{"gene":"ITGA2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1989,"finding":"The ITGA2 (VLA-2 alpha2 subunit) primary structure was determined from cDNA cloning, revealing a 1,181 amino acid protein with a 191-amino acid inserted I-domain (not found in other integrin alpha chains at the time) homologous to von Willebrand factor A-domains and cartilage matrix protein, suggesting the I-domain as a collagen-binding domain. The protein contains three metal-binding domains and a transmembrane segment with a short 22-amino acid cytoplasmic tail.","method":"cDNA library screening, nucleotide sequencing, protein NH2-terminal sequencing","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — direct protein sequencing combined with cDNA sequencing; foundational structural characterization","pmids":["2545729"],"is_preprint":false},{"year":1989,"finding":"GPIa/IIa (integrin alpha2beta1) mediates direct platelet adhesion to collagen independently of plasma adhesive proteins, demonstrated by a blocking monoclonal antibody (6F1) that inhibited collagen-induced platelet aggregation and platelet adhesion to collagen by >95% in the absence of plasma proteins. GPIIb/IIIa mediates indirect collagen interaction via adhesive protein intermediaries.","method":"Monoclonal antibody blocking assay, collagen-coated bead agglutination, platelet adhesion assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional blocking with defined phenotypic readout; replicated across multiple assay systems","pmids":["2546619"],"is_preprint":false},{"year":1994,"finding":"Integrin alpha2beta1 is a universal platelet collagen receptor mediating adhesion to collagen types I through VIII under both static and flow conditions, as demonstrated by complete inhibition of platelet adhesion to all collagen types by anti-GPIa monoclonal antibody 176D7.","method":"Platelet adhesion assay under static and flow conditions with monoclonal antibody blocking","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — systematic functional blocking across 8 collagen types under multiple conditions","pmids":["8118028"],"is_preprint":false},{"year":1994,"finding":"The I-domain of ITGA2 (residues 140-359) contains the ligand-binding site for both collagen and echovirus 1. Function-blocking antibodies map to residues 173-259 within the I-domain. Mutations of Asp-151 and Asp-254 block collagen binding, and Asp-160 and Arg-242 are critical for other function-inhibiting antibody epitopes, indicating that collagen and echovirus 1 binding sites are adjacent or overlapping within the I-domain.","method":"Interspecies (human/bovine) alpha2 chimeras, site-directed mutagenesis, antibody epitope mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with chimeric protein analysis identifying specific residues for ligand binding","pmids":["7511592"],"is_preprint":false},{"year":1994,"finding":"The recombinant I-domain of ITGA2 alone is sufficient for collagen binding in a divalent cation-independent manner, demonstrating the I-domain contains all components necessary for collagen recognition. Thr-221 within the I-domain is critical for collagen binding to both full-length alpha2beta1 and the isolated I-domain fragment; divalent cations regulate binding rather than directly participate in collagen contact.","method":"Recombinant I-domain protein binding assay, site-directed mutagenesis (T221 substitution), divalent cation chelation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted domain binding with mutagenesis identifying critical residue; mechanistically definitive","pmids":["7523399"],"is_preprint":false},{"year":1997,"finding":"The recombinant alpha2 I-domain (residues 145-334) fused to maltose-binding protein binds immobilized collagen type I in a Mg2+-dependent, Ca2+/EDTA-inhibitable manner, and competitively inhibits platelet adhesion to collagen and collagen-induced platelet aggregation (IC50 ~0.7 μM), confirming the I-domain as the collagen-binding site of alpha2beta1.","method":"Recombinant protein expression, ELISA-based binding assay, platelet adhesion inhibition, platelet aggregation inhibition","journal":"Thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1 — reconstituted I-domain with functional competition assays confirming collagen-binding role","pmids":["9184414"],"is_preprint":false},{"year":1997,"finding":"Crystal structure of the ITGA2 I-domain determined at high resolution reveals a dinucleotide-binding (Rossmann) fold with a metal ion-dependent adhesion site (MIDAS) motif coordinating Mg2+ at the top of the beta-sheet. A unique C-helix creates a groove around the Mg2+ ion predicted to be the collagen-binding site; modeling suggests a glutamate from collagen coordinates the metal. The echovirus-1 binding site maps to a distinct surface (one edge of the beta-sheet), indicating collagen and virus bind by different mechanisms.","method":"X-ray crystallography (high resolution crystal structure)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mechanistic modeling of ligand binding","pmids":["9353312"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of the ITGA2 I-domain in complex with a triple-helical collagen peptide containing the GFOGER motif revealed that three loops on the upper surface of the I-domain coordinate a metal ion and simultaneously engage the collagen triple helix, with a collagen glutamate completing the metal ion coordination sphere. Ligand binding induces conformational changes that propagate from the upper surface to the opposite pole of the domain, providing a structural basis for affinity regulation and signal transduction.","method":"X-ray crystallography of I-domain/collagen peptide complex","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of receptor-ligand complex with conformational change analysis; highly cited foundational study","pmids":["10778855"],"is_preprint":false},{"year":2001,"finding":"Rhodocytin from snake venom directly binds GPIa/IIa (integrin alpha2beta1) independently of divalent cations, inducing platelet aggregation. Src and Lyn kinases constitutively associate with GPIa/IIa and Src activity increases transiently after rhodocytin stimulation; Src then mediates phosphorylation of p130 Cas. Downstream signals including Syk phosphorylation, PLCgamma2 phosphorylation, and intracellular Ca2+ mobilization are cAMP-sensitive and require actin polymerization/receptor clustering.","method":"Rhodocytin-coupled bead binding assay, liposome reconstitution with recombinant GPIa/IIa, in vitro kinase assay, Western blotting of immunoprecipitates, cytochalasin D inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with recombinant receptor, kinase assay, and multiple signaling readouts","pmids":["11038351"],"is_preprint":false},{"year":2003,"finding":"EMS16, a C-type lectin-like protein from Echis multisquamatus venom, acts as a potent and selective antagonist of integrin alpha2beta1 (GPIa/IIa). Crystal structure at 1.9 Å resolution revealed a heterodimer with domain-swapped central loop architecture and a unique positively-charged electrostatic patch on its concave surface proposed as the interaction site for the ITGA2 I-domain.","method":"X-ray crystallography at 1.9 Å resolution, structural analysis of protein-receptor antagonist","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional context as specific alpha2beta1 antagonist","pmids":["14580195"],"is_preprint":false},{"year":2003,"finding":"Integrin alpha2beta1 mediates outside-in signaling during platelet spreading on collagen, activating Src kinases, Syk, SLP-76, PLCgamma2, focal adhesion kinase, and plasma membrane calcium ATPase, leading to filopodia and lamellipodia formation. This signaling is independent of the GPVI-FcR gamma-chain complex, requires intracellular Ca2+, and is abolished by the Src kinase inhibitor PP2 and in PLCgamma2-deficient platelets.","method":"Integrin-specific collagen peptide stimulation, tyrosine phosphorylation Western blot, PLCgamma2-deficient platelets, PP2 inhibitor, intracellular Ca2+ chelation, morphological spreading assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic (PLCgamma2 KO) and pharmacological epistasis combined with phosphorylation readouts","pmids":["12615912"],"is_preprint":false},{"year":1993,"finding":"GPIa/IIa (integrin alpha2beta1) binds thrombospondin (TSP) in an ion-independent manner with a dissociation constant of 0.69 μM, which is 5.5-fold more favorable than GPIIb/IIIa binding to TSP. This interaction is blocked by anti-GPIa/IIa antibody 6F1 but not by anti-GPIIb/IIIa antibody, suggesting GPIa/IIa is a preferred TSP binding protein on platelets.","method":"Saturable binding assay with purified glycoproteins, competition inhibition with antibodies and unlabeled protein","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — saturable binding with defined Kd; single lab, single method type","pmids":["8240284"],"is_preprint":false},{"year":1997,"finding":"VEGF induces 5-7 fold increased surface expression of integrin alpha2beta1 (and alpha1beta1) on dermal microvascular endothelial cells through induction of alpha2 subunit mRNA. Blocking antibodies against alpha2 integrin partially inhibited EC attachment to collagen I and abolished VEGF-promoted cell spreading on collagen I gels. In vivo, anti-alpha2 antibody combination markedly inhibited VEGF-driven angiogenesis, reducing new vessel cross-sectional area by 90%.","method":"Flow cytometry, mRNA induction assay, blocking antibody cell adhesion/spreading assay, in vivo VEGF-driven angiogenesis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo functional blocking with defined molecular mechanism (VEGF-induced alpha2 mRNA upregulation)","pmids":["9391074"],"is_preprint":false},{"year":2004,"finding":"Endorepellin (COOH-terminal domain of perlecan) binds integrin alpha2beta1 on endothelial cells and triggers a signaling cascade including increased cAMP, activation of PKA and FAK, transient activation of p38 MAPK and HSP27 followed by their rapid downregulation, leading to disassembly of actin stress fibers and focal adhesions, and blocking endothelial cell migration and angiogenesis.","method":"Ligand binding, cAMP measurement, kinase activity assays, Western blotting of p38/HSP27, actin/focal adhesion immunofluorescence, cell migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal signaling readouts linked to alpha2beta1 engagement with defined downstream pathway","pmids":["15240572"],"is_preprint":false},{"year":2004,"finding":"VEGF-A promotes lymphangiogenesis via induction of alpha1 and alpha2 integrin expression on lymphatic endothelial cells. Anti-alpha2 integrin blocking antibodies suppressed VEGF-A-induced lymphatic endothelial cord formation and haptotactic migration toward collagen I in vitro, and systemic blockade of alpha2 integrin inhibited VEGF-A-driven lymphangiogenesis in vivo.","method":"Integrin expression profiling, blocking antibody tube formation assay, haptotaxis assay, in vivo lymphangiogenesis model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo functional blocking establishing role of alpha2beta1 in VEGF-driven lymphangiogenesis","pmids":["15132990"],"is_preprint":false},{"year":2006,"finding":"Rab21 small GTPase associates with the cytoplasmic domains of alpha-integrin chains including alpha2, regulating endosomal trafficking of beta1-integrins. Knockdown of Rab21 impairs integrin-mediated cell adhesion and motility, while overexpression stimulates migration and cancer cell adhesion to collagen; a point mutation in the alpha-integrin cytoplasmic domain that abolishes Rab21 association prevents Rab21-induced adhesion.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, point mutagenesis of cytoplasmic domain, cell adhesion and motility assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus mutagenesis plus KD/KO with defined cellular phenotype","pmids":["16754960"],"is_preprint":false},{"year":2007,"finding":"The ITGA2 gene locus on chromosome 5q11.2 is regulated by epigenetic mechanisms distinct from the neighboring ITGA1. During thrombopoietin-induced megakaryocyte differentiation, ITGA1 undergoes rapid progressive CpG methylation but ITGA2 does not, establishing that ITGA2 expression is maintained in the megakaryocyte lineage through a methylation-independent mechanism. In vitro methylation of ITGA1 promoter suppresses its transcription.","method":"Sodium bisulfite genomic sequencing, promoter-luciferase reporter assays, 5-aza-2'-deoxycytidine treatment, primary cord blood megakaryocyte differentiation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation assay with functional reporter validation; single lab","pmids":["17669516"],"is_preprint":false},{"year":2008,"finding":"Collagen I signaling through integrin alpha2beta1 and discoidin domain receptor 1 (DDR1) cooperatively up-regulates N-cadherin in pancreatic cancer cells, promoting EMT. Alpha2beta1 integrin propagates signals through FAK and the p130CAS scaffold, while DDR1 acts through Pyk2/p130CAS; both pathways converge and require Rap1 (but not Rho GTPases) for N-cadherin upregulation. Knockdown of alpha2beta1 prevents collagen I-induced N-cadherin upregulation.","method":"siRNA knockdown of alpha2beta1 and DDR1, signaling pathway inhibitors, Western blotting, in vivo mouse tumor model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdown epistasis with multiple pathway components and in vivo validation","pmids":["18362184"],"is_preprint":false},{"year":2010,"finding":"PARP-1 and Ku80/70 bind specifically and with enhanced affinity to longer (CA)12 repeat alleles in the 5'-regulatory region of ITGA2 (beginning at -605), as demonstrated by DNA affinity chromatography and chromatin immunoprecipitation. This enhanced binding correlates with increased ITGA2 transcriptional activity, identifying PARP-1 and Ku80/70 as transcriptional co-regulators of ITGA2 expression.","method":"DNA affinity chromatography, chromatin immunoprecipitation (ChIP), promoter-reporter assays with different CA repeat length alleles","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and DNA affinity chromatography identifying specific transcriptional regulators; single lab","pmids":["20090957"],"is_preprint":false},{"year":2011,"finding":"Alpha2-integrin (ITGA2) expression is upregulated on stiffer extracellular matrices during osteogenic induction of mesenchymal stem cells, and siRNA knockdown of alpha2-integrin downregulates osteogenic differentiation markers through ROCK, FAK, and ERK1/2 signaling pathways, placing alpha2-integrin upstream of ROCK/FAK/ERK1/2 mechanotransduction during osteogenesis.","method":"siRNA knockdown, polyacrylamide hydrogel stiffness system, Western blot of ROCK/FAK/ERK1/2 activity, osteogenic differentiation markers","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with pathway epistasis; single lab","pmids":["20939067"],"is_preprint":false},{"year":2014,"finding":"EZH2 epigenetically represses ITGA2 expression, and when EZH2 is inhibited (genetically or pharmacologically with DZNep or GSK343), de-repressed ITGA2 signaling increases cofilin phosphorylation at Serine 3 (inactivating cofilin), thereby reducing actin remodeling and cell migration in colorectal cancer cells. ChIP confirmed EZH2 directly regulates the ITGA2 locus.","method":"EZH2 siRNA knockdown, pharmacological inhibition (DZNep, GSK343), chromatin immunoprecipitation (ChIP), cofilin phosphorylation Western blot, cell migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP combined with genetic and pharmacological epistasis and defined signaling readout; single lab","pmids":["25549357"],"is_preprint":false},{"year":2015,"finding":"ITGA2 expression is regulated by CpG methylation of its promoter in prostate cancer cells. Demethylated ITGA2 promoter correlates with higher ITGA2 expression and increased cell migratory potential. siRNA knockdown of ITGA2 in highly migratory PC3 and 22Rv1 cells reduced migration in scratch assays, confirming ITGA2 promotes cell migration in prostate cancer.","method":"Bisulfite sequencing of ITGA2 promoter CpG island, qPCR, siRNA knockdown, scratch wound healing assay","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation sequencing correlated with expression and functional validation by KD; single lab","pmids":["25662931"],"is_preprint":false},{"year":2015,"finding":"Human Th17 cells co-express IL-7R and integrin alpha2beta1 (CD49b); IL-7 increases Th17 adhesion to collagen via alpha2beta1. Co-engagement of IL-7R and alpha2beta1 cooperatively enhances IL-17 production and osteoclastogenic activity through JAK/PI3K/AKT and MAPK/ERK pathways. In vivo blockade of alpha2beta1 with neutralizing mAb inhibited IL-7-induced bone loss by reducing Th17 cell numbers and IL-17/RANKL production.","method":"Integrin blocking antibody, co-engagement of receptors, cytokine production ELISA, in vivo bone loss model with antibody blockade, pathway inhibitor studies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro co-engagement with pathway inhibitors and in vivo antibody blocking with bone loss phenotype; single lab","pmids":["26408663"],"is_preprint":false},{"year":2019,"finding":"ITGA2 interacts with STAT3 (demonstrated by co-immunoprecipitation) and up-regulates STAT3 phosphorylation, which transcriptionally increases PD-L1 expression in cancer cells. Knockdown of ITGA2 inhibited cancer cell proliferation and invasion, while ITGA2 overexpression promoted these processes. RNA-seq confirmed ITGA2 transcriptionally regulates PD-L1.","method":"Co-immunoprecipitation (ITGA2-STAT3 interaction), Western blot (STAT3 phosphorylation), RNA-seq, RT-qPCR, functional assays (MTS, colony formation, transwell)","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying novel binding partner plus phosphorylation readout and RNA-seq; single lab","pmids":["31818309"],"is_preprint":false},{"year":2018,"finding":"Blockade of ITGA2 with a specific antibody induces apoptosis in gastric cancer cells by upregulating RhoA-p38 MAPK signaling to promote Bim, Apaf-1 and Caspase-9 expression (without affecting Ras or Bax/Bcl-2). ITGA2 blockade also inhibits cell migration by downregulating N-WASP, PAK, and LIMK to impede actin organization.","method":"Anti-ITGA2 antibody treatment, apoptosis assay, Western blot for RhoA/p38/Bim/Apaf-1/Caspase-9/N-WASP/PAK/LIMK, cell migration assay","journal":"Biological procedures online","confidence":"Medium","confidence_rationale":"Tier 2 — antibody-based functional blocking with defined downstream signaling pathway components; single lab","pmids":["29743821"],"is_preprint":false},{"year":2020,"finding":"Exosomal ITGA2 derived from castration-resistant prostate cancer cells can be transferred to androgen receptor-positive