{"gene":"ITGA1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1985,"finding":"VLA-1 (ITGA1/CD49a) is a heterodimeric cell-surface complex composed of an Mr 210,000 alpha1 subunit in acid-labile association with an Mr 130,000 beta subunit (beta1), as demonstrated by cross-linking and immunoprecipitation experiments. The alpha1 and beta subunits each contain substantial sialic acid and N-linked carbohydrate, and are non-homologous to each other by one-dimensional peptide mapping.","method":"Immunoprecipitation, chemical cross-linking, neuraminidase/endoglycosidase F digestion, 1D peptide mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution/characterization with multiple orthogonal methods in a foundational study","pmids":["2415516"],"is_preprint":false},{"year":1990,"finding":"VLA-1 integrin purified from human smooth muscle by collagen-Sepharose affinity chromatography mediates adhesion to type I, II, III, and IV collagens, C1q, and laminin in a Ca2+/Mg2+-dependent manner, but does not bind gelatin, fibronectin, or thrombospondin, establishing the substrate specificity of ITGA1-containing integrin.","method":"Affinity chromatography purification, liposome adhesion assay, inhibition with divalent cations, immunoblotting","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified protein and functional adhesion assay, multiple substrates tested","pmids":["2229189"],"is_preprint":false},{"year":1991,"finding":"Purified VLA-1 from human smooth muscle interacts via a Ca2+/Mg2+-dependent mechanism with interstitial collagens I, II, and III and basement membrane proteins (collagen IV and laminin) but not with fibronectin, thrombospondin, or albumin; denaturation of collagen I reduces binding 5-7-fold, and GRGDSP peptide does not inhibit binding, indicating a non-RGD-dependent collagen-binding mechanism.","method":"Affinity chromatography purification, liposome binding assay, substrate denaturation, peptide inhibition","journal":"Biokhimiia (Moscow, Russia)","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted adhesion with purified integrin, mechanistic substrate specificity defined","pmids":["1807406"],"is_preprint":false},{"year":1994,"finding":"VLA-1-mediated adhesion of neuroblastoma NB100 cells to collagen type I is supported by Mg2+ or Mn2+ but not Ca2+ alone; Ca2+ inhibits Mg2+-supported adhesion. VLA-1 can be directly activated by the stimulatory anti-beta1 monoclonal antibody TS2/16, demonstrating inside-out and outside-in regulation of integrin activity.","method":"Cell adhesion assay with divalent cation manipulation, blocking and activating monoclonal antibodies, novel blocking anti-alpha1 mAb 5E8D9","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — clean functional adhesion assay with pharmacological manipulation and antibody tools, single lab","pmids":["7516898"],"is_preprint":false},{"year":1994,"finding":"VLA-1 (CD49a/alpha1beta1) on long-term activated human T lymphocytes functions as a specific collagen IV receptor; antibody blockade of CD49a inhibits adhesion to collagen IV by ~94% and collagen I by ~82%, and ligation of VLA-1 induces spreading on collagen IV in a Mg2+-dependent manner and can signal IL-2 receptor expression in gamma-delta T cells.","method":"Radiolabeled adhesion assay, blocking monoclonal antibody (1B3.1), cell spreading morphology, IL-2R induction readout","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — blocking antibody adhesion assay with defined readouts, single lab","pmids":["8025956"],"is_preprint":false},{"year":1995,"finding":"Glomerular epithelial cells use VLA-1 and VLA-2 cooperatively for adhesion to laminin but rely on VLA-2 alone for collagen adhesion, whereas mesangial cells use VLA-1 for laminin adhesion and both VLA-1 and VLA-2 for collagen, demonstrating cell-type-specific modulation of VLA-1 ligand-binding specificity.","method":"Blocking monoclonal antibodies against rat VLA-1 and VLA-2, cell adhesion assay to ECM proteins, ELISA and immunocytochemistry","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 — functional blocking antibody experiments in two cell types, single