"pmids\": [\"30219480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGALS3BP induces ITGAV expression in hepatocellular carcinoma cells by enhancing JunB (JUNB) transcriptional activity; ChIP assays confirmed JunB binding at ITGAV promoter sites; LGALS3BP knockdown suppresses ITGAV expression and reduces cell-to-cell adhesion and invasiveness.\",\n      \"method\": \"ChIP assay (JunB at ITGAV promoter), recombinant LGALS3BP treatment, siRNA knockdown, qRT-PCR, western blot, cell adhesion and invasion assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming promoter binding plus functional KD readout, single lab\",\n      \"pmids\": [\"40578967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD51 (ITGAV) is expressed on the basal surface of myoepithelial cells at the myoepithelial-stromal junction in normal breast tissue and co-distributes with TSP1 in invasive lobular carcinoma cells, suggesting a functional receptor-ligand relationship between TSP1 and CD51 at these sites.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization by IHC/ISH only, no direct binding or functional experiment performed\",\n      \"pmids\": [\"7680285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The ITGAV gene encodes a 150-kDa mature peptide from a 3,146-bp coding sequence; gene structure characterization revealed the genomic organization enabling mechanistic studies of this integrin subunit.\",\n      \"method\": \"Gene cloning, cDNA characterization, genomic sequencing\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene cloning without functional assays\",\n      \"pmids\": [\"10965141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human ITGAV gene (vitronectin receptor alpha subunit, VNRA) was regionally mapped to chromosome 2q31→q32 by fluorescence in situ hybridization.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) with GTG-banding on human-rodent somatic cell hybrids\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — chromosomal localization only, no functional mechanism established\",\n      \"pmids\": [\"7678549\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGAV (integrin αV, CD51) encodes the αV subunit that heterodimerizes with multiple β subunits (β1, β3, β5, β6, β8) to form RGD-binding integrin receptors mediating cell adhesion to extracellular matrix proteins (vitronectin, osteopontin/SPP1, fibronectin, thrombospondin-1); it transduces outside-in signals through FAK/PI3K/AKT, TGF-β/SMAD, MAPK/ERK, NFκB, and Hippo/YAP-TAZ pathways to regulate cell proliferation, migration, invasion, autophagy, stem cell quiescence, and tissue fibrosis; its transcription is directly controlled by Runx2, TAZ, CASZ1, SOX11, and the LGALS3BP-JUNB axis, and repressed by p53 via Sp1/Sp3; FURIN proteolytically matures ITGAV enabling astrocytic lipophagy, while γ-secretase cleavage generates a nuclear intracellular domain (CD51-ICD) that acts as a transcriptional co-activator (partnering with NR4A3 in colorectal cancer and driving oxidative phosphorylation genes in HCC), thereby explaining the failure of surface-targeted inhibitors such as cilengitide; biallelic human loss-of-function variants cause a syndrome of brain/eye malformations, colitis, and immune dysregulation linked to disrupted TGF-β and αVβ3 immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGAV (integrin αV, CD51) encodes an αV integrin subunit that pairs with β subunits to form RGD-binding adhesion receptors mediating attachment to extracellular matrix and matricellular ligands including vitronectin, SPP1/osteopontin, periostin, thrombospondin-1, and collagen-associated scaffolds, and it transduces these contacts into intracellular signaling controlling proliferation, migration, invasion, stem-cell behavior, and tissue homeostasis [#2, #5, #4, #13, #23]. Outside-in signaling through αV integrins engages divergent pathways: periostin–ITGAV ligation suppresses FAK/PI3K/AKT to enforce hematopoietic stem cell quiescence via p27Kip1 [#4], CD51 binds TGF-β receptors and amplifies TGF-β/SMAD signaling to confer cancer stem-cell and invasive traits [#6, #18], and ITGAV feeds a Hippo/YAP-TAZ feedback loop in which TAZ drives ITGAV transcription and ITGAV in turn sustains nuclear YAP/TAZ and actin stress-fiber assembly [#8]. ITGAV is also a node in non-adhesive proteolytic signaling: γ-secretase cleaves CD51 to release a nuclear intracellular domain (CD51-ICD) that acts as a transcriptional co-activator, partnering with NR4A3 to drive neurotropic genes in colorectal cancer and inducing oxidative-phosphorylation genes to promote hepatocellular carcinoma invasion, with periostin driving the cleavage event [#11, #10]. FURIN-mediated maturation of cytosolic ITGAV is required for lysosomal function and lipophagic flux in astrocytes, and αV-dependent noncanonical autophagy operates in germinal-center and memory B cells [#15, #16]. ITGAV transcription is directly controlled by Runx2, TAZ, SOX11, CASZ1, and a LGALS3BP–JunB axis, and repressed by p53 via Sp1/Sp3 [#9, #8, #19, #20, #28, #12]. Biallelic human loss-of-function ITGAV variants cause a syndrome of eye/brain malformations, inflammatory bowel disease, and immune dysregulation linked to disrupted TGF-β and αVβ3 immune signaling [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the gene's chromosomal location and protein product provided the foundation for mechanistic study of the vitronectin-receptor αV subunit.