recipient cells, promoting proliferation, migration, invasion and epithelial-mesenchymal transition. These effects were reversed by ITGA2 knockdown in donor cells or inhibition of exosomal uptake by methyl-β-cyclodextrin, and reproduced by ectopic ITGA2 overexpression in recipient cells.","method":"Exosome co-incubation, ITGA2 knockdown, ectopic overexpression, methyl-β-cyclodextrin inhibition, EMT marker Western blot, cell migration/invasion assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays with gain/loss of function; single lab","pmids":["32824235"],"is_preprint":false},{"year":2020,"finding":"ITGA2 overexpression in ovarian cancer promotes cell proliferation and mediates paclitaxel resistance by activating AKT phosphorylation, which in turn phosphorylates FoxO1, preventing FoxO1-mediated transcription of pro-apoptotic genes.","method":"ITGA2 overexpression/knockdown, Western blot for AKT and FoxO1 phosphorylation, paclitaxel sensitivity assay, cell proliferation assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — defined phosphorylation cascade from ITGA2 to AKT to FoxO1 with drug resistance phenotype; single lab","pmids":["32202508"],"is_preprint":false},{"year":2021,"finding":"Cyclic mechanical stretch promotes nucleus pulposus cell proliferation and inhibits apoptosis via the ITGA2/PI3K/AKT signaling pathway. Gene expression profiling identified 31 differentially expressed genes in this pathway after stretch; siRNA knockdown of ITGA2 and AKT confirmed that the PI3K/AKT pathway mediates stretch-induced COL2A1 expression and cell proliferation.","method":"Cyclic tensile stress system, gene expression microarray, siRNA knockdown of ITGA2 and AKT, Western blot, cell proliferation and apoptosis assays","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis with defined pathway and functional readout; single lab","pmids":["33815660"],"is_preprint":false},{"year":2021,"finding":"ITGA2 overexpression in esophageal squamous cell carcinoma activates FAK/AKT signaling and promotes EMT. ITGA2 silencing inhibits FAK/AKT phosphorylation and suppresses EMT markers, while ITGA2 overexpression activates this pathway. Treatment with AKT inhibitor MK-2206 repressed ITGA2-overexpression-driven ESCC progression, establishing FAK/AKT as the downstream pathway.","method":"ITGA2 knockdown/overexpression, Western blot for FAK/AKT/EMT markers, AKT inhibitor MK-2206, tumor xenograft model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with AKT inhibitor plus KD/OE confirming FAK/AKT pathway; single lab","pmids":["34113124"],"is_preprint":false},{"year":2022,"finding":"ITGA2 inhibits the non-homologous end joining (NHEJ) DNA repair pathway by restraining the recruitment of DNA-PKcs to the Ku70/80 heterodimer during the DNA damage response, conferring sensitivity to radiotherapy in pancreatic cancer. Nuclear ITGA2 overexpression correlates with genome instability parameters in TCGA data.","method":"DNA-PKcs/Ku70/Ku80 recruitment assay, NHEJ activity assay, ITGA2 nuclear localization analysis, TCGA correlation analysis, radiation sensitivity assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — defined mechanistic inhibition of DNA-PKcs recruitment to Ku70/80 by nuclear ITGA2; single lab","pmids":["35998796"],"is_preprint":false},{"year":2022,"finding":"Elevated ITGA2 expression promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma cells. Depletion of ITGA2 or treatment with an integrin alpha2beta1-selective inhibitor abolished robust interaction of iCCA cells with collagen type I and blocked collagen type I-induced colony growth enhancement (3-6 fold), confirming a functional collagen type I-integrin alpha2 axis in cholangiocarcinoma.","method":"ITGA2 siRNA knockdown, integrin alpha2beta1-selective inhibitor, collagen binding assay, clonogenic growth assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — both genetic and pharmacological inhibition with defined ligand-receptor functional readout; single lab","pmids":["36575207"],"is_preprint":false},{"year":2023,"finding":"BACH1 directly binds to the upstream sequence of the ITGA2 promoter to transcriptionally activate ITGA2 expression. The BACH1-ITGA2 axis promotes lung adenocarcinoma cell migration and invasion through activation of the FAK-RAC1-PAK signaling pathway and cytoskeletal regulation, as demonstrated by ChIP and dual-luciferase reporter assays.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, BACH1/ITGA2 knockdown/overexpression, RNA-seq, FAK-RAC1-PAK pathway Western blot, cell adhesion and migration assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirming direct transcriptional regulation; downstream pathway defined; single lab","pmids":["37311571"],"is_preprint":false},{"year":2024,"finding":"Genomic deletion or loss of ITGA2 (together with ITGA1) in benign prostate epithelial cells activates TGFβ1 autocrine signaling and nuclear YAP1 targeting, inducing EMT and converting cells to a tumorigenic phenotype in vivo. TEAD1 was identified as a key transcriptional regulator of both ITGA1 and ITGA2 expression; TEAD1 loss phenocopies dual alpha1/alpha2 integrin loss, triggering TGFβ1-driven EMT.","method":"CRISPR genomic deletion of ITGA1/ITGA2, TGFβ1 neutralization, YAP1 nuclear localization assay, genome-wide co-expression analysis, in vivo tumorigenesis assay, TEAD1 knockdown","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR loss-of-function with defined signaling pathway (TGFβ1/YAP1) and in vivo tumorigenesis; single lab","pmids":["38169150"],"is_preprint":false},{"year":2024,"finding":"In 3D bioprinted glioma models, ITGA2 expression is significantly elevated compared to 2D models and mediates radiation tolerance through the p-AKT signaling pathway. shRNA-mediated knockdown of ITGA2 reduced radiation tolerance and concomitantly inhibited p-AKT pathway activation in 3D glioma models.","method":"3D bioprinted tumor model, shRNA ITGA2 knockdown, radiation treatment, p-AKT Western blot, differential gene expression profiling","journal":"Advanced healthcare materials","confidence":"Medium","confidence_rationale":"Tier 2 — shRNA knockdown with defined downstream pathway in a novel 3D model; single lab","pmids":["38288911"],"is_preprint":false},{"year":2020,"finding":"ITGA2 knockdown in breast cancer cells suppressed self-renewal (mammosphere formation), pluripotency marker expression, inhibited cell cycling (G1 arrest), compromised migration/invasion, and decreased lung metastasis. ITGA2 overexpression reversed miR-206-caused G1 cell cycle arrest. RNA sequencing revealed ITGA2 regulates CCND1 (cyclin D1) and ACLY (ATP citrate lyase), with CCND1 being required downstream for cell cycle progression and lung colonization.","method":"ITGA2 knockdown/overexpression, mammosphere formation assay, cell cycle analysis, RNA sequencing, CCND1/ACLY knockdown rescue experiments, in vivo lung metastasis model","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq combined with rescue experiments identifying CCND1/ACLY as downstream targets; in vivo validation","pmids":["34179312"],"is_preprint":false},{"year":2021,"finding":"ITGA2 overexpression in rheumatoid arthritis PBMCs promotes T cell proliferation, inhibits apoptosis, and induces expression of IL-8, IFN-γ, and TNF-α in Jurkat T cells, demonstrating a functional role for ITGA2 in T cell activation and pro-inflammatory cytokine production.","method":"ITGA2 overexpression in Jurkat T cells, cell proliferation assay, apoptosis analysis, cytokine (IL-8, IFN-γ, TNF-α) measurement by ELISA","journal":"Clinica chimica acta","confidence":"Low","confidence_rationale":"Tier 3 — single overexpression experiment with cytokine readout, no pathway placement; single lab","pmids":["34599900"],"is_preprint":false},{"year":2010,"finding":"In the pregnant rat cervix, ITGA2 expression increases progressively over gestation. Mifepristone (progesterone receptor antagonist) increases ITGA2 expression and activates ERK1/2 phosphorylation both in vivo and in primary cervical stromal cells in vitro; inhibition of ERK1/2 abrogated mifepristone-induced ITGA2 upregulation, placing ERK1/2 downstream of progesterone withdrawal in ITGA2 regulation.","method":"Rat gestational model, mifepristone treatment, primary cervical stromal cell culture, Western blot for ITGA2/pERK1/2/pFAK, ERK1/2 inhibitor rescue","journal":"Reproductive sciences","confidence":"Low","confidence_rationale":"Tier 3 — in vivo and in vitro pharmacological epistasis for regulation; single lab, limited mechanistic depth","pmids":["20959644"],"is_preprint":false},{"year":2020,"finding":"TSPAN1 transcriptionally regulates ITGA2 expression in pancreatic cancer, and epigenetically controls ITGA2 by modulating TET2, DNMT3B, and DNMT1, resulting in hypomethylation of the ITGA2 promoter CpG island. ITGA2 knockdown abolished TSPAN1 overexpression-driven pancreatic cancer cell proliferation and invasion.","method":"RNA-seq after TSPAN1 manipulation, DNMT/TET2 expression analysis, CpG methylation analysis, ITGA2 siRNA rescue experiments","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 — epigenetic regulation identified by correlation and rescue; limited mechanistic depth for ITGA2 itself; single lab","pmids":["32368389"],"is_preprint":false},{"year":2020,"finding":"HOXD3, whose expression is regulated by YY1 recruiting HDAC1, promotes HCC progression by binding the ITGA2 promoter and upregulating ITGA2 expression, thereby activating ERK1/2 signaling to drive proliferation, metastasis, and migration. ChIP-PCR confirmed HOXD3 binding to the ITGA2 promoter; dual luciferase reporter assays confirmed transcriptional activation.","method":"ChIP-PCR, dual luciferase reporter assay, HOXD3/ITGA2 knockdown/overexpression, Co-IP (YY1-HDAC1), ERK1/2 Western blot","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase confirming HOXD3 as direct ITGA2 transcriptional regulator with ERK1/2 downstream pathway; single lab","pmids":["32557953"],"is_preprint":false},{"year":2025,"finding":"A novel enhancer-associated lncRNA (LncRNA-ITGA2) located at the ITGA2 locus promotes VSMC proliferation and migration by upregulating ITGA2 expression. Mechanistically, LncRNA-ITGA2 binds the ITGA2 enhancer region, increases H3K27 acetylation at both the ITGA2 enhancer and promoter, and interacts with DNA-binding protein NONO which also binds the ITGA2 promoter, thereby mediating enhancer-promoter looping interactions. CRISPR-Cas9 knockout of NONO or LncRNA-ITGA2 validated this regulatory mechanism.","method":"CUT&Tag, promoter-capture Hi-C, RNA-seq, CRISPR-Cas9 knockout, ChIP-seq, CHIRP, RIP, H3K27ac ChIP, carotid artery wire injury in vivo model","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — multiomics with CRISPR validation and in vivo model; however describes regulatory mechanism of ITGA2 expression via lncRNA, not ITGA2 protein mechanism directly; single lab","pmids":["40321134"],"is_preprint":false}],"current_model":"ITGA2 encodes the alpha2 subunit of integrin alpha2beta1, a collagen receptor whose I-domain (residues ~140-359) directly binds collagen via a MIDAS metal ion coordinated by three I-domain loops that also engage the GFOGER collagen motif (with a collagen glutamate completing metal coordination), as established by crystal structures of the free and collagen-bound I-domain; collagen binding activates outside-in signaling through constitutively-associated Src/Lyn kinases leading to Syk, PLCgamma2, and FAK phosphorylation to drive platelet spreading and cell migration; in cancer and other contexts ITGA2 activates FAK/AKT, RhoA/p38 MAPK, STAT3/PD-L1, and ERK1/2 signaling pathways to promote proliferation, invasion, EMT, and drug/radiation resistance, while nuclear ITGA2 additionally inhibits NHEJ DNA repair by blocking DNA-PKcs recruitment to Ku70/80; ITGA2 expression is transcriptionally regulated by BACH1, HOXD3, TEAD1, EZH2 (epigenetic repression), and PARP-1/Ku80/70 binding to CA-repeat promoter elements, and is induced by VEGF on endothelial cells to promote angiogenesis and lymphangiogenesis via alpha2beta1-dependent collagen adhesion."},"narrative":{"teleology":[{"year":1989,"claim":"Cloning and antibody-blocking experiments established that VLA-2 (α2β1) is a collagen receptor on platelets and that the α2 subunit harbors a unique ~191-residue I-domain homologous to vWF A-domains, identifying the likely collagen-binding module.","evidence":"cDNA cloning/sequencing of α2 subunit and monoclonal antibody 6F1 blocking of platelet–collagen adhesion","pmids":["2545729","2546619"],"confidence":"High","gaps":["I-domain collagen-binding function was inferred by homology, not yet demonstrated directly","β1 subunit contribution to ligand binding was unknown"]},{"year":1994,"claim":"Chimeric constructs, mutagenesis, and recombinant I-domain binding assays demonstrated that the I-domain alone is necessary and sufficient for collagen recognition, mapping critical residues (Asp-151, Asp-254, Thr-221) and showing α2β1 binds all collagen types I–VIII.","evidence":"Human/bovine α2 chimeras, site-directed mutagenesis, recombinant I-domain collagen-binding assay, systematic antibody blocking across 8 collagen types","pmids":["7511592","7523399","8118028"],"confidence":"High","gaps":["Atomic-resolution structure of I-domain not yet available","Role of divalent cations in binding was debated"]},{"year":1997,"claim":"The crystal structure of the free I-domain revealed a Rossmann fold with a MIDAS motif coordinating Mg²⁺, resolving how divalent cations participate in collagen recognition and predicting a collagen glutamate would complete metal coordination.","evidence":"X-ray crystallography of the α2 I-domain; recombinant I-domain competition of platelet adhesion","pmids":["9353312","9184414"],"confidence":"High","gaps":["Ligand-bound structure not yet solved","Conformational changes upon collagen binding uncharacterized"]},{"year":2000,"claim":"The co-crystal structure of the I-domain with a triple-helical GFOGER collagen peptide proved that collagen glutamate completes MIDAS coordination and showed that ligand binding propagates conformational changes to the opposite pole, providing a structural basis for affinity regulation and outside-in signaling.","evidence":"X-ray crystallography of I-domain–collagen peptide complex","pmids":["10778855"],"confidence":"High","gaps":["Mechanism coupling C-terminal conformational shift to β1 subunit activation undetermined","Full ectodomain structure with β1 unavailable"]},{"year":2001,"claim":"Identification of the outside-in signaling cascade downstream of α2β1 engagement—constitutive Src/Lyn association, Syk and PLCγ2 phosphorylation, FAK activation, and intracellular Ca²⁺ mobilization—established the receptor as an autonomous signaling entity independent of GPVI.","evidence":"Rhodocytin-stimulated liposome-reconstituted α2β1 kinase assays; collagen peptide-stimulated platelet spreading with PLCγ2-KO platelets and PP2 inhibitor","pmids":["11038351","12615912"],"confidence":"High","gaps":["Adaptor proteins linking Src/Syk to downstream effectors incompletely defined","Role of cytoplasmic tail phosphorylation unclear"]},{"year":1997,"claim":"VEGF was shown to transcriptionally upregulate α2β1 on endothelial cells, and functional blocking of α2 integrin inhibited VEGF-driven angiogenesis by ~90% in vivo, placing α2β1–collagen interaction as a required step in neovascularization.","evidence":"Flow cytometry, mRNA induction, anti-α2 blocking antibody in vivo angiogenesis assay; extended to lymphangiogenesis in a subsequent study","pmids":["9391074","15132990"],"confidence":"High","gaps":["Specific intracellular signals linking VEGF-induced α2β1 to endothelial tube formation not fully mapped"]},{"year":2008,"claim":"Cooperative signaling through α2β1 (via FAK/p130CAS) and DDR1 (via Pyk2) converging on Rap1 was shown to upregulate N-cadherin in pancreatic cancer, providing a mechanistic link between collagen sensing by α2β1 and EMT.","evidence":"siRNA knockdown of α2β1 and DDR1, signaling pathway inhibitors, in vivo tumor model","pmids":["18362184"],"confidence":"High","gaps":["Rap1 activation mechanism downstream of FAK/p130CAS incompletely characterized","Generalizability to other epithelia unconfirmed"]},{"year":2014,"claim":"Transcriptional and epigenetic regulation of ITGA2 was elaborated: EZH2 directly represses the locus, PARP-1/Ku80 bind CA-repeat promoter elements to enhance transcription, and promoter CpG methylation status controls expression in prostate cancer, establishing ITGA2 as an epigenetically regulated gene.","evidence":"ChIP for EZH2, DNA affinity chromatography for PARP-1/Ku80, bisulfite sequencing in prostate cancer cells, pharmacological inhibition of EZH2","pmids":["25549357","20090957","25662931"],"confidence":"Medium","gaps":["Relative contribution of each epigenetic regulator in different lineages unclear","Whether EZH2-mediated repression is H3K27me3-dependent was not confirmed by histone mark ChIP"]},{"year":2019,"claim":"ITGA2 was found to interact with STAT3, promote its phosphorylation, and thereby transcriptionally upregulate PD-L1, revealing a non-canonical signaling output linking α2β1 to immune evasion.","evidence":"Co-immunoprecipitation (ITGA2–STAT3), RNA-seq, ITGA2 knockdown/overexpression in cancer cells","pmids":["31818309"],"confidence":"Medium","gaps":["Reciprocal co-IP or proximity ligation not reported","Whether STAT3 interaction is direct or bridged by FAK/Src unknown","Functional impact on anti-tumor immunity not tested in vivo"]},{"year":2022,"claim":"Nuclear ITGA2 was shown to inhibit NHEJ DNA repair by blocking DNA-PKcs recruitment to the Ku70/80 heterodimer, linking integrin expression to genome instability and radiation sensitivity in pancreatic cancer.","evidence":"DNA-PKcs/Ku70/Ku80 recruitment assay, NHEJ functional assay, ITGA2 nuclear localization analysis, radiation sensitivity assay","pmids":["35998796"],"confidence":"Medium","gaps":["Mechanism of ITGA2 nuclear translocation undefined","Structural basis of ITGA2–Ku70/80 interaction unknown","Not independently replicated"]},{"year":2023,"claim":"BACH1 and HOXD3 were identified as direct transcriptional activators of ITGA2 by ChIP and reporter assays, with BACH1–ITGA2 signaling through FAK-RAC1-PAK and HOXD3–ITGA2 through ERK1/2, connecting upstream transcription factor programs to α2β1-dependent invasion.","evidence":"ChIP-PCR, dual-luciferase reporter, knockdown/overexpression of BACH1/HOXD3, downstream pathway Western blots","pmids":["37311571","32557953"],"confidence":"Medium","gaps":["Whether BACH1 and HOXD3 co-operate or act in distinct contexts is unknown","Genomic occupancy validated at single locus only"]},{"year":2024,"claim":"CRISPR deletion of ITGA2 (with ITGA1) in benign prostate epithelium activated TGFβ1 autocrine signaling and nuclear YAP1, converting cells to a tumorigenic phenotype, while TEAD1 was identified as a transcriptional regulator whose loss phenocopies integrin deletion.","evidence":"CRISPR genomic deletion, TGFβ1 neutralization, YAP1 localization, in vivo tumorigenesis assay, TEAD1 knockdown","pmids":["38169150"],"confidence":"Medium","gaps":["Individual contribution of ITGA2 versus ITGA1 loss not separable in the dual-knockout design","Whether TEAD1 directly binds the ITGA2 promoter was not shown by ChIP"]},{"year":null,"claim":"Key unresolved questions include the mechanism of ITGA2 nuclear translocation, the structural basis of α2β1 full-ectodomain interaction with β1, how the I-domain conformational switch is coupled to cytoplasmic signaling, and whether the ITGA2–STAT3 interaction is direct.