lab","pmids":["7898055"],"is_preprint":false},{"year":1999,"finding":"Integrin alpha1beta1 (VLA-1) is the primary collagen receptor on human intestinal intraepithelial lymphocytes (IELs); antibody blockade of both alpha1 (CD49a) and beta1 subunits inhibited adhesion to collagen I by 82% and collagen IV by 94%, and adhesion was dependent on extracellular divalent cations (Mg2+ and Mn2+ supported; Ca2+ inhibited) and upregulated by PKC stimulation.","method":"51Cr-labelled lymphocyte adhesion assay, blocking antibodies, divalent cation manipulation, phorbol ester/staurosporine treatment","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional adhesion assay with blocking antibodies and mechanistic dissection of cation dependence","pmids":["10457223"],"is_preprint":false},{"year":2000,"finding":"VLA-1 (integrin alpha1beta1) is required for normal numbers of gut intraepithelial lymphocytes; VLA1-null mice show ~50% reduction in intestinal IELs despite normal peripheral lymphocyte distribution, and IL-2-stimulated VLA1-null splenocytes show deficient adhesion to fibrillar and basement membrane collagen and reduced proliferation on collagen substrate.","method":"Genetic knockout mouse (VLA1-null), flow cytometry, adhesion assay, proliferation assay","journal":"Cellular immunology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with specific cellular phenotype and in vitro adhesion/proliferation readouts","pmids":["10805967"],"is_preprint":false},{"year":2002,"finding":"VLA-1 (alpha1beta1 integrin) mediates both glomerular and interstitial fibrosis in crescentic glomerulonephritis; delayed antibody blockade of VLA-1 reduced glomerular and tubulointerstitial scarring, decreased type IV collagen and ED-A fibronectin deposition, and increased MMP-9 expression in the glomeruli of treated rats.","method":"Anti-VLA-1 antibody treatment (Ha31/8) in rat nephrotoxic nephritis model, immunohistochemistry, serum creatinine, Kaplan-Meier renal survival","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo antibody blockade with defined fibrosis phenotype and MMP-9 mechanistic readout, single lab","pmids":["12368200"],"is_preprint":false},{"year":2003,"finding":"VLA-1 (alpha1beta1 integrin) expression marks a stable phenotypic subset of human CD4+ memory T cells enriched for Th1 cytokine production; VLA-1+ CD4+ T cells are selectively enriched for recall antigen-responsive cells, and depletion of the small VLA-1+ fraction from CD4+ PBLs significantly abrogated the proliferative response to recall antigens.","method":"Flow cytometry, T cell depletion and reconstitution, recall antigen proliferation assay, cytokine polarization","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — depletion experiment with defined functional readout (recall antigen proliferation), single lab","pmids":["14597770"],"is_preprint":false},{"year":2004,"finding":"The collagen-binding alpha1beta1 integrin (VLA-1/CD49a) is responsible for retention of influenza-specific CD8 memory T cells in the lung and other nonlymphoid tissues; antibody blockade or genetic deficiency of VLA-1 decreased virus-specific CTL in lung/nonlymphoid tissues and increased them in spleen, and impaired secondary heterosubtypic immunity.","method":"Antibody blockade and genetic KO mouse model, flow cytometry of tissue-specific T cells, heterosubtypic challenge model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — two independent approaches (antibody and KO) with defined tissue retention and immunity phenotypes","pmids":["14975239"],"is_preprint":false},{"year":2007,"finding":"The ITGA1 promoter contains a CArG box bound by serum response factor (SRF). Selective CpG methylation of a CpG-rich ITGA1 promoter region is the epigenetic mechanism suppressing ITGA1 expression during megakaryocyte differentiation; 5-aza-2'-deoxycytidine (but not trichostatin A) induced de novo ITGA1 expression in megakaryocytic cells, and progressive CpG methylation at 19 CpG sites occurs during thrombopoietin-induced megakaryocyte differentiation.","method":"Sodium bisulfite genomic sequencing, promoter-LUC reporter transfection, 5-aza-CdR