\",\n      \"evidence\": \"FISH mapping to 2q31→q32 and cDNA/genomic characterization of the 150-kDa subunit\",\n      \"pmids\": [\"7678549\", \"10965141\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"chromosomal localization alone establishes no function\", \"no signaling or ligand engagement defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying functional αvβ3 on differentiated mast cells and its vitronectin binding defined ITGAV as an adhesion receptor for matrix ligands in immune-lineage cells.\",\n      \"evidence\": \"Adhesion and antibody-blocking assays in SCF-cultured human fetal mast cells\",\n      \"pmids\": [\"7542504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream signaling not addressed\", \"no in vivo relevance shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that an RGD-less coxsackievirus mutant still binds αvβ3 showed the receptor engages ligands through both RGD-dependent and RGD-independent modes.\",\n      \"evidence\": \"Binding studies on αvβ3-expressing and chimeric CHO cells with blocking antibodies and vitronectin competition\",\n      \"pmids\": [\"10773347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"the RGD-independent contact residues on ITGAV not mapped\", \"physiological ligands using this mode not enumerated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that αvβ3 binds endothelial Thy-1/CD90 extended ITGAV's ligand repertoire beyond classical matrix proteins to a cell-surface counter-receptor mediating transendothelial migration.\",\n      \"evidence\": \"Reciprocal purified-protein and transfected-cell binding plus flow/static adhesion blockade in melanoma\",\n      \"pmids\": [\"15897908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"intracellular signaling consequence not defined\", \"single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic models defined opposing context-dependent ITGAV signaling outputs: periostin–ITGAV suppression of FAK/PI3K/AKT maintains HSC quiescence, while ITGAV restrains adipogenic differentiation via TAZ.\",\n      \"evidence\": \"Reciprocal Postn-KO and Itgav conditional-KO mice with HSC repopulation assays; siRNA/overexpression in adipose-derived stem cells\",\n      \"pmids\": [\"27905395\", \"27363302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how the same receptor selects FAK inhibition versus TAZ regulation is unresolved\", \"ligand-specific signaling thresholds not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing CD51 binds TGF-β receptors and amplifies TGF-β/SMAD signaling linked ITGAV directly to cancer stem-cell and invasive phenotypes.\",\n      \"evidence\": \"Co-IP of CD51–TGF-β receptor, siRNA knockdown, sphere assays and in vivo tumor models in colorectal cancer\",\n      \"pmids\": [\"27593923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"stoichiometry/structure of the CD51–TGFβR complex unknown\", \"whether engagement requires β-subunit pairing not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying p53/Sp1/Sp3 repression and epigenetic demethylation control of ITGAV revealed that its expression is tightly regulated transcriptionally to gate stemness and differentiation programs.\",\n      \"evidence\": \"Reporter assays and ChIP in prostate cancer; bisulfite sequencing and osteogenic assays in mesenchymal cells\",\n      \"pmids\": [\"29743605\", \"30219480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"interplay of activating versus repressive regulators in a single cell context not integrated\", \"direct p53 occupancy versus indirect Sp-mediated effect not fully separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing macrophage CD51 confers stemness on neighboring tumor cells via TGF-β1/Smad2/3 paracrine signaling established a cell-non-autonomous, microenvironmental role for ITGAV.\",\n      \"evidence\": \"siRNA knockdown in macrophages with co-culture and Smad2/3 pathway readouts in pancreatic cancer\",\n      \"pmids\": [\"31199988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"the ligand engaging macrophage CD51 not identified\", \"single-lab co-culture model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining a TAZ→ITGAV→nuclear YAP/TAZ positive-feedback loop showed ITGAV both responds to and amplifies Hippo pathway activity through actin remodeling.\",\n      \"evidence\": \"RNAi of TAZ/YAP/ITGAV, actin staining, migration/invasion and nuclear fractionation in HCC\",\n      \"pmids\": [\"31904487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism coupling ITGAV adhesion to YAP/TAZ nuclear retention not detailed\", \"TAZ-specific versus YAP selectivity at the promoter not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple transcription factors were shown to bind the ITGAV promoter directly, establishing Runx2, SOX11, and CASZ1 as drivers that route ITGAV into fibrosis, EMT, and metastasis programs.\",\n      \"evidence\": \"ChIP/ChIP-seq plus knockdown and in vivo models (Runx2 in hepatic stellate cell fibrosis; SOX11 in HNSCC; CASZ1 in lung cancer)\",\n      \"pmids\": [\"37403784\", \"38534932\", \"36777515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"combinatorial control by these factors in a single tissue not addressed\", \"whether they regulate specific αV/β heterodimers unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that γ-secretase cleaves CD51 to a nuclear ICD that co-activates NR4A3 redefined ITGAV as a signaling molecule acting in the nucleus, not only at the membrane.