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length α2β1 structure available","Nuclear import pathway of ITGA2 uncharacterized","STAT3 interaction awaits reciprocal validation and proximity labeling"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,7,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8,10,13,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[29]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,2,8,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13,17,23,26,28]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,12,30]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,2,7,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[29]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,26,28,34]}],"complexes":["integrin α2β1"],"partners":["ITGB1","SRC","LYN","SYK","PLCG2","PTK2","STAT3","RAB21"],"other_free_text":[]},"mechanistic_narrative":"ITGA2 encodes the alpha-2 subunit of integrin α2β1, the principal collagen receptor on platelets and many other cell types, mediating direct adhesion to collagen types I–VIII as well as thrombospondin and echovirus 1 [PMID:2546619, PMID:8118028, PMID:8240284]. Ligand recognition is conferred by the I-domain (residues ~140–359), whose MIDAS motif coordinates a divalent cation and engages the GFOGER collagen motif through three surface loops, with a collagen glutamate completing metal coordination; ligand binding induces conformational changes that propagate to the domain's opposite pole, coupling adhesion to outside-in signaling [PMID:7523399, PMID:9353312, PMID:10778855]. Collagen engagement of α2β1 activates constitutively associated Src/Lyn kinases, leading to Syk, PLCγ2, and FAK phosphorylation that drive platelet spreading, and in epithelial and cancer cells signals through FAK/AKT, RhoA/p38 MAPK, STAT3, and ERK1/2 to promote proliferation, EMT, migration, and chemoresistance [PMID:11038351, PMID:12615912, PMID:31818309, PMID:34113124]. ITGA2 expression is transcriptionally regulated by BACH1, HOXD3, TEAD1, and EZH2, is induced by VEGF on endothelial cells to support angiogenesis and lymphangiogenesis, and nuclear ITGA2 additionally inhibits NHEJ DNA repair by blocking DNA-PKcs recruitment to the Ku70/80 heterodimer [PMID:37311571, PMID:9391074, PMID:15132990, PMID:35998796]."},"prefetch_data":{"uniprot":{"accession":"P17301","full_name":"Integrin alpha-2","aliases":["CD49 antigen-like family member B","Collagen receptor","Platelet membrane glycoprotein Ia","GPIa","VLA-2 subunit alpha"],"length_aa":1181,"mass_kda":129.3,"function":"Integrin alpha-2/beta-1 is a receptor for laminin, collagen, collagen C-propeptides, fibronectin and E-cadherin. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. It is responsible for adhesion of platelets and other cells to collagens, modulation of collagen and collagenase gene expression, force generation and organization of newly synthesized extracellular matrix (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus A (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P17301/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA2","total_profiled":1310},"omim":[{"mim_id":"621267","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 3; FMAIT3","url":"https://www.omim.org/entry/621267"},{"mim_id":"621264","title":"FETOMATERNAL ALLOIMMUNE THROMBOCYTOPENIA 1; FMAIT1","url":"https://www.omim.org/entry/621264"},{"mim_id":"617569","title":"KINESIN FAMILY, MEMBER 15; KIF15","url":"https://www.omim.org/entry/617569"},{"mim_id":"614200","title":"BLEEDING DISORDER, PLATELET-TYPE, 9; BDPLT9","url":"https://www.omim.org/entry/614200"},{"mim_id":"612759","title":"SYNESTHESIA","url":"https://www.omim.org/entry/612759"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGA2"},"hgnc":{"alias_symbol":["GPIa","VLAA2","HPA-5"],"prev_symbol":["CD49B"]},"alphafold":{"accession":"P17301","domains":[{"cath_id":"3.40.50.410","chopping":"174-367","consensus_level":"high","plddt":90.0159,"start":174,"end":367},{"cath_id":"2.60.40.1460","chopping":"654-784","consensus_level":"high","plddt":84.3218,"start":654,"end":784},{"cath_id":"2.60.40.1510","chopping":"800-935","consensus_level":"high","plddt":86.8921,"start":800,"end":935},{"cath_id":"2.60.40.1530","chopping":"940-1123","consensus_level":"high","plddt":86.3727,"start":940,"end":1123},{"cath_id":"1.20.5","chopping":"1132-1157","consensus_level":"medium","plddt":77.3923,"start":1132,"end":1157}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17301","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17301-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17301-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA2","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA2"},"sequence":{"accession":"P17301","fasta_url":"https://rest.uniprot.org/uniprotkb/P17301.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17301/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17301"}},"corpus_meta":[{"pmid":"23624599","id":"PMC_23624599","title":"Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells.","date":"2013","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23624599","citation_count":642,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2545729","id":"PMC_2545729","title":"The primary structure of the VLA-2/collagen receptor alpha 2 subunit (platelet GPIa): homology to other integrins and the presence of a possible collagen-binding domain.","date":"1989","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2545729","citation_count":332,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2546619","id":"PMC_2546619","title":"Collagen-platelet interactions: evidence for a direct interaction of collagen with platelet GPIa/IIa and an indirect interaction with platelet GPIIb/IIIa mediated by adhesive proteins.","date":"1989","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/2546619","citation_count":279,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8118028","id":"PMC_8118028","title":"Platelet adhesion to collagen types I through VIII under conditions of stasis and flow is mediated by GPIa/IIa (alpha 2 beta 1-integrin).","date":"1994","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8118028","citation_count":196,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11466327","id":"PMC_11466327","title":"Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2).","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11466327","citation_count":184,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24500968","id":"PMC_24500968","title":"Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24500968","citation_count":179,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7511592","id":"PMC_7511592","title":"Identification of putative ligand binding sites within I domain of integrin alpha 2 beta 1 (VLA-2, CD49b/CD29).","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7511592","citation_count":161,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7523399","id":"PMC_7523399","title":"Direct binding of collagen to the I domain of integrin alpha 2 beta 1 (VLA-2, CD49b/CD29) in a divalent cation-independent manner.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7523399","citation_count":151,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9227689","id":"PMC_9227689","title":"Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke.","date":"1997","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/9227689","citation_count":108,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31818309","id":"PMC_31818309","title":"Overexpressed ITGA2 promotes malignant tumor aggression by up-regulating PD-L1 expression through the activation of the STAT3 signaling pathway.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31818309","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16951342","id":"PMC_16951342","title":"Immature dendritic cells suppress collagen-induced arthritis by in vivo expansion of CD49b+ regulatory T cells.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16951342","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25658015","id":"PMC_25658015","title":"Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo.","date":"2015","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25658015","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10997989","id":"PMC_10997989","title":"Detection of Gov system antibodies by MAIPA reveals an immunogenicity similar to the HPA-5 alloantigens.","date":"2000","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10997989","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29743821","id":"PMC_29743821","title":"Blockade of ITGA2 Induces Apoptosis and Inhibits Cell Migration in Gastric Cancer.","date":"2018","source":"Biological procedures online","url":"https://pubmed.ncbi.nlm.nih.gov/29743821","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7916494","id":"PMC_7916494","title":"Localization of the Br polymorphism on a 144 bp exon of the GPIa gene and its application in platelet DNA typing.","date":"1994","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/7916494","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10468872","id":"PMC_10468872","title":"The GPIa C807T dimorphism associated with platelet collagen receptor density is not a risk factor for myocardial infarction.","date":"1999","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10468872","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34274947","id":"PMC_34274947","title":"The ELF3-regulated lncRNA UBE2CP3 is over-stabilized by RNA-RNA interactions and drives gastric cancer metastasis via miR-138-5p/ITGA2 axis.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34274947","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21591983","id":"PMC_21591983","title":"Investigation of TNF-alpha, TGF-beta 1, IL-10, IL-6, IFN-gamma, MBL, GPIA, and IL1A gene polymorphisms in patients with idiopathic thrombocytopenic purpura.","date":"2011","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/21591983","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32824235","id":"PMC_32824235","title":"Exosomes-Mediated Transfer of Itga2 Promotes Migration and Invasion of Prostate Cancer Cells by Inducing Epithelial-Mesenchymal Transition.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32824235","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25549357","id":"PMC_25549357","title":"EZH2 regulates cofilin activity and colon cancer cell migration by targeting ITGA2 gene.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25549357","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30996239","id":"PMC_30996239","title":"ITGA2 as a potential nanotherapeutic target for glioblastoma.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30996239","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11038351","id":"PMC_11038351","title":"Rhodocytin induces platelet aggregation by interacting with glycoprotein Ia/IIa (GPIa/IIa, Integrin alpha 2beta 1). Involvement of GPIa/IIa-associated src and protein tyrosine phosphorylation.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11038351","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26258411","id":"PMC_26258411","title":"Epigenetic silencing of ITGA2 by MiR-373 promotes cell migration in breast cancer.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26258411","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34179312","id":"PMC_34179312","title":"ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis.","date":"2020","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34179312","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25375377","id":"PMC_25375377","title":"IFN-γ induces aberrant CD49b⁺ NK cell recruitment through regulating CX3CL1: a novel mechanism by which IFN-γ provokes pregnancy failure.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25375377","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30569514","id":"PMC_30569514","title":"Coexpression of UCA1 and ITGA2 in pancreatic cancer cells target the expression of miR-107 through focal adhesion pathway.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30569514","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10191228","id":"PMC_10191228","title":"The hookworm platelet inhibitor: functional blockade of integrins GPIIb/IIIa (alphaIIbbeta3) and GPIa/IIa (alpha2beta1) inhibits platelet aggregation and adhesion in vitro.","date":"1999","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/10191228","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32202508","id":"PMC_32202508","title":"Overexpressed ITGA2 contributes to paclitaxel resistance by ovarian cancer cells through the activation of the AKT/FoxO1 pathway.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32202508","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10220262","id":"PMC_10220262","title":"The number of platelet glycoprotein Ia molecules is associated with the genetically linked 807 C/T and HPA-5 polymorphisms.","date":"1999","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/10220262","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30355617","id":"PMC_30355617","title":"CD49b defines functionally mature Treg cells that survey skin and vascular tissues.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30355617","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28277274","id":"PMC_28277274","title":"Therapeutic reversal of food allergen sensitivity by mature retinoic acid-differentiated dendritic cell induction of LAG3+CD49b-Foxp3- regulatory T cells.","date":"2016","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28277274","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30510554","id":"PMC_30510554","title":"Beyond Type 1 Regulatory T Cells: Co-expression of LAG3 and CD49b in IL-10-Producing T Cell Lineages.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30510554","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16177083","id":"PMC_16177083","title":"DX5/CD49b-positive T cells are not synonymous with CD1d-dependent NKT cells.","date":"2005","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16177083","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11812069","id":"PMC_11812069","title":"Association of the GPIa C807T and GPIIIa PlA1/A2 polymorphisms with premature myocardial infarction in men.","date":"2002","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/11812069","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16818752","id":"PMC_16818752","title":"Functional specialization of memory Th cells revealed by expression of integrin CD49b.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16818752","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9759626","id":"PMC_9759626","title":"Analysis of platelet glycoprotein Ia (alpha2 integrin) allele frequencies in three North American populations reveals genetic association between nucleotide 807C/T and amino acid 505 Glu/Lys (HPA-5) dimorphisms.","date":"1998","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/9759626","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15569237","id":"PMC_15569237","title":"Real-time PCR genotyping of human platelet alloantigens HPA-1, HPA-2, HPA-3 and HPA-5 is superior to the standard PCR-SSP method.","date":"2004","source":"Transfusion medicine (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15569237","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26550456","id":"PMC_26550456","title":"miR-128 modulates hepatocellular carcinoma by inhibition of ITGA2 and ITGA5 expression.","date":"2015","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/26550456","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12482840","id":"PMC_12482840","title":"Increased platelet-collagen interaction associated with double homozygosity for receptor polymorphisms of platelet GPIa and GPIIIa.","date":"2002","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12482840","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25662931","id":"PMC_25662931","title":"Regulation of the ITGA2 gene by epigenetic mechanisms in prostate cancer.","date":"2015","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/25662931","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32557953","id":"PMC_32557953","title":"HOXD3 was negatively regulated by YY1 recruiting HDAC1 to suppress progression of hepatocellular carcinoma cells via ITGA2 pathway.","date":"2020","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/32557953","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16601351","id":"PMC_16601351","title":"Enhanced frequency of CD18- and CD49b-expressing T cells in peripheral blood of asthmatic patients correlates with disease severity.","date":"2006","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16601351","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19880290","id":"PMC_19880290","title":"Adoptive transfer of IL-10-secreting CD4+CD49b+ regulatory T cells suppresses ongoing arthritis.","date":"2009","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/19880290","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20653774","id":"PMC_20653774","title":"An unexpected twist in alopecia areata pathogenesis: are NK cells protective and CD49b+ T cells pathogenic?","date":"2010","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20653774","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14580195","id":"PMC_14580195","title":"Structural characterization of EMS16, an antagonist of collagen receptor (GPIa/IIa) from the venom of Echis multisquamatus.","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14580195","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33815660","id":"PMC_33815660","title":"Cyclic Mechanical Stretch Ameliorates the Degeneration of Nucleus Pulposus Cells through Promoting the ITGA2/PI3K/AKT Signaling Pathway.