treatment, mRNA expression analysis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — direct sequencing of methylation status combined with functional reporter assay and pharmacological rescue, multiple orthogonal methods","pmids":["17669516"],"is_preprint":false},{"year":2007,"finding":"CD49a (alpha1beta1) and CD49b (alpha2beta1) show reciprocal expression on CD8 and CD4 T cells in influenza-infected lung, correlating with distinct spatial localizations: CD8+ T cells associate with collagen IV-rich basement membranes of airways/blood vessels, while CD4+ T cells localize in collagen I-rich interstitial spaces.","method":"Flow cytometry, immunofluorescent tissue analysis of collagen distribution and T cell localization","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — correlative localization with defined spatial mechanistic implication, single lab","pmids":["17372009"],"is_preprint":false},{"year":2010,"finding":"VLA-1 (CD49a/alpha1beta1) is required for the accumulation and maintenance of a tissue-memory CD4+ T cell population in the airways after influenza infection; alpha1-/- mice showed fewer memory/effector CD4+ T cells in airways (but not lymphoid tissues), and CD49a+ airway CD4+ T cells were enriched for early IFN-gamma secretion upon secondary challenge and showed reduced apoptosis markers.","method":"Alpha1-/- knockout mice, flow cytometry, intracellular cytokine staining, apoptosis markers","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with tissue-specific phenotype and functional effector readout, clean experimental design","pmids":["20200271"],"is_preprint":false},{"year":2014,"finding":"CD49a promotes T-cell-mediated hepatitis; CD49a-/- mice were protected from ConA-induced hepatitis with significantly reduced serum ALT and decreased IFN-gamma and IL-17A production. CD49a blockade in vivo ameliorated hepatitis with reduced inflammatory cytokine production by CD4+ T and invariant NKT cells.","method":"CD49a-/- knockout mouse, ConA-induced hepatitis model, serum ALT, intracellular cytokine staining, in vivo antibody blockade","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and antibody blockade with defined inflammatory phenotype, two orthogonal approaches","pmids":["24164540"],"is_preprint":false},{"year":2017,"finding":"TGF-beta and IL-12 induce CD49a expression by CD8+ T cells in vitro; CD49a is expressed early following T cell activation in vivo but is not required for generation of a primary CD8+ T cell response to cutaneous HSV infection or migration across epidermal basement membrane. Rather, CD49a supports CD8+ TRM persistence in skin, regulates epidermal TRM dendritic extensions, and increases the frequency of IFN-gamma+ CD8+ TRM following local antigen challenge.","method":"In vitro cytokine stimulation, CD49a KO mouse, cutaneous HSV infection model, flow cytometry, intravital imaging of dendritic extensions","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple defined functional readouts (persistence, morphology, antigen recall), single lab with orthogonal methods","pmids":["32877667"],"is_preprint":false},{"year":2017,"finding":"ITGA1 is required for collagen-induced tumorigenic potential in pancreatic ductal adenocarcinoma cells; ITGA1 depletion revealed it promotes survival of ALDH1-positive stem-like cells, cooperates with TGF-beta to drive gemcitabine resistance, and is required for TGF-beta/collagen-induced EMT and metastasis.","method":"ITGA1 siRNA/shRNA knockdown, collagen adhesion/invasion assays, ALDH1 stem cell marker analysis, gemcitabine resistance assay, EMT marker western blot, in vivo metastasis model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple defined phenotypic readouts, single lab","pmids":["28855593"],"is_preprint":false},{"year":2017,"finding":"E2F1 transcription factor directly upregulates ITGA1 expression; dual luciferase reporter assay and chromatin immunoprecipitation showed E2F1 binds the ITGA1 promoter to activate transcription, and d-ICD treatment inhibits E2F1 expression, thereby reducing ITGA1 levels and suppressing HCC cell migration and invasion.