\",\n      \"evidence\": \"γ-secretase cleavage assay, CD51-ICD/NR4A3 Co-IP, reporter assays and pharmacological γ-secretase inhibition in colorectal cancer\",\n      \"pmids\": [\"37174090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"full ICD target gene network beyond NTRK1/NTRK3/SEMA3E not mapped\", \"single-lab interaction\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The CD51-ICD axis was extended in HCC where periostin drives cleavage and the ICD induces oxidative-phosphorylation genes, explaining why surface-only inhibitors fail and motivating combined γ-secretase blockade.\",\n      \"evidence\": \"Cleavage and nuclear ICD assays, RNA-seq, periostin-KO mice, patient-derived organoids/xenografts with cilengitide+LY3039478\",\n      \"pmids\": [\"37604269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"proportion of ITGAV signaling routed through ICD versus surface adhesion not quantified across tissues\", \"regulation of cleavage by β-subunit pairing unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ITGAV was identified as a node integrating matricellular and innate-immune cues into NF-κB and TGF-β/THBS1 signaling, broadening its pro-tumor signaling beyond canonical FAK/SMAD routes.\",\n      \"evidence\": \"NET-DNA pull-down/MS and ChIP in cholangiocarcinoma; THBS1/ITGAV/TβRI Co-IP with CRISPR/siRNA and xenografts in CRPC\",\n      \"pmids\": [\"38326837\", \"39304722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether the same heterodimer mediates NET-DNA and THBS1 binding unclear\", \"direct versus scaffold-mediated NF-κB activation not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Biallelic human loss-of-function variants causally linked ITGAV to a multisystem disorder, anchoring its physiological roles in TGF-β and αVβ3 immune signaling in vivo.\",\n      \"evidence\": \"Human genetics with patient-cell functional studies, RNA-seq, and zebrafish itgav deletion recapitulating retinal/brain, microglial, and colitis phenotypes\",\n      \"pmids\": [\"39526957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"tissue-specific contributions of distinct αV heterodimers to the syndrome not dissected\", \"genotype–phenotype correlation across variants limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"FURIN-dependent maturation of cytosolic ITGAV was shown to be required for lysosomal function and lipophagy, revealing a proteolytic-maturation requirement distinct from surface integrin assembly.\",\n      \"evidence\": \"IP-MS substrate identification, cleavage-site mutagenesis, lipophagic flux/lipidomics, and rescue with mature versus mutant ITGAV in FURIN-deficient astrocytes/mice\",\n      \"pmids\": [\"41376284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how the FURIN-matured form supports lysosomal/lipophagic machinery mechanistically unresolved\", \"relationship to canonical surface ITGAV pool unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Further mechanisms diversified ITGAV's roles—autophagy regulation in cardiomyocytes, Notch trafficking in gastric cancer stemness, efferocytosis as an apoptotic-cell ligand, and context-dependent SMAD4 versus MAPK/ERK signaling—while a cell-type-specific knockout established that macrophage ITGAV is dispensable for post-infarction repair.\",\n      \"evidence\": \"Co-IP, trafficking and autophagy-flux assays, fibroblast/macrophage-specific KO mice, isogenic SMAD4+/- PDAC lines, and patient-derived models\",\n      \"pmids\": [\"42056922\", \"40555320\", \"40736047\", \"40739706\", \"41318687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"unifying determinant of which downstream pathway ITGAV selects per context not defined\", \"negative macrophage-MI result delimits but does not explain tissue-specific requirements\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single αV subunit's β-partner choice, ligand identity, and proteolytic processing (FURIN maturation versus γ-secretase ICD release) are coordinated to select among the many divergent downstream pathways attributed to ITGAV.\",\n      \"evidence\": \"No single study reconciles surface adhesion, ICD nuclear signaling, and FURIN-dependent maturation within one cellular system\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no structural model of the CD51-ICD or its cofactor complexes\", \"determinants of β-subunit pairing across the documented functions not established\", \"quantitative balance between membrane and nuclear ITGAV signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 5, 23, 0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 8, 13]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 5, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 16, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [16, 17, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\"αvβ3 integrin\", \"αvβ1 integrin\", \"THBS1/ITGAV/TβRI complex\"],\n    \"partners\": [\"ITGB3\", \"POSTN\", \"THBS1\", \"TGFBR1\", \"NR4A3\", \"FURIN\", \"NUMB\", \"ADAM9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}