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33815660","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10604254","id":"PMC_10604254","title":"Simultaneous genotyping of human platelet antigens (HPA) 1 through 6 using new sequence-specific primers for HPA-5.","date":"1999","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/10604254","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26408663","id":"PMC_26408663","title":"Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26408663","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27094978","id":"PMC_27094978","title":"Levels of human platelet-derived soluble CD40 ligand depend on haplotypes of CD40LG-CD40-ITGA2.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27094978","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33619119","id":"PMC_33619119","title":"Differential Expression of CD49a and CD49b Determines Localization and Function of Tumor-Infiltrating CD8+ T Cells.","date":"2021","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/33619119","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23897120","id":"PMC_23897120","title":"CD49b-dependent establishment of T helper cell memory.","date":"2013","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23897120","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31428583","id":"PMC_31428583","title":"CD49b, CD87, and CD95 Are Markers for Activated Cancer-Associated Fibroblasts Whereas CD39 Marks Quiescent Normal Fibroblasts in Murine Tumor Models.","date":"2019","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31428583","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32112274","id":"PMC_32112274","title":"microRNA-30a arbitrates intestinal-type early gastric carcinogenesis by directly targeting ITGA2.","date":"2020","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/32112274","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30798327","id":"PMC_30798327","title":"ADAR1 p110 Enhances Adhesion of Tumor Cells to Extracellular Matrix in Hepatocellular Carcinoma via Up-Regulating ITGA2 Expression.","date":"2019","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/30798327","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25970100","id":"PMC_25970100","title":"Both PIGA and PIGL mutations cause GPI-a deficient isolates in the Tk6 cell line.","date":"2015","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25970100","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9184414","id":"PMC_9184414","title":"The integrin alpha 2 beta 1 (GPIa/IIa)-I-domain inhibits platelet-collagen interaction.","date":"1997","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/9184414","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32368389","id":"PMC_32368389","title":"miR-216a-mediated upregulation of TSPAN1 contributes to pancreatic cancer progression via transcriptional regulation of ITGA2.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32368389","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19321657","id":"PMC_19321657","title":"Prevention of embryo loss in non-obese diabetic mice using adoptive ITGA2(+)ISG20(+) natural killer-cell transfer.","date":"2009","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19321657","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17669516","id":"PMC_17669516","title":"Transcriptional and epigenetic regulation of the integrin collagen receptor locus ITGA1-PELO-ITGA2.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17669516","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20485444","id":"PMC_20485444","title":"Common polymorphisms in ITGA2, PON1 and THBS2 are associated with coronary atherosclerosis in a candidate gene association study of the Chinese Han population.","date":"2010","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20485444","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32314406","id":"PMC_32314406","title":"Ropivacaine inhibits proliferation, invasion, migration and promotes apoptosis of papillary thyroid cancer cells via regulating ITGA2 expression.","date":"2020","source":"Drug development research","url":"https://pubmed.ncbi.nlm.nih.gov/32314406","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20959644","id":"PMC_20959644","title":"Progesterone modulates integrin {alpha}2 (ITGA2) and {alpha}11 (ITGA11) in the pregnant cervix.","date":"2010","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/20959644","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21734795","id":"PMC_21734795","title":"Association between ITGA2 C807T polymorphism and gastric cancer risk.","date":"2011","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/21734795","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7913826","id":"PMC_7913826","title":"The human platelet alloantigens, HPA-5(a+, b-) and HPA-5(a-, b+), are associated with a Glu505/Lys505 polymorphism of glycoprotein Ia (the alpha 2 subunit of VLA-2).","date":"1994","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/7913826","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35998796","id":"PMC_35998796","title":"ITGA2 overexpression inhibits DNA repair and confers sensitivity to radiotherapies in pancreatic cancer.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35998796","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24397542","id":"PMC_24397542","title":"Genetic polymorphism of ITGA2 C807T can increase the risk of ischemic stroke.","date":"2014","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24397542","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28123887","id":"PMC_28123887","title":"CD4+CD25hiCD127- Treg and CD4+CD45R0+CD49b+LAG3+ Tr1 cells in bone marrow and peripheral blood samples from children with neuroblastoma.","date":"2016","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/28123887","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26192268","id":"PMC_26192268","title":"Increased Frequency of CD49b/LAG-3(+) Type 1 Regulatory T Cells in HIV-Infected Individuals.","date":"2015","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/26192268","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34113124","id":"PMC_34113124","title":"ITGA2 Overexpression Promotes Esophageal Squamous Cell Carcinoma Aggression via FAK/AKT Signaling Pathway.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34113124","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34687203","id":"PMC_34687203","title":"MicroRNA-99a-3p/GRP94 axis affects metastatic progression of human papillary thyroid carcinoma by regulating ITGA2 expression and localization.","date":"2021","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/34687203","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38169150","id":"PMC_38169150","title":"Dampened Regulatory Circuitry of TEAD1/ITGA1/ITGA2 Promotes TGFβ1 Signaling to Orchestrate Prostate Cancer Progression.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38169150","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34055094","id":"PMC_34055094","title":"Long non-coding RNA SLC25A25-AS1 exhibits oncogenic roles in non-small cell lung cancer by regulating the microRNA-195-5p/ITGA2 axis.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34055094","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18802064","id":"PMC_18802064","title":"Induction of a VLA-2 (CD49b)-expressing effector T cell population by a cell-based neuroblastoma vaccine expressing CD137L.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18802064","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25207168","id":"PMC_25207168","title":"Polymorphism in Integrin ITGA2 is Associated with Ischemic Stroke and Altered Serum Cholesterol in Chinese Individuals.","date":"2014","source":"Balkan medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/25207168","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30288359","id":"PMC_30288359","title":"Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma.","date":"2018","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/30288359","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38640717","id":"PMC_38640717","title":"Genkwanin alleviates intervertebral disc degeneration via regulating ITGA2/PI3K/AKT pathway and inhibiting apoptosis and senescence.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38640717","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36720715","id":"PMC_36720715","title":"Long non-coding RNA AC018926.2 regulates palmitic acid exposure-compromised osteogenic potential of periodontal ligament stem cells via the ITGA2/FAK/AKT pathway.","date":"2023","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/36720715","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23847623","id":"PMC_23847623","title":"CD49b/CD69-Dependent Generation of Resting T Helper Cell Memory.","date":"2013","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23847623","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26590312","id":"PMC_26590312","title":"Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26590312","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32335843","id":"PMC_32335843","title":"CD49a+CD49b+ NK cells induced by viral infection reflect an activated state of conventional NK cells.","date":"2020","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32335843","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29236307","id":"PMC_29236307","title":"Interleukin-4 induces a CD44high /CD49bhigh PC3 subpopulation with tumor-initiating characteristics.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29236307","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29121049","id":"PMC_29121049","title":"Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29121049","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28948649","id":"PMC_28948649","title":"Association of GPIa and COX-2 gene polymorphism with aspirin resistance.","date":"2017","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/28948649","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8240284","id":"PMC_8240284","title":"Interaction of thrombospondin with platelet glycoproteins GPIa-IIa and GPIIb-IIIa.","date":"1993","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8240284","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24581850","id":"PMC_24581850","title":"Alpha 2 integrin gene (ITGA2) polymorphism in renal transplant recipients with and without drug induced gingival overgrowth.","date":"2013","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/24581850","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40321134","id":"PMC_40321134","title":"Enhancer-Associated LncRNA-ITGA2 Promotes Vascular Remodeling Through ITGA2.","date":"2025","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/40321134","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38889513","id":"PMC_38889513","title":"Selumetinib overcomes ITGA2-induced 5-fluorouracil resistance in colorectal cancer.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38889513","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20090957","id":"PMC_20090957","title":"Enhanced binding of poly(ADP-ribose)polymerase-1 and Ku80/70 to the ITGA2 promoter via an extended cytosine-adenosine repeat.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20090957","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15087780","id":"PMC_15087780","title":"Impact of disparity of minor histocompatibility antigens HA-1, CD31, and CD49b in hematopoietic stem cell transplantation of patients with chronic myeloid leukemia with sibling and unrelated donors.","date":"2004","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/15087780","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35714596","id":"PMC_35714596","title":"CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells.","date":"2022","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35714596","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36575207","id":"PMC_36575207","title":"Elevated ITGA2 expression promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36575207","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37311571","id":"PMC_37311571","title":"BACH1 promotes lung adenocarcinoma cell metastasis through transcriptional activation of ITGA2.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37311571","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34599900","id":"PMC_34599900","title":"ITGA2 protein is associated with rheumatoid arthritis in Chinese and affects cellular function of T cells.","date":"2021","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34599900","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38288911","id":"PMC_38288911","title":"Radiotherapy Resistance of 3D Bioprinted Glioma via ITGA2/p-AKT Signaling Pathway.","date":"2024","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/38288911","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33227664","id":"PMC_33227664","title":"Overexpression of long non-coding RNA00355 enhances proliferation, chemotaxis, and metastasis in colon cancer via promoting GTF2B-mediated ITGA2.","date":"2020","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33227664","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24575405","id":"PMC_24575405","title":"CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24575405","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12802345","id":"PMC_12802345","title":"Expression of CD18, CD49b, CD49c and CD49e on lens anterior capsules in human cataracts.","date":"2003","source":"Eye (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12802345","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12944366","id":"PMC_12944366","title":"Characterization and preliminary crystallographic studies of EMS16, an antagonist of collagen receptor (GPIa/IIa) from the venom of Echis multisquamatus.","date":"2003","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12944366","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37062785","id":"PMC_37062785","title":"ATF4-mediated circTDRD3 promotes gastric cancer cell proliferation and metastasis by regulating the miR-891b/ITGA2 axis and AKT signaling pathway.","date":"2023","source":"Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association","url":"https://pubmed.ncbi.nlm.nih.gov/37062785","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39199378","id":"PMC_39199378","title":"PSAT1 Promotes Metastasis via p-AKT/SP1/ITGA2 Axis in Estrogen Receptor-Negative Breast Cancer Cell.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39199378","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19693543","id":"PMC_19693543","title":"Integrins.","date":"2009","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/19693543","citation_count":1256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10778855","id":"PMC_10778855","title":"Structural basis of collagen recognition by integrin alpha2beta1.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10778855","citation_count":819,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"3546305","id":"PMC_3546305","title":"The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight beta subunit.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3546305","citation_count":519,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21423176","id":"PMC_21423176","title":"Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21423176","citation_count":490,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2933589","id":"PMC_2933589","title":"Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia.","date":"1985","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2933589","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9391074","id":"PMC_9391074","title":"Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9391074","citation_count":417,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20939067","id":"PMC_20939067","title":"Matrix stiffness regulation of integrin-mediated mechanotransduction during osteogenic differentiation of human mesenchymal stem cells.","date":"2011","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/20939067","citation_count":322,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17638891","id":"PMC_17638891","title":"Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17638891","citation_count":281,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16754960","id":"PMC_16754960","title":"Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16754960","citation_count":275,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15146197","id":"PMC_15146197","title":"Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.","date":"2004","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15146197","citation_count":266,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15132990","id":"PMC_15132990","title":"VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.","date":"2004","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15132990","citation_count":261,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15174051","id":"PMC_15174051","title":"An investigation into the human serum \"interactome\".","date":"2004","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/15174051","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9353312","id":"PMC_9353312","title":"Crystal structure of the I domain from integrin alpha2beta1.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9353312","citation_count":246,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15240572","id":"PMC_15240572","title":"Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15240572","citation_count":219,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12615912","id":"PMC_12615912","title":"Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12615912","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8387021","id":"PMC_8387021","title":"Integrin and Arg-Gly-Asp dependence of cell adhesion to the native and unfolded triple helix of collagen type VI.","date":"1993","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/8387021","citation_count":200,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18362184","id":"PMC_18362184","title":"Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18362184","citation_count":195,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51903,"output_tokens":6910,"usd":0.12968},"stage2":{"model":"claude-opus-4-6","input_tokens":10608,"output_tokens":3873,"usd":0.224798},"total_usd":0.777107,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":65023,"output_tokens":10803,"usd":0.178557},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":14748,"output_tokens":3559,"usd":0.244072}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"ITGA2 (VLA-2 alpha 2 subunit) encodes a 1181 amino acid protein with a long extracellular domain, transmembrane domain, short cytoplasmic tail, three metal-binding domains, and a 191-amino acid I-domain insert (not found in other integrin alpha chains at the time), suggesting the I-domain is involved in collagen binding based on homology to von Willebrand factor A domains.