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, western blot, wound healing and transwell invasion assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1/2 — ChIP and reporter assay demonstrate direct E2F1-ITGA1 promoter interaction, single lab","pmids":["28264467"],"is_preprint":false},{"year":2019,"finding":"CD49a on decidual NK cells regulates their cytotoxic activity, migration, and adhesion; neutralization of CD49a with blocking antibody increased perforin, granzyme B, and IFN-gamma expression, increased killing activity in 51Cr release assay, and decreased migration and adhesion of dNK cells. A newly identified lncRNA (lnc-49a) was identified as a positive regulator of CD49a expression in primary human NK cells.","method":"CD49a neutralizing antibody, flow cytometry, 51Cr release cytotoxicity assay, migration and adhesion assay, lncRNA microarray analysis","journal":"American journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blockade with multiple functional readouts and identification of upstream lncRNA regulator","pmids":["30756436"],"is_preprint":false},{"year":2020,"finding":"CD49a (VLA-1) facilitates locomotion of virus-specific CD8 T cells both in vitro and in vivo in the pulmonary system after influenza infection, contrary to an expected pure retention function; CD49a facilitates T cell motility rather than immobilizing cells, potentially contributing to local surveillance.","method":"In vitro motility assay, intravital imaging (in vivo), flow cytometry of TRM phenotype development","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct motility measurement in vitro and in vivo, single lab","pmids":["32439709"],"is_preprint":false},{"year":2021,"finding":"CD49a expression on tumor-infiltrating CD8+ T cells increases their motility in the tumor microenvironment, particularly in proximity to tumor cells, suggesting CD49a may interfere with productive TCR engagement of tumor cells; expression of CD49a was driven by antigen-independent elements in the TME and further increased by TCR stimulation.","method":"Live tumor slice imaging of T cell motility, flow cytometry, Nur77 reporter for TCR engagement, short-term CD49a blockade","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 — direct live imaging of motility with mechanistic dissection, single lab","pmids":["33619119"],"is_preprint":false},{"year":2021,"finding":"VLA-1 binding to collagen IV provides the substrate for extended contact times between myeloid-derived suppressor cells (MDSCs) and effector CD4+ T cells required for T cell suppression; Itga1-/- A-MDSCs showed equivalent splenic homing but shorter interaction times with Teff on collagen IV (but not fibronectin) and reduced suppressive capacity, as measured by T cell proliferation inhibition and apoptosis induction.","method":"Itga1-/- genetic KO, in vitro suppression assay on collagen IV vs. fibronectin substrate, intravital two-photon microscopy, T cell proliferation and apoptosis assay","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + intravital two-photon microscopy with quantitative interaction time measurement, mechanistic link to suppression","pmids":["33584706"],"is_preprint":false},{"year":2023,"finding":"RUNX2 and RUNX3 transcription factors are required for IL-15/TGF-beta-induced CD49a expression and the cytotoxic transcriptional profile in circulating CD8+ T cells differentiating toward epidermal TRM cells; RUNX-binding motifs are enriched in epidermal CD8+CD103+CD49a+ TRM cells and RUNX2/RUNX3 protein is highly expressed in this population.","method":"RUNX2/3 siRNA knockdown, in vitro stimulation with IL-15+TGF-beta, flow cytometry, RNA-seq transcriptional profiling, ATAC-seq motif enrichment, single-cell paired skin/blood clonotype analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1/2 — loss-of-function (siRNA) + transcriptomics + chromatin accessibility, multiple orthogonal methods","pmids":["37269830"],"is_preprint":false},{"year":2023,"finding":"ITGA1 loss in cartilage increases TGFBR2 signaling, and this enhanced TGFBR2 signaling drives early and more severe knee osteoarthritis in itga1-null mice; cartilage-specific