\",\n      \"method\": \"cDNA cloning, nucleotide sequencing, direct protein NH2-terminal sequencing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary structure determination with direct protein sequencing confirmation\",\n      \"pmids\": [\"2545729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) directly mediates platelet adhesion to collagen; a blocking monoclonal antibody (6F1) against GPIa/IIa inhibited platelet adhesion to collagen by >95% in the absence of plasma proteins and nearly completely blocked collagen-induced platelet aggregation, establishing GPIa/IIa as a direct collagen receptor distinct from GPIIb/IIIa.\",\n      \"method\": \"Monoclonal antibody blockade, collagen-coated bead agglutination assay, platelet adhesion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional blockade with defined phenotypic readout, replicated across multiple assay conditions\",\n      \"pmids\": [\"2546619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) is a major and universal platelet receptor for collagen types I through VII (and partially VIII), mediating platelet adhesion under both static and flow conditions; anti-GPIa mAb 176D7 completely inhibited adhesion to all collagen types tested.\",\n      \"method\": \"Monoclonal antibody blockade, platelet adhesion assays under static and flow conditions\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic functional blockade across eight collagen types and multiple shear rates\",\n      \"pmids\": [\"8118028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The I-domain of integrin alpha2beta1 contains the collagen-binding site; function-blocking anti-alpha2 antibodies (6F1, RMAC11, 12F1, AA10) map to residues 173-259 within the I-domain, and mutations at Asp-151, Asp-254, and Thr-221 block collagen binding, while collagen and echovirus 1 binding sites are adjacent or overlapping within the I-domain.\",\n      \"method\": \"Interspecies chimeric alpha2 constructs, site-directed mutagenesis, antibody epitope mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with functional binding assays identifying specific residues\",\n      \"pmids\": [\"7511592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The recombinant I-domain of integrin alpha2 subunit is sufficient for direct collagen binding in a divalent cation-independent manner; Thr-221 within the I-domain is critical for collagen binding to both the full-length alpha2beta1 and the isolated I-domain fragment, indicating divalent cations regulate binding rather than participating directly in collagen contact.\",\n      \"method\": \"Recombinant I-domain fragment production, collagen-binding assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with isolated domain plus mutagenesis\",\n      \"pmids\": [\"7523399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) directly and specifically binds thrombospondin (TSP) in a divalent cation-independent manner with a dissociation constant of 0.69 µM; this interaction is distinct from GPIIb/IIIa binding to TSP and is blocked by anti-GPIa/IIa antibody 6F1.\",\n      \"method\": \"In vitro binding assay with purified proteins, antibody blockade, saturation binding kinetics\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with purified proteins, single study\",\n      \"pmids\": [\"8240284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The recombinant alpha2 I-domain (residues D145-S334) fused to maltose binding protein binds immobilized collagen type I in a Mg2+-dependent manner and competitively inhibits platelet adhesion to collagen and collagen-induced platelet aggregation (IC50 ~0.7 µM), confirming the I-domain as the collagen-binding site of alpha2beta1.\",\n      \"method\": \"Recombinant protein expression, ELISA binding assay, platelet adhesion inhibition assay, platelet aggregation assay\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted binding with isolated domain, functional inhibition assay\",\n      \"pmids\": [\"9184414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) density on the platelet surface is associated with a silent C807T dimorphism in the GPIa cDNA (codon 224); the 807T allele correlates with higher GPIa/IIa receptor density.\",\n      \"method\": \"PCR genotyping, flow cytometry quantification of receptor density\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic association with receptor density measurement, replicated in multiple populations\",\n      \"pmids\": [\"10468872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Both the 807 C/T and HPA-5 (Glu/Lys505) polymorphisms of the GPIa gene independently correlate with GPIa/IIa molecule number on the platelet surface, with 807T and HPA-5b alleles associated with increased receptor density; the two polymorphisms are genetically linked.\",\n      \"method\": \"PCR-RFLP genotyping, flow cytometry quantification of platelet receptor density, linkage analysis\",\n      \"journal\": \"Transfusion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic-phenotypic correlation with receptor quantification\",\n      \"pmids\": [\"10220262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Rhodocytin from snake venom directly binds to GPIa/IIa (integrin alpha2beta1) independently of divalent cations, inducing platelet aggregation; GPIa/IIa-associated Src and Lyn kinases are constitutively associated with GPIa/IIa, and Src activity increases transiently after rhodocytin stimulation, leading to Cas phosphorylation and downstream Syk/PLCγ2 activation; receptor clustering by actin polymerization is required for all signaling.\",\n      \"method\": \"Rhodocytin-coupled bead binding assay, liposome reconstitution with recombinant GPIa/IIa, co-immunoprecipitation, in vitro kinase assay, Western blotting, cytochalasin D treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding, Co-IP, kinase assays with multiple orthogonal methods\",\n      \"pmids\": [\"11038351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EMS16, a C-type lectin-like protein from snake venom, is a potent and selective antagonist of integrin alpha2beta1 (GPIa/IIa); its crystal structure at 1.9 Å resolution reveals a heterodimer with domain swapping and a positively charged electrostatic patch on the concave surface that likely interacts with the I-domain of GPIa/IIa.\",\n      \"method\": \"X-ray crystallography at 1.9 Å resolution\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determination with functional context\",\n      \"pmids\": [\"14580195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The ITGA2 gene at the integrin collagen receptor locus (5q11.2) is transcriptionally regulated differently from the adjacent ITGA1 gene; during megakaryocyte differentiation, the ITGA1 promoter undergoes progressive CpG methylation (silencing) while the ITGA2 promoter remains unmethylated and expressed, demonstrating locus-specific epigenetic regulation.\",\n      \"method\": \"Sodium bisulfite genomic sequencing, promoter-luciferase reporter assays, 5-aza-2'-deoxycytidine treatment, thrombopoietin-induced differentiation of cord blood cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — methylation sequencing plus functional reporter assays in multiple cell systems\",\n      \"pmids\": [\"17669516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PARP-1 and Ku80/70 bind specifically and with enhanced affinity to longer (CA)12 repeat alleles in the 5'-regulatory region of ITGA2, correlating with enhanced alpha2beta1 expression; this identifies a mechanism by which a CA-repeat length polymorphism at -605 regulates ITGA2 transcription.\",\n      \"method\": \"DNA affinity chromatography, chromatin immunoprecipitation (ChIP), promoter-reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — DNA affinity chromatography and ChIP with functional correlation\",\n      \"pmids\": [\"20090957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD49b (ITGA2) is required for migration of memory CD4 T-cell precursors from blood into bone marrow sinusoids; CD49b-deficient or -blocked memory precursors fail to transmigrate through sinusoidal endothelial cells, and memory CD4 T cells in marrow contact collagen II- and collagen XI-expressing stromal cells.\",\n      \"method\": \"CD49b-deficient mice, antibody blockade, adoptive transfer, in vivo localization studies\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout and antibody blockade with defined cellular phenotype\",\n      \"pmids\": [\"23897120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EZH2 epigenetically silences ITGA2 via histone methylation; pharmacological or genetic inhibition of EZH2 de-represses ITGA2, which then signals through integrin pathways to hyperphosphorylate cofilin at Ser3, impairing actin remodeling and reducing colorectal cancer cell migration.\",\n      \"method\": \"EZH2 siRNA/pharmacological inhibition (DZNep, GSK343), chromatin immunoprecipitation, cell migration assay, Western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional migration assays with pharmacological and genetic perturbation\",\n      \"pmids\": [\"25549357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-373 directly inhibits ITGA2 translation by binding to the ITGA2 3'UTR; silencing of ITGA2 by miR-373 disrupts cell-cell interactions, depolymerizes stress fiber F-actin, and stimulates breast cancer cell migration; ITGA2 protein level is inversely correlated with miR-373 levels in breast cancer tissues.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, miR-373 overexpression/inhibition, Western blotting, F-actin staining, cell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation by reporter assay plus functional migration readout\",\n      \"pmids\": [\"26258411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Collagen-binding integrin alpha2beta1 (CD49b) cooperates with IL-7 receptor on human Th17 cells to enhance IL-17 production and osteoclastogenic function; co-engagement activates JAK/PI3K/AKT and MAPK/ERK pathways, and blockade of alpha2beta1 in vivo inhibits IL-7-induced bone loss by reducing Th17 cell numbers and IL-17 production.\",\n      \"method\": \"Co-engagement of IL-7R and alpha2beta1 on primary human Th17 cells, neutralizing antibody blockade in vivo, pathway inhibition, Western blotting, bone loss quantification\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional studies with defined signaling pathway readouts\",\n      \"pmids\": [\"26408663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Blockade of ITGA2 in gastric cancer cells induces apoptosis via upregulation of RhoA-p38 MAPK signaling, promoting Bim, Apaf-1, and Caspase-9 expression, while also inhibiting cell migration by downregulating N-WASP, PAK, and LIMK to impede actin organization.\",\n      \"method\": \"Anti-ITGA2 antibody treatment, apoptosis assays, Western blotting, cell migration assay\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody-mediated functional blockade with defined pathway readouts\",\n      \"pmids\": [\"29743821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGA2 interacts with STAT3 (detected by co-immunoprecipitation) and upregulates STAT3 phosphorylation, which transcriptionally increases PD-L1 expression in pancreatic cancer cells, identifying a mechanism by which ITGA2 modulates cancer immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, RT-qPCR, RNA-seq, immunohistochemistry\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus supporting functional data\",\n      \"pmids\": [\"31818309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGA2 transferred via exosomes from castration-resistant prostate cancer cells to androgen receptor-positive cells promotes epithelial-mesenchymal transition, increasing proliferation, migration, and invasion; these effects are reversed by ITGA2 knockdown or inhibition of exosomal uptake by MβCD.\",\n      \"method\": \"Exosome isolation and co-incubation, ITGA2 knockdown, ectopic ITGA2 expression, functional assays (proliferation, migration, invasion)\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rescue experiments with knockdown/overexpression and exosomal transfer mechanism\",\n      \"pmids\": [\"32824235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGA2 knockdown in breast cancer cells suppresses mammosphere formation, pluripotency marker expression, cell cycling, migration, invasion, and lung metastasis; RNA-seq reveals ITGA2 regulates CCND1 (cyclin D1) and ACLY as downstream targets; CCND1 overexpression rescues ITGA2-knockdown-induced cell cycle arrest.\",\n      \"method\": \"siRNA knockdown, RNA sequencing, mammosphere formation assay, in vivo lung metastasis model, rescue overexpression\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq with rescue experiments and in vivo validation\",\n      \"pmids\": [\"34179312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cyclic mechanical stretch promotes nucleus pulposus cell proliferation and inhibits apoptosis through the ITGA2/PI3K/AKT signaling pathway; microarray analysis identified 31 differentially expressed genes in this pathway, and siRNA knockdown of ITGA2 or AKT blocked stretch-induced proliferation and COL2A1 expression.\",\n      \"method\": \"Cyclic tensile stress application, gene expression microarray, siRNA knockdown, Western blotting, flow cytometry\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined by siRNA knockdown with functional readouts\",\n      \"pmids\": [\"33815660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear ITGA2 inhibits the non-homologous end joining (NHEJ) DNA repair pathway by restraining the recruitment of DNA-PKcs to the Ku70/80 heterodimer during DNA damage response, thereby conferring sensitivity to radiotherapy in pancreatic cancer cells.\",\n      \"method\": \"ITGA2 overexpression/knockdown, NHEJ pathway activity assay, DNA-PKcs recruitment assay, TCGA data correlation\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular mechanism with functional pathway assay, single study\",\n      \"pmids\": [\"35998796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Elevated ITGA2 promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma cells; ITGA2 depletion or integrin alpha2beta1-selective inhibitor treatment abolishes robust interaction of iCCA cells with collagen type I and blocks collagen type I-induced colony growth.\",\n      \"method\": \"ITGA2 siRNA knockdown, integrin alpha2beta1 inhibitor treatment, collagen-binding assay, clonogenic growth assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct collagen-binding and functional knockdown assays in multiple cell lines\",\n      \"pmids\": [\"36575207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BACH1 transcription factor directly binds the upstream sequence of the ITGA2 promoter to transcriptionally activate ITGA2 expression; the BACH1-ITGA2 axis activates FAK-RAC1-PAK signaling to regulate cytoskeletal organization and promote migration and invasion of lung adenocarcinoma cells.\",\n      \"method\": \"Chromatin immunoprecipitation, dual-luciferase reporter assay, RNA sequencing, Western blotting, cell immunofluorescence, cell adhesion assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter confirm direct transcriptional regulation with pathway validation\",\n      \"pmids\": [\"37311571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LncRNA-ITGA2 is an enhancer-associated lncRNA that, in a NONO protein-dependent manner, mediates promoter-enhancer interactions at the ITGA2 locus leading to increased H3K27 acetylation and ITGA2 expression, thereby promoting vascular smooth muscle cell proliferation and migration and neointimal hyperplasia.\",\n      \"method\": \"CUT&Tag, promoter capture Hi-C, microarray, CRISPR-Cas9 knockout, RNA-seq, ChIP-seq, chromatin isolation by RNA purification (ChIRP), RNA immunoprecipitation, carotid artery wire injury model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiomics with CRISPR validation and in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"40321134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXD3 transcription factor binds to the promoter region of ITGA2 and upregulates its expression, activating ERK1/2 signaling to induce hepatocellular carcinoma cell proliferation and metastasis; YY1 recruits HDAC1 to suppress HOXD3, thereby indirectly suppressing the ITGA2/ERK1/2 axis.\",\n      \"method\": \"ChIP-PCR, dual luciferase reporter assay, Co-immunoprecipitation, RNA-seq, Western blotting, Pearson correlation analysis\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays establish direct transcriptional regulation\",\n      \"pmids\": [\"32557953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 transcription factor directly regulates ITGA2 expression in prostate cancer cells; deletion of both ITGA1 and ITGA2 enhances TGFβ1 secretion and autocrine signaling with nuclear YAP1 targeting, inducing EMT and converting benign prostate epithelial cells to tumorigenic cells in vivo.\",\n      \"method\": \"Genome-wide co-expression analysis, in vitro KO with functional EMT assays, in vivo tumorigenicity assay, TGFβ1 secretion measurement\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion with defined in vitro and in vivo phenotypic readouts and mechanistic pathway\",\n      \"pmids\": [\"38169150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSAT1 promotes ER-negative breast cancer cell migration via the p-AKT/SP1/ITGA2 axis; PSAT1 upregulates p-AKT, facilitating SP1 nuclear entry, and ChIP analysis confirms SP1 directly binds and activates the ITGA2 promoter; ITGA2 depletion or p-AKT inhibition reverses PSAT1-induced migration.\",\n      \"method\": \"RNA-seq, ChIP assay, Western blotting, cell migration assay, p-AKT inhibitor treatment, ITGA2 knockdown rescue\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct SP1-ITGA2 promoter binding with functional rescue experiments\",\n      \"pmids\": [\"39199378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD49b (ITGA2) expression on tumor-infiltrating CD8+ T cells promotes their motility in the tumor microenvironment, particularly near tumor cells, via collagen-dependent mechanisms; CD49b+ intratumoral CD8 T cells show a tissue-resident memory-like phenotype with constitutive CD69 and failure to upregulate TCR-dependent Nur77, suggesting collagen engagement via CD49b interferes with productive tumor antigen engagement.\",\n      \"method\": \"Flow cytometry, live tumor slice imaging, TCR stimulation experiments, Nur77 reporter assay\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging plus receptor reporter assays in multiple experimental systems\",\n      \"pmids\": [\"33619119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA2 (CD49b) encodes the alpha2 subunit of the collagen receptor integrin alpha2beta1 (GPIa/IIa); its I-domain (with Thr-221 and Asp-151/Asp-254 as critical residues) directly and sufficiently mediates binding to collagen types I–VII in a divalent cation-regulated manner, and constitutively associates with Src/Lyn kinases that transmit signals through Cas, Syk, and PLCγ2 upon receptor clustering; nuclear ITGA2 additionally inhibits NHEJ DNA repair by blocking DNA-PKcs recruitment to Ku70/80; transcriptional regulation involves TEAD1, BACH1, HOXD3/YY1-HDAC1, SP1/AKT, EZH2, CpG methylation, and an enhancer-associated lncRNA-ITGA2/NONO mechanism, while post-transcriptional silencing is achieved by miR-373 and other miRNAs; downstream signaling activates PI3K/AKT, FAK/AKT, STAT3/PD-L1, RhoA/p38 MAPK, ERK1/2, and FAK-RAC1-PAK pathways to control cell adhesion, migration, actin remodeling, proliferation, and immune modulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify papers and extract discoveries only from KEEP papers (those about canonical ITGA2/integrin alpha2 protein).\n\n**Classification summary:**\n- Papers about CD49b as immune cell marker (Tr1, NK, Treg identity/function) without mechanistic findings about ITGA2 protein itself → EXCLUDE (not about ITGA2 mechanism)\n- Papers about ITGA2 gene polymorphisms/association studies → EXCLUDE (no mechanism)\n- Papers describing lncRNA/circRNA/miRNA axes where ITGA2 is just a downstream target with no new ITGA2 mechanism → mostly EXCLUDE unless ITGA2 mechanism is directly studied\n- Papers with direct mechanistic findings about ITGA2 protein (structure, binding, signaling, function) → KEEP\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The ITGA2 (VLA-2 alpha2 subunit) primary structure was determined from cDNA cloning, revealing a 1,181 amino acid protein with a 191-amino acid inserted I-domain (not found in other integrin alpha chains at the time) homologous to von Willebrand factor A-domains and cartilage matrix protein, suggesting the I-domain as a collagen-binding domain. The protein contains three metal-binding domains and a transmembrane segment with a short 22-amino acid cytoplasmic tail.\",\n      \"method\": \"cDNA library screening, nucleotide sequencing, protein NH2-terminal sequencing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing combined with cDNA sequencing; foundational structural characterization\",\n      \"pmids\": [\"2545729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) mediates direct platelet adhesion to collagen independently of plasma adhesive proteins, demonstrated by a blocking monoclonal antibody (6F1) that inhibited collagen-induced platelet aggregation and platelet adhesion to collagen by >95% in the absence of plasma proteins. GPIIb/IIIa mediates indirect collagen interaction via adhesive protein intermediaries.\",\n      \"method\": \"Monoclonal antibody blocking assay, collagen-coated bead agglutination, platelet adhesion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional blocking with defined phenotypic readout; replicated across multiple assay systems\",\n      \"pmids\": [\"2546619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Integrin alpha2beta1 is a universal platelet collagen receptor mediating adhesion to collagen types I through VIII under both static and flow conditions, as demonstrated by complete inhibition of platelet adhesion to all collagen types by anti-GPIa monoclonal antibody 176D7.\",\n      \"method\": \"Platelet adhesion assay under static and flow conditions with monoclonal antibody blocking\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic functional blocking across 8 collagen types under multiple conditions\",\n      \"pmids\": [\"8118028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The I-domain of ITGA2 (residues 140-359) contains the ligand-binding site for both collagen and echovirus 1. Function-blocking antibodies map to residues 173-259 within the I-domain. Mutations of Asp-151 and Asp-254 block collagen binding, and Asp-160 and Arg-242 are critical for other function-inhibiting antibody epitopes, indicating that collagen and echovirus 1 binding sites are adjacent or overlapping within the I-domain.\",\n      \"method\": \"Interspecies (human/bovine) alpha2 chimeras, site-directed mutagenesis, antibody epitope mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with chimeric protein analysis identifying specific residues for ligand binding\",\n      \"pmids\": [\"7511592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The recombinant I-domain of ITGA2 alone is sufficient for collagen binding in a divalent cation-independent manner, demonstrating the I-domain contains all components necessary for collagen recognition. Thr-221 within the I-domain is critical for collagen binding to both full-length alpha2beta1 and the isolated I-domain fragment; divalent cations regulate binding rather than directly participate in collagen contact.\",\n      \"method\": \"Recombinant I-domain protein binding assay, site-directed mutagenesis (T221 substitution), divalent cation chelation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted domain binding with mutagenesis identifying critical residue; mechanistically definitive\",\n      \"pmids\": [\"7523399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The recombinant alpha2 I-domain (residues 145-334) fused to maltose-binding protein binds immobilized collagen type I in a Mg2+-dependent, Ca2+/EDTA-inhibitable manner, and competitively inhibits platelet adhesion to collagen and collagen-induced platelet aggregation (IC50 ~0.7 μM), confirming the I-domain as the collagen-binding site of alpha2beta1.\",\n      \"method\": \"Recombinant protein expression, ELISA-based binding assay, platelet adhesion inhibition, platelet aggregation inhibition\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted I-domain with functional competition assays confirming collagen-binding role\",\n      \"pmids\": [\"9184414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Crystal structure of the ITGA2 I-domain determined at high resolution reveals a dinucleotide-binding (Rossmann) fold with a metal ion-dependent adhesion site (MIDAS) motif coordinating Mg2+ at the top of the beta-sheet. A unique C-helix creates a groove around the Mg2+ ion predicted to be the collagen-binding site; modeling suggests a glutamate from collagen coordinates the metal. The echovirus-1 binding site maps to a distinct surface (one edge of the beta-sheet), indicating collagen and virus bind by different mechanisms.\",\n      \"method\": \"X-ray crystallography (high resolution crystal structure)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mechanistic modeling of ligand binding\",\n      \"pmids\": [\"9353312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of the ITGA2 I-domain in complex with a triple-helical collagen peptide containing the GFOGER motif revealed that three loops on the upper surface of the I-domain coordinate a metal ion and simultaneously engage the collagen triple helix, with a collagen glutamate completing the metal ion coordination sphere. Ligand binding induces conformational changes that propagate from the upper surface to the opposite pole of the domain, providing a structural basis for affinity regulation and signal transduction.\",\n      \"method\": \"X-ray crystallography of I-domain/collagen peptide complex\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of receptor-ligand complex with conformational change analysis; highly cited foundational study\",\n      \"pmids\": [\"10778855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Rhodocytin from snake venom directly binds GPIa/IIa (integrin alpha2beta1) independently of divalent cations, inducing platelet aggregation. Src and Lyn kinases constitutively associate with GPIa/IIa and Src activity increases transiently after rhodocytin stimulation; Src then mediates phosphorylation of p130 Cas. Downstream signals including Syk phosphorylation, PLCgamma2 phosphorylation, and intracellular Ca2+ mobilization are cAMP-sensitive and require actin polymerization/receptor clustering.\",\n      \"method\": \"Rhodocytin-coupled bead binding assay, liposome reconstitution with recombinant GPIa/IIa, in vitro kinase assay, Western blotting of immunoprecipitates, cytochalasin D inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with recombinant receptor, kinase assay, and multiple signaling readouts\",\n      \"pmids\": [\"11038351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EMS16, a C-type lectin-like protein from Echis multisquamatus venom, acts as a potent and selective antagonist of integrin alpha2beta1 (GPIa/IIa). Crystal structure at 1.9 Å resolution revealed a heterodimer with domain-swapped central loop architecture and a unique positively-charged electrostatic patch on its concave surface proposed as the interaction site for the ITGA2 I-domain.\",\n      \"method\": \"X-ray crystallography at 1.9 Å resolution, structural analysis of protein-receptor antagonist\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional context as specific alpha2beta1 antagonist\",\n      \"pmids\": [\"14580195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Integrin alpha2beta1 mediates outside-in signaling during platelet spreading on collagen, activating Src kinases, Syk, SLP-76, PLCgamma2, focal adhesion kinase, and plasma membrane calcium ATPase, leading to filopodia and lamellipodia formation. This signaling is independent of the GPVI-FcR gamma-chain complex, requires intracellular Ca2+, and is abolished by the Src kinase inhibitor PP2 and in PLCgamma2-deficient platelets.\",\n      \"method\": \"Integrin-specific collagen peptide stimulation, tyrosine phosphorylation Western blot, PLCgamma2-deficient platelets, PP2 inhibitor, intracellular Ca2+ chelation, morphological spreading assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (PLCgamma2 KO) and pharmacological epistasis combined with phosphorylation readouts\",\n      \"pmids\": [\"12615912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"GPIa/IIa (integrin alpha2beta1) binds thrombospondin (TSP) in an ion-independent manner with a dissociation constant of 0.69 μM, which is 5.5-fold more favorable than GPIIb/IIIa binding to TSP. This interaction is blocked by anti-GPIa/IIa antibody 6F1 but not by anti-GPIIb/IIIa antibody, suggesting GPIa/IIa is a preferred TSP binding protein on platelets.\",\n      \"method\": \"Saturable binding assay with purified glycoproteins, competition inhibition with antibodies and unlabeled protein\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — saturable binding with defined Kd; single lab, single method type\",\n      \"pmids\": [\"8240284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"VEGF induces 5-7 fold increased surface expression of integrin alpha2beta1 (and alpha1beta1) on dermal microvascular endothelial cells through induction of alpha2 subunit mRNA. Blocking antibodies against alpha2 integrin partially inhibited EC attachment to collagen I and abolished VEGF-promoted cell spreading on collagen I gels. In vivo, anti-alpha2 antibody combination markedly inhibited VEGF-driven angiogenesis, reducing new vessel cross-sectional area by 90%.\",\n      \"method\": \"Flow cytometry, mRNA induction assay, blocking antibody cell adhesion/spreading assay, in vivo VEGF-driven angiogenesis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional blocking with defined molecular mechanism (VEGF-induced alpha2 mRNA upregulation)\",\n      \"pmids\": [\"9391074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Endorepellin (COOH-terminal domain of perlecan) binds integrin alpha2beta1 on endothelial cells and triggers a signaling cascade including increased cAMP, activation of PKA and FAK, transient activation of p38 MAPK and HSP27 followed by their rapid downregulation, leading to disassembly of actin stress fibers and focal adhesions, and blocking endothelial cell migration and angiogenesis.\",\n      \"method\": \"Ligand binding, cAMP measurement, kinase activity assays, Western blotting of p38/HSP27, actin/focal adhesion immunofluorescence, cell migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal signaling readouts linked to alpha2beta1 engagement with defined downstream pathway\",\n      \"pmids\": [\"15240572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"VEGF-A promotes lymphangiogenesis via induction of alpha1 and alpha2 integrin expression on lymphatic endothelial cells. Anti-alpha2 integrin blocking antibodies suppressed VEGF-A-induced lymphatic endothelial cord formation and haptotactic migration toward collagen I in vitro, and systemic blockade of alpha2 integrin inhibited VEGF-A-driven lymphangiogenesis in vivo.\",\n      \"method\": \"Integrin expression profiling, blocking antibody tube formation assay, haptotaxis assay, in vivo lymphangiogenesis model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo functional blocking establishing role of alpha2beta1 in VEGF-driven lymphangiogenesis\",\n      \"pmids\": [\"15132990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab21 small GTPase associates with the cytoplasmic domains of alpha-integrin chains including alpha2, regulating endosomal trafficking of beta1-integrins. Knockdown of Rab21 impairs integrin-mediated cell adhesion and motility, while overexpression stimulates migration and cancer cell adhesion to collagen; a point mutation in the alpha-integrin cytoplasmic domain that abolishes Rab21 association prevents Rab21-induced adhesion.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, point mutagenesis of cytoplasmic domain, cell adhesion and motility assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus mutagenesis plus KD/KO with defined cellular phenotype\",\n      \"pmids\": [\"16754960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The ITGA2 gene locus on chromosome 5q11.2 is regulated by epigenetic mechanisms distinct from the neighboring ITGA1. During thrombopoietin-induced megakaryocyte differentiation, ITGA1 undergoes rapid progressive CpG methylation but ITGA2 does not, establishing that ITGA2 expression is maintained in the megakaryocyte lineage through a methylation-independent mechanism. In vitro methylation of ITGA1 promoter suppresses its transcription.\",\n      \"method\": \"Sodium bisulfite genomic sequencing, promoter-luciferase reporter assays, 5-aza-2'-deoxycytidine treatment, primary cord blood megakaryocyte differentiation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation assay with functional reporter validation; single lab\",\n      \"pmids\": [\"17669516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Collagen I signaling through integrin alpha2beta1 and discoidin domain receptor 1 (DDR1) cooperatively up-regulates N-cadherin in pancreatic cancer cells, promoting EMT. Alpha2beta1 integrin propagates signals through FAK and the p130CAS scaffold, while DDR1 acts through Pyk2/p130CAS; both pathways converge and require Rap1 (but not Rho GTPases) for N-cadherin upregulation. Knockdown of alpha2beta1 prevents collagen I-induced N-cadherin upregulation.\",\n      \"method\": \"siRNA knockdown of alpha2beta1 and DDR1, signaling pathway inhibitors, Western blotting, in vivo mouse tumor model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown epistasis with multiple pathway components and in vivo validation\",\n      \"pmids\": [\"18362184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PARP-1 and Ku80/70 bind specifically and with enhanced affinity to longer (CA)12 repeat alleles in the 5'-regulatory region of ITGA2 (beginning at -605), as demonstrated by DNA affinity chromatography and chromatin immunoprecipitation. This enhanced binding correlates with increased ITGA2 transcriptional activity, identifying PARP-1 and Ku80/70 as transcriptional co-regulators of ITGA2 expression.\",\n      \"method\": \"DNA affinity chromatography, chromatin immunoprecipitation (ChIP), promoter-reporter assays with different CA repeat length alleles\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and DNA affinity chromatography identifying specific transcriptional regulators; single lab\",\n      \"pmids\": [\"20090957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Alpha2-integrin (ITGA2) expression is upregulated on stiffer extracellular matrices during osteogenic induction of mesenchymal stem cells, and siRNA knockdown of alpha2-integrin downregulates osteogenic differentiation markers through ROCK, FAK, and ERK1/2 signaling pathways, placing alpha2-integrin upstream of ROCK/FAK/ERK1/2 mechanotransduction during osteogenesis.\",\n      \"method\": \"siRNA knockdown, polyacrylamide hydrogel stiffness system, Western blot of ROCK/FAK/ERK1/2 activity, osteogenic differentiation markers\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with pathway epistasis; single lab\",\n      \"pmids\": [\"20939067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EZH2 epigenetically represses ITGA2 expression, and when EZH2 is inhibited (genetically or pharmacologically with DZNep or GSK343), de-repressed ITGA2 signaling increases cofilin phosphorylation at Serine 3 (inactivating cofilin), thereby reducing actin remodeling and cell migration in colorectal cancer cells. ChIP confirmed EZH2 directly regulates the ITGA2 locus.\",\n      \"method\": \"EZH2 siRNA knockdown, pharmacological inhibition (DZNep, GSK343), chromatin immunoprecipitation (ChIP), cofilin phosphorylation Western blot, cell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP combined with genetic and pharmacological epistasis and defined signaling readout; single lab\",\n      \"pmids\": [\"25549357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ITGA2 expression is regulated by CpG methylation of its promoter in prostate cancer cells. Demethylated ITGA2 promoter correlates with higher ITGA2 expression and increased cell migratory potential. siRNA knockdown of ITGA2 in highly migratory PC3 and 22Rv1 cells reduced migration in scratch assays, confirming ITGA2 promotes cell migration in prostate cancer.\",\n      \"method\": \"Bisulfite sequencing of ITGA2 promoter CpG island, qPCR, siRNA knockdown, scratch wound healing assay\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation sequencing correlated with expression and functional validation by KD; single lab\",\n      \"pmids\": [\"25662931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human Th17 cells co-express IL-7R and integrin alpha2beta1 (CD49b); IL-7 increases Th17 adhesion to collagen via alpha2beta1. Co-engagement of IL-7R and alpha2beta1 cooperatively enhances IL-17 production and osteoclastogenic activity through JAK/PI3K/AKT and MAPK/ERK pathways. In vivo blockade of alpha2beta1 with neutralizing mAb inhibited IL-7-induced bone loss by reducing Th17 cell numbers and IL-17/RANKL production.\",\n      \"method\": \"Integrin blocking antibody, co-engagement of receptors, cytokine production ELISA, in vivo bone loss model with antibody blockade, pathway inhibitor studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro co-engagement with pathway inhibitors and in vivo antibody blocking with bone loss phenotype; single lab\",\n      \"pmids\": [\"26408663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGA2 interacts with STAT3 (demonstrated by co-immunoprecipitation) and up-regulates STAT3 phosphorylation, which transcriptionally increases PD-L1 expression in cancer cells. Knockdown of ITGA2 inhibited cancer cell proliferation and invasion, while ITGA2 overexpression promoted these processes. RNA-seq confirmed ITGA2 transcriptionally regulates PD-L1.\",\n      \"method\": \"Co-immunoprecipitation (ITGA2-STAT3 interaction), Western blot (STAT3 phosphorylation), RNA-seq, RT-qPCR, functional assays (MTS, colony formation, transwell)\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying novel binding partner plus phosphorylation readout and RNA-seq; single lab\",\n      \"pmids\": [\"31818309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Blockade of ITGA2 with a specific antibody induces apoptosis in gastric cancer cells by upregulating RhoA-p38 MAPK signaling to promote Bim, Apaf-1 and Caspase-9 expression (without affecting Ras or Bax/Bcl-2). ITGA2 blockade also inhibits cell migration by downregulating N-WASP, PAK, and LIMK to impede actin organization.\",\n      \"method\": \"Anti-ITGA2 antibody treatment, apoptosis assay, Western blot for RhoA/p38/Bim/Apaf-1/Caspase-9/N-WASP/PAK/LIMK, cell migration assay\",\n      \"journal\": \"Biological procedures online\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody-based functional blocking with defined downstream signaling pathway components; single lab\",\n      \"pmids\": [\"29743821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Exosomal ITGA2 derived from castration-resistant prostate cancer cells can be transferred to androgen receptor-positive recipient cells, promoting proliferation, migration, invasion and epithelial-mesenchymal transition. These effects were reversed by ITGA2 knockdown in donor cells or inhibition of exosomal uptake by methyl-β-cyclodextrin, and reproduced by ectopic ITGA2 overexpression in recipient cells.\",\n      \"method\": \"Exosome co-incubation, ITGA2 knockdown, ectopic overexpression, methyl-β-cyclodextrin inhibition, EMT marker Western blot, cell migration/invasion assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays with gain/loss of function; single lab\",\n      \"pmids\": [\"32824235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGA2 overexpression in ovarian cancer promotes cell proliferation and mediates paclitaxel resistance by activating AKT phosphorylation, which in turn phosphorylates FoxO1, preventing FoxO1-mediated transcription of pro-apoptotic genes.\",\n      \"method\": \"ITGA2 overexpression/knockdown, Western blot for AKT and FoxO1 phosphorylation, paclitaxel sensitivity assay, cell proliferation assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined phosphorylation cascade from ITGA2 to AKT to FoxO1 with drug resistance phenotype; single lab\",\n      \"pmids\": [\"32202508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cyclic mechanical stretch promotes nucleus pulposus cell proliferation and inhibits apoptosis via the ITGA2/PI3K/AKT signaling pathway. Gene expression profiling identified 31 differentially expressed genes in this pathway after stretch; siRNA knockdown of ITGA2 and AKT confirmed that the PI3K/AKT pathway mediates stretch-induced COL2A1 expression and cell proliferation.\",\n      \"method\": \"Cyclic tensile stress system, gene expression microarray, siRNA knockdown of ITGA2 and AKT, Western blot, cell proliferation and apoptosis assays\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis with defined pathway and functional readout; single lab\",\n      \"pmids\": [\"33815660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGA2 overexpression in esophageal squamous cell carcinoma activates FAK/AKT signaling and promotes EMT. ITGA2 silencing inhibits FAK/AKT phosphorylation and suppresses EMT markers, while ITGA2 overexpression activates this pathway. Treatment with AKT inhibitor MK-2206 repressed ITGA2-overexpression-driven ESCC progression, establishing FAK/AKT as the downstream pathway.\",\n      \"method\": \"ITGA2 knockdown/overexpression, Western blot for FAK/AKT/EMT markers, AKT inhibitor MK-2206, tumor xenograft model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with AKT inhibitor plus KD/OE confirming FAK/AKT pathway; single lab\",\n      \"pmids\": [\"34113124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA2 inhibits the non-homologous end joining (NHEJ) DNA repair pathway by restraining the recruitment of DNA-PKcs to the Ku70/80 heterodimer during the DNA damage response, conferring sensitivity to radiotherapy in pancreatic cancer. Nuclear ITGA2 overexpression correlates with genome instability parameters in TCGA data.\",\n      \"method\": \"DNA-PKcs/Ku70/Ku80 recruitment assay, NHEJ activity assay, ITGA2 nuclear localization analysis, TCGA correlation analysis, radiation sensitivity assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined mechanistic inhibition of DNA-PKcs recruitment to Ku70/80 by nuclear ITGA2; single lab\",\n      \"pmids\": [\"35998796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Elevated ITGA2 expression promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma cells. Depletion of ITGA2 or treatment with an integrin alpha2beta1-selective inhibitor abolished robust interaction of iCCA cells with collagen type I and blocked collagen type I-induced colony growth enhancement (3-6 fold), confirming a functional collagen type I-integrin alpha2 axis in cholangiocarcinoma.\",\n      \"method\": \"ITGA2 siRNA knockdown, integrin alpha2beta1-selective inhibitor, collagen binding assay, clonogenic growth assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — both genetic and pharmacological inhibition with defined ligand-receptor functional readout; single lab\",\n      \"pmids\": [\"36575207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BACH1 directly binds to the upstream sequence of the ITGA2 promoter to transcriptionally activate ITGA2 expression. The BACH1-ITGA2 axis promotes lung adenocarcinoma cell migration and invasion through activation of the FAK-RAC1-PAK signaling pathway and cytoskeletal regulation, as demonstrated by ChIP and dual-luciferase reporter assays.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, BACH1/ITGA2 knockdown/overexpression, RNA-seq, FAK-RAC1-PAK pathway Western blot, cell adhesion and migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirming direct transcriptional regulation; downstream pathway defined; single lab\",\n      \"pmids\": [\"37311571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genomic deletion or loss of ITGA2 (together with ITGA1) in benign prostate epithelial cells activates TGFβ1 autocrine signaling and nuclear YAP1 targeting, inducing EMT and converting cells to a tumorigenic phenotype in vivo. TEAD1 was identified as a key transcriptional regulator of both ITGA1 and ITGA2 expression; TEAD1 loss phenocopies dual alpha1/alpha2 integrin loss, triggering TGFβ1-driven EMT.\",\n      \"method\": \"CRISPR genomic deletion of ITGA1/ITGA2, TGFβ1 neutralization, YAP1 nuclear localization assay, genome-wide co-expression analysis, in vivo tumorigenesis assay, TEAD1 knockdown\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR loss-of-function with defined signaling pathway (TGFβ1/YAP1) and in vivo tumorigenesis; single lab\",\n      \"pmids\": [\"38169150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In 3D bioprinted glioma models, ITGA2 expression is significantly elevated compared to 2D models and mediates radiation tolerance through the p-AKT signaling pathway. shRNA-mediated knockdown of ITGA2 reduced radiation tolerance and concomitantly inhibited p-AKT pathway activation in 3D glioma models.\",\n      \"method\": \"3D bioprinted tumor model, shRNA ITGA2 knockdown, radiation treatment, p-AKT Western blot, differential gene expression profiling\",\n      \"journal\": \"Advanced healthcare materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — shRNA knockdown with defined downstream pathway in a novel 3D model; single lab\",\n      \"pmids\": [\"38288911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ITGA2 knockdown in breast cancer cells suppressed self-renewal (mammosphere formation), pluripotency marker expression, inhibited cell cycling (G1 arrest), compromised migration/invasion, and decreased lung metastasis. ITGA2 overexpression reversed miR-206-caused G1 cell cycle arrest. RNA sequencing revealed ITGA2 regulates CCND1 (cyclin D1) and ACLY (ATP citrate lyase), with CCND1 being required downstream for cell cycle progression and lung colonization.\",\n      \"method\": \"ITGA2 knockdown/overexpression, mammosphere formation assay, cell cycle analysis, RNA sequencing, CCND1/ACLY knockdown rescue experiments, in vivo lung metastasis model\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq combined with rescue experiments identifying CCND1/ACLY as downstream targets; in vivo validation\",\n      \"pmids\": [\"34179312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGA2 overexpression in rheumatoid arthritis PBMCs promotes T cell proliferation, inhibits apoptosis, and induces expression of IL-8, IFN-γ, and TNF-α in Jurkat T cells, demonstrating a functional role for ITGA2 in T cell activation and pro-inflammatory cytokine production.\",\n      \"method\": \"ITGA2 overexpression in Jurkat T cells, cell proliferation assay, apoptosis analysis, cytokine (IL-8, IFN-γ, TNF-α) measurement by ELISA\",\n      \"journal\": \"Clinica chimica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single overexpression experiment with cytokine readout, no pathway placement; single lab\",\n      \"pmids\": [\"34599900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In the pregnant rat cervix, ITGA2 expression increases progressively over gestation. Mifepristone (progesterone receptor antagonist) increases ITGA2 expression and activates ERK1/2 phosphorylation both in vivo and in primary cervical stromal cells in vitro; inhibition of ERK1/2 abrogated mifepristone-induced ITGA2 upregulation, placing ERK1/2 downstream of progesterone withdrawal in ITGA2 regulation.\",\n      \"method\": \"Rat gestational model, mifepristone treatment, primary cervical stromal cell culture, Western blot for ITGA2/pERK1/2/pFAK, ERK1/2 inhibitor rescue\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vivo and in vitro pharmacological epistasis for regulation; single lab, limited mechanistic depth\",\n      \"pmids\": [\"20959644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TSPAN1 transcriptionally regulates ITGA2 expression in pancreatic cancer, and epigenetically controls ITGA2 by modulating TET2, DNMT3B, and DNMT1, resulting in hypomethylation of the ITGA2 promoter CpG island. ITGA2 knockdown abolished TSPAN1 overexpression-driven pancreatic cancer cell proliferation and invasion.\",\n      \"method\": \"RNA-seq after TSPAN1 manipulation, DNMT/TET2 expression analysis, CpG methylation analysis, ITGA2 siRNA rescue experiments\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — epigenetic regulation identified by correlation and rescue; limited mechanistic depth for ITGA2 itself; single lab\",\n      \"pmids\": [\"32368389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXD3, whose expression is regulated by YY1 recruiting HDAC1, promotes HCC progression by binding the ITGA2 promoter and upregulating ITGA2 expression, thereby activating ERK1/2 signaling to drive proliferation, metastasis, and migration. ChIP-PCR confirmed HOXD3 binding to the ITGA2 promoter; dual luciferase reporter assays confirmed transcriptional activation.\",\n      \"method\": \"ChIP-PCR, dual luciferase reporter assay, HOXD3/ITGA2 knockdown/overexpression, Co-IP (YY1-HDAC1), ERK1/2 Western blot\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase confirming HOXD3 as direct ITGA2 transcriptional regulator with ERK1/2 downstream pathway; single lab\",\n      \"pmids\": [\"32557953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel enhancer-associated lncRNA (LncRNA-ITGA2) located at the ITGA2 locus promotes VSMC proliferation and migration by upregulating ITGA2 expression. Mechanistically, LncRNA-ITGA2 binds the ITGA2 enhancer region, increases H3K27 acetylation at both the ITGA2 enhancer and promoter, and interacts with DNA-binding protein NONO which also binds the ITGA2 promoter, thereby mediating enhancer-promoter looping interactions. CRISPR-Cas9 knockout of NONO or LncRNA-ITGA2 validated this regulatory mechanism.\",\n      \"method\": \"CUT&Tag, promoter-capture Hi-C, RNA-seq, CRISPR-Cas9 knockout, ChIP-seq, CHIRP, RIP, H3K27ac ChIP, carotid artery wire injury in vivo model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiomics with CRISPR validation and in vivo model; however describes regulatory mechanism of ITGA2 expression via lncRNA, not ITGA2 protein mechanism directly; single lab\",\n      \"pmids\": [\"40321134\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA2 encodes the alpha2 subunit of integrin alpha2beta1, a collagen receptor whose I-domain (residues ~140-359) directly binds collagen via a MIDAS metal ion coordinated by three I-domain loops that also engage the GFOGER collagen motif (with a collagen glutamate completing metal coordination), as established by crystal structures of the free and collagen-bound I-domain; collagen binding activates outside-in signaling through constitutively-associated Src/Lyn kinases leading to Syk, PLCgamma2, and FAK phosphorylation to drive platelet spreading and cell migration; in cancer and other contexts ITGA2 activates FAK/AKT, RhoA/p38 MAPK, STAT3/PD-L1, and ERK1/2 signaling pathways to promote proliferation, invasion, EMT, and drug/radiation resistance, while nuclear ITGA2 additionally inhibits NHEJ DNA repair by blocking DNA-PKcs recruitment to Ku70/80; ITGA2 expression is transcriptionally regulated by BACH1, HOXD3, TEAD1, EZH2 (epigenetic repression), and PARP-1/Ku80/70 binding to CA-repeat promoter elements, and is induced by VEGF on endothelial cells to promote angiogenesis and lymphangiogenesis via alpha2beta1-dependent collagen adhesion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGA2 encodes the alpha2 subunit of integrin α2β1 (GPIa/IIa, CD49b), a principal collagen receptor that mediates cell adhesion to collagen types I–VII and regulates platelet activation, immune cell trafficking, and tissue remodeling [PMID:2546619, PMID:8118028, PMID:23897120]. Collagen binding is mediated by a unique 191-residue I-domain within the extracellular region, with critical residues Thr-221, Asp-151, and Asp-254, and the isolated I-domain is sufficient for Mg²⁺-dependent collagen engagement [PMID:7511592, PMID:7523399, PMID:9184414]. Upon receptor clustering, constitutively associated Src-family kinases (Src, Lyn) initiate signaling through Cas, Syk, and PLCγ2, while downstream pathways including PI3K/AKT, FAK–RAC1–PAK, RhoA/p38 MAPK, ERK1/2, and STAT3 control cell survival, cytoskeletal remodeling, migration, and PD-L1-mediated immune modulation [PMID:11038351, PMID:31818309, PMID:37311571, PMID:29743821]. A nuclear pool of ITGA2 inhibits non-homologous end joining DNA repair by blocking DNA-PKcs recruitment to the Ku70/80 heterodimer, while transcription of ITGA2 is regulated by BACH1, HOXD3, TEAD1, SP1, EZH2-mediated histone methylation, CpG methylation, and an enhancer-associated lncRNA-ITGA2/NONO chromatin-looping mechanism [PMID:35998796, PMID:37311571, PMID:32557953, PMID:25549357, PMID:40321134].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Cloning of ITGA2 revealed its primary structure including a unique I-domain not found in other integrin α chains, and antibody blockade established GPIa/IIa as a direct collagen receptor on platelets, answering the question of which integrin subunit mediates platelet–collagen adhesion.\",\n      \"evidence\": \"cDNA cloning with protein sequencing (PMID:2545729); monoclonal antibody 6F1 blocking platelet adhesion to collagen (PMID:2546619)\",\n      \"pmids\": [\"2545729\", \"2546619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific region within ITGA2 responsible for collagen binding was not yet mapped\",\n        \"Whether the I-domain alone was sufficient for binding was unknown\",\n        \"Signaling pathways downstream of receptor engagement were uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mutagenesis and chimeric constructs pinpointed the I-domain as the collagen-binding module, identifying Asp-151, Asp-254, and Thr-221 as critical residues, and showed the recombinant I-domain is sufficient for collagen binding, resolving the minimal binding unit and key contact sites.\",\n      \"evidence\": \"Site-directed mutagenesis and chimeric α2 constructs with binding assays; recombinant I-domain fragment binding collagen\",\n      \"pmids\": [\"7511592\", \"7523399\", \"8118028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of the I-domain–collagen complex was not yet available\",\n        \"The role of divalent cations in regulating (versus directly participating in) binding remained to be structurally clarified\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Functional confirmation that the recombinant I-domain competitively inhibits platelet adhesion to collagen (IC50 ~0.7 µM) validated it as a potential therapeutic target and established the Mg²⁺-dependent nature of the interaction.\",\n      \"evidence\": \"Recombinant I-domain protein inhibiting platelet adhesion and aggregation in vitro\",\n      \"pmids\": [\"9184414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo therapeutic utility of I-domain antagonism was not tested\",\n        \"Structural basis for Mg²⁺ regulation remained unresolved at atomic level\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of C807T and HPA-5 polymorphisms linked to GPIa/IIa receptor density on platelets provided a genetic explanation for inter-individual variation in collagen-mediated platelet responses.\",\n      \"evidence\": \"PCR genotyping with flow cytometric quantification of surface receptor density in multiple donor cohorts\",\n      \"pmids\": [\"10468872\", \"10220262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The causal molecular mechanism linking silent polymorphisms to expression level was unknown\",\n        \"Clinical significance for thrombotic risk was correlative, not proven causal\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Discovery that Src and Lyn kinases are constitutively associated with GPIa/IIa and that receptor clustering activates Src→Cas and Syk/PLCγ2 signaling established the first proximal signaling framework for α2β1, answering how collagen engagement transduces intracellular signals.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro kinase assays, and cytochalasin D perturbation using rhodocytin as agonist on platelets and reconstituted liposomes\",\n      \"pmids\": [\"11038351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which cytoplasmic tail residues mediate kinase association was not defined\",\n        \"The relative contributions of Src versus Lyn to downstream outcomes were not dissected\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that the ITGA2 promoter remains unmethylated during megakaryocyte differentiation (while ITGA1 is silenced by CpG methylation) and that PARP-1/Ku80 bind CA-repeat polymorphisms to regulate expression revealed the first epigenetic and cis-regulatory mechanisms controlling ITGA2 transcription.\",\n      \"evidence\": \"Bisulfite sequencing and promoter-reporter assays during megakaryopoiesis; DNA affinity chromatography and ChIP for CA-repeat binding factors\",\n      \"pmids\": [\"17669516\", \"20090957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether CA-repeat length variation is causally responsible for inter-individual platelet α2β1 density was not formally proven\",\n        \"Upstream signals controlling CpG methylation status at the locus were undefined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CD49b was shown to be required for memory CD4+ T cell migration into bone marrow sinusoids via collagen engagement, expanding ITGA2's role beyond platelets to adaptive immune cell homing.\",\n      \"evidence\": \"CD49b-deficient mice and antibody blockade with adoptive T cell transfer\",\n      \"pmids\": [\"23897120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific collagen types in marrow sinusoids serve as ligands in vivo was not fully resolved\",\n        \"Whether CD49b is required for memory T cell survival or only migration was unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"EZH2-mediated H3K27 trimethylation was identified as a repressive epigenetic mark silencing ITGA2 in colorectal cancer, linking chromatin modification to actin remodeling through cofilin phosphorylation upon ITGA2 de-repression.\",\n      \"evidence\": \"EZH2 inhibition (DZNep, GSK343, siRNA), ChIP, and migration assays in CRC cells\",\n      \"pmids\": [\"25549357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether EZH2-mediated ITGA2 silencing is context-dependent across tumor types was not assessed\",\n        \"The kinase pathway linking ITGA2 to cofilin Ser3 phosphorylation was not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Consolidation of multiple cancer signaling studies established that ITGA2 activates divergent downstream pathways—RhoA/p38 MAPK controlling apoptosis, STAT3 driving PD-L1 immune evasion, and FAK–RAC1–PAK organizing the cytoskeleton—depending on cellular context, revealing ITGA2 as a signaling hub in tumor biology.\",\n      \"evidence\": \"Antibody blockade in gastric cancer (PMID:29743821); co-IP of ITGA2–STAT3 in pancreatic cancer (PMID:31818309); ChIP-validated BACH1→ITGA2→FAK-RAC1-PAK axis in lung adenocarcinoma (PMID:37311571)\",\n      \"pmids\": [\"29743821\", \"31818309\", \"37311571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ITGA2–STAT3 interaction relies on a single co-IP without reciprocal validation\",\n        \"Whether ITGA2 engages STAT3 directly or via an intermediary kinase is unknown\",\n        \"Structural basis for how the short cytoplasmic tail nucleates multiple signaling complexes is undefined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple transcription factors (HOXD3, TEAD1, SP1) were shown by ChIP to directly bind the ITGA2 promoter, and negative regulators (YY1/HDAC1 repressing HOXD3; miR-373 targeting the 3′UTR) were defined, building a multi-layered transcriptional/post-transcriptional regulatory model for ITGA2 expression.\",\n      \"evidence\": \"ChIP-PCR and dual-luciferase reporters for HOXD3 (PMID:32557953), TEAD1 (PMID:38169150), SP1 (PMID:39199378); luciferase 3′UTR reporter for miR-373 (PMID:26258411)\",\n      \"pmids\": [\"32557953\", \"38169150\", \"39199378\", \"26258411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Combinatorial or competitive regulation by these factors at the endogenous locus is unexplored\",\n        \"Whether these regulators operate simultaneously or in tissue-restricted fashion is not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A nuclear pool of ITGA2 was discovered to inhibit NHEJ DNA repair by blocking DNA-PKcs recruitment to Ku70/80, providing the first non-canonical (non-adhesion) function for this integrin subunit and linking it to radiosensitivity.\",\n      \"evidence\": \"ITGA2 overexpression/knockdown with NHEJ pathway activity assays and DNA-PKcs recruitment analysis in pancreatic cancer cells\",\n      \"pmids\": [\"35998796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of ITGA2 nuclear import is unknown\",\n        \"Whether nuclear ITGA2 retains its I-domain or is proteolytically processed is undefined\",\n        \"Finding is from a single study and has not been independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An enhancer-associated lncRNA (lncRNA-ITGA2) was shown to recruit NONO to mediate promoter–enhancer looping at the ITGA2 locus, increasing H3K27 acetylation and ITGA2 expression, driving vascular smooth muscle cell proliferation and neointimal hyperplasia in vivo.\",\n      \"evidence\": \"CRISPR knockout, CUT&Tag, promoter capture Hi-C, ChIRP, RNA immunoprecipitation, carotid wire injury model\",\n      \"pmids\": [\"40321134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this lncRNA-NONO mechanism operates in cell types beyond vascular smooth muscle is unknown\",\n        \"The signals triggering lncRNA-ITGA2 upregulation during vascular injury are not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete structural model of how the short ITGA2 cytoplasmic tail simultaneously organizes Src-family kinases, FAK, and STAT3 signaling complexes, and the mechanism by which ITGA2 translocates to the nucleus, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length α2β1 in complex with collagen exists\",\n        \"Nuclear import mechanism for ITGA2 is uncharacterized\",\n        \"Context-dependent switching between pro-survival and pro-apoptotic signaling downstream of ITGA2 is not mechanistically explained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 13, 23]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 16, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 7, 8, 13, 29]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 2, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 16, 17, 18, 21, 24]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 13, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 16, 29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2, 15]}\n    ],\n    \"complexes\": [\n      \"integrin α2β1 (GPIa/IIa)\"\n    ],\n    \"partners\": [\n      \"ITGB1\",\n      \"SRC\",\n      \"LYN\",\n      \"STAT3\",\n      \"NONO\",\n      \"BACH1\",\n      \"SP1\",\n      \"FAK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ITGA2 encodes the alpha-2 subunit of integrin α2β1, the principal collagen receptor on platelets and many other cell types, mediating direct adhesion to collagen types I–VIII as well as thrombospondin and echovirus 1 [PMID:2546619, PMID:8118028, PMID:8240284]. Ligand recognition is conferred by the I-domain (residues ~140–359), whose MIDAS motif coordinates a divalent cation and engages the GFOGER collagen motif through three surface loops, with a collagen glutamate completing metal coordination; ligand binding induces conformational changes that propagate to the domain's opposite pole, coupling adhesion to outside-in signaling [PMID:7523399, PMID:9353312, PMID:10778855]. Collagen engagement of α2β1 activates constitutively associated Src/Lyn kinases, leading to Syk, PLCγ2, and FAK phosphorylation that drive platelet spreading, and in epithelial and cancer cells signals through FAK/AKT, RhoA/p38 MAPK, STAT3, and ERK1/2 to promote proliferation, EMT, migration, and chemoresistance [PMID:11038351, PMID:12615912, PMID:31818309, PMID:34113124]. ITGA2 expression is transcriptionally regulated by BACH1, HOXD3, TEAD1, and EZH2, is induced by VEGF on endothelial cells to support angiogenesis and lymphangiogenesis, and nuclear ITGA2 additionally inhibits NHEJ DNA repair by blocking DNA-PKcs recruitment to the Ku70/80 heterodimer [PMID:37311571, PMID:9391074, PMID:15132990, PMID:35998796].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Cloning and antibody-blocking experiments established that VLA-2 (α2β1) is a collagen receptor on platelets and that the α2 subunit harbors a unique ~191-residue I-domain homologous to vWF A-domains, identifying the likely collagen-binding module.\",\n      \"evidence\": \"cDNA cloning/sequencing of α2 subunit and monoclonal antibody 6F1 blocking of platelet–collagen adhesion\",\n      \"pmids\": [\"2545729\", \"2546619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"I-domain collagen-binding function was inferred by homology, not yet demonstrated directly\", \"β1 subunit contribution to ligand binding was unknown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Chimeric constructs, mutagenesis, and recombinant I-domain binding assays demonstrated that the I-domain alone is necessary and sufficient for collagen recognition, mapping critical residues (Asp-151, Asp-254, Thr-221) and showing α2β1 binds all collagen types I–VIII.\",\n      \"evidence\": \"Human/bovine α2 chimeras, site-directed mutagenesis, recombinant I-domain collagen-binding assay, systematic antibody blocking across 8 collagen types\",\n      \"pmids\": [\"7511592\", \"7523399\", \"8118028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of I-domain not yet available\", \"Role of divalent cations in binding was debated\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The crystal structure of the free I-domain revealed a Rossmann fold with a MIDAS motif coordinating Mg²⁺, resolving how divalent cations participate in collagen recognition and predicting a collagen glutamate would complete metal coordination.\",\n      \"evidence\": \"X-ray crystallography of the α2 I-domain; recombinant I-domain competition of platelet adhesion\",\n      \"pmids\": [\"9353312\", \"9184414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand-bound structure not yet solved\", \"Conformational changes upon collagen binding uncharacterized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The co-crystal structure of the I-domain with a triple-helical GFOGER collagen peptide proved that collagen glutamate completes MIDAS coordination and showed that ligand binding propagates conformational changes to the opposite pole, providing a structural basis for affinity regulation and outside-in signaling.\",\n      \"evidence\": \"X-ray crystallography of I-domain–collagen peptide complex\",\n      \"pmids\": [\"10778855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling C-terminal conformational shift to β1 subunit activation undetermined\", \"Full ectodomain structure with β1 unavailable\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of the outside-in signaling cascade downstream of α2β1 engagement—constitutive Src/Lyn association, Syk and PLCγ2 phosphorylation, FAK activation, and intracellular Ca²⁺ mobilization—established the receptor as an autonomous signaling entity independent of GPVI.\",\n      \"evidence\": \"Rhodocytin-stimulated liposome-reconstituted α2β1 kinase assays; collagen peptide-stimulated platelet spreading with PLCγ2-KO platelets and PP2 inhibitor\",\n      \"pmids\": [\"11038351\", \"12615912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor proteins linking Src/Syk to downstream effectors incompletely defined\", \"Role of cytoplasmic tail phosphorylation unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"VEGF was shown to transcriptionally upregulate α2β1 on endothelial cells, and functional blocking of α2 integrin inhibited VEGF-driven angiogenesis by ~90% in vivo, placing α2β1–collagen interaction as a required step in neovascularization.\",\n      \"evidence\": \"Flow cytometry, mRNA induction, anti-α2 blocking antibody in vivo angiogenesis assay; extended to lymphangiogenesis in a subsequent study\",\n      \"pmids\": [\"9391074\", \"15132990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific intracellular signals linking VEGF-induced α2β1 to endothelial tube formation not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cooperative signaling through α2β1 (via FAK/p130CAS) and DDR1 (via Pyk2) converging on Rap1 was shown to upregulate N-cadherin in pancreatic cancer, providing a mechanistic link between collagen sensing by α2β1 and EMT.\",\n      \"evidence\": \"siRNA knockdown of α2β1 and DDR1, signaling pathway inhibitors, in vivo tumor model\",\n      \"pmids\": [\"18362184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rap1 activation mechanism downstream of FAK/p130CAS incompletely characterized\", \"Generalizability to other epithelia unconfirmed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Transcriptional and epigenetic regulation of ITGA2 was elaborated: EZH2 directly represses the locus, PARP-1/Ku80 bind CA-repeat promoter elements to enhance transcription, and promoter CpG methylation status controls expression in prostate cancer, establishing ITGA2 as an epigenetically regulated gene.\",\n      \"evidence\": \"ChIP for EZH2, DNA affinity chromatography for PARP-1/Ku80, bisulfite sequencing in prostate cancer cells, pharmacological inhibition of EZH2\",\n      \"pmids\": [\"25549357\", \"20090957\", \"25662931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each epigenetic regulator in different lineages unclear\", \"Whether EZH2-mediated repression is H3K27me3-dependent was not confirmed by histone mark ChIP\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ITGA2 was found to interact with STAT3, promote its phosphorylation, and thereby transcriptionally upregulate PD-L1, revealing a non-canonical signaling output linking α2β1 to immune evasion.\",\n      \"evidence\": \"Co-immunoprecipitation (ITGA2–STAT3), RNA-seq, ITGA2 knockdown/overexpression in cancer cells\",\n      \"pmids\": [\"31818309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal co-IP or proximity ligation not reported\", \"Whether STAT3 interaction is direct or bridged by FAK/Src unknown\", \"Functional impact on anti-tumor immunity not tested in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Nuclear ITGA2 was shown to inhibit NHEJ DNA repair by blocking DNA-PKcs recruitment to the Ku70/80 heterodimer, linking integrin expression to genome instability and radiation sensitivity in pancreatic cancer.\",\n      \"evidence\": \"DNA-PKcs/Ku70/Ku80 recruitment assay, NHEJ functional assay, ITGA2 nuclear localization analysis, radiation sensitivity assay\",\n      \"pmids\": [\"35998796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ITGA2 nuclear translocation undefined\", \"Structural basis of ITGA2–Ku70/80 interaction unknown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"BACH1 and HOXD3 were identified as direct transcriptional activators of ITGA2 by ChIP and reporter assays, with BACH1–ITGA2 signaling through FAK-RAC1-PAK and HOXD3–ITGA2 through ERK1/2, connecting upstream transcription factor programs to α2β1-dependent invasion.\",\n      \"evidence\": \"ChIP-PCR, dual-luciferase reporter, knockdown/overexpression of BACH1/HOXD3, downstream pathway Western blots\",\n      \"pmids\": [\"37311571\", \"32557953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BACH1 and HOXD3 co-operate or act in distinct contexts is unknown\", \"Genomic occupancy validated at single locus only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CRISPR deletion of ITGA2 (with ITGA1) in benign prostate epithelium activated TGFβ1 autocrine signaling and nuclear YAP1, converting cells to a tumorigenic phenotype, while TEAD1 was identified as a transcriptional regulator whose loss phenocopies integrin deletion.\",\n      \"evidence\": \"CRISPR genomic deletion, TGFβ1 neutralization, YAP1 localization, in vivo tumorigenesis assay, TEAD1 knockdown\",\n      \"pmids\": [\"38169150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual contribution of ITGA2 versus ITGA1 loss not separable in the dual-knockout design\", \"Whether TEAD1 directly binds the ITGA2 promoter was not shown by ChIP\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the mechanism of ITGA2 nuclear translocation, the structural basis of α2β1 full-ectodomain interaction with β1, how the I-domain conformational switch is coupled to cytoplasmic signaling, and whether the ITGA2–STAT3 interaction is direct.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length α2β1 structure available\", \"Nuclear import pathway of ITGA2 uncharacterized\", \"STAT3 interaction awaits reciprocal validation and proximity labeling\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 7, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8, 10, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 2, 8, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13, 17, 23, 26, 28]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 12, 30]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2, 7, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 26, 28, 34]}\n    ],\n    \"complexes\": [\n      \"integrin α2β1\"\n    ],\n    \"partners\": [\n      \"ITGB1\",\n      \"SRC\",\n      \"LYN\",\n      \"SYK\",\n      \"PLCG2\",\n      \"PTK2\",\n      \"STAT3\",\n      \"RAB21\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}