depletion of TGFBR2 in itga1-null mice attenuated OA progression, establishing an epistatic relationship where integrin alpha1beta1 normally dampens TGFBR2 signaling to protect against OA.","method":"Itga1-/- global KO mouse, tamoxifen-inducible cartilage-specific TGFBR2 depletion (double-mutant epistasis), histological OA scoring, behavioral pain assessment, longitudinal study","journal":"Osteoarthritis and cartilage open","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis (double-mutant rescue) with defined tissue-specific phenotype","pmids":["37649532"],"is_preprint":false},{"year":2023,"finding":"Linc00662 recruits GTF2B to activate ITGA1 transcription in a m6A-dependent manner; ITGA1 then initiates focal adhesion formation through the ITGA1-FAK-ERK pathway, promoting malignant behavior in pancreatic cancer cells. FAK inhibitor Y15 suppressed tumor progression in Linc00662-overexpressing cells.","method":"RNA pull-down, co-IP, ChIP showing GTF2B at ITGA1 promoter, western blot for FAK/ERK phosphorylation, in vitro invasion/migration, in vivo xenograft","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and co-IP with defined downstream signaling readout, single lab","pmids":["37293163"],"is_preprint":false},{"year":2024,"finding":"TEAD1 is a key transcriptional regulator of ITGA1 (and ITGA2) expression in prostate cancer cells; TEAD1 loss phenocopies dual ITGA1/ITGA2 deletion in promoting EMT via enhanced TGF-beta1 secretion/autocrine activation and nuclear YAP1 targeting. Genomic deletion of both ITGA1 and ITGA2 activates EMT and converts benign prostate epithelial cells into tumorigenic cells in vivo.","method":"TEAD1 siRNA knockdown, ITGA1/ITGA2 genomic deletion, genome-wide co-expression analysis, EMT assay, TGF-beta1 ELISA, YAP1 nuclear localization, in vivo tumorigenicity assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with mechanistic pathway dissection (TEAD1→ITGA1→TGFβ1→YAP1→EMT), single lab","pmids":["38169150"],"is_preprint":false},{"year":2025,"finding":"Microglial CD49a (Itga1) drives neuroinflammation in Parkinson's disease models through PGAM5 as a central regulatory node; microglial Itga1 knockdown attenuates hyperreactivity, ameliorates mitochondrial dysfunction, suppresses NLRP3 inflammasome assembly via PGAM5 downregulation, and preserves dopaminergic neurons. The disintegrin polypeptide obtustatin specifically antagonizes microglial CD49a, suppressing neuroinflammation and improving motor deficits.","method":"Conditional microglial Itga1 knockdown, transcriptomic profiling of isolated microglia, mitochondrial function assay, NLRP3 inflammasome assembly assay, PD mouse models, obtustatin pharmacological antagonism","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KD with transcriptomics and multiple mechanistic readouts (PGAM5, NLRP3, mitochondria), single lab","pmids":["41462565"],"is_preprint":false},{"year":2025,"finding":"ITGA1 knockdown or pharmacological inhibition with obtustatin impairs retinoblastoma cell proliferation, migration, and clonogenicity; STAT3 was identified as a key downstream mediator of ITGA1 signaling, and a STAT3 agonist (ML115) partially rescued the inhibitory effects of ITGA1 suppression. ITGA1 partners with ITGB1 in retinoblastoma cells.","method":"Lentiviral ITGA1 knockdown, obtustatin treatment, transcriptome analysis, western blot, STAT3 agonist rescue, in vivo xenograft model","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with rescue experiment identifying downstream signaling pathway, single lab","pmids":["40939856"],"is_preprint":false},{"year":2025,"finding":"Luteolin suppresses ITGA1 transcription in endothelial cells by inhibiting KDM4C-mediated demethylation of H3K9me3 at the ITGA1 promoter; ITGA1 knockdown improved AGEs-induced senescent HUVEC functional impairments (proliferation, migration, tube formation) and reduced senescence markers, while ITGA1 overexpression abrogated luteolin's protective effects. The EGFR/MEK/ERK pathway is downstream of ITGA1 in this context.","method":"ITGA1 siRNA knockdown, ITGA1 overexpression, ChIP for H3K9me3 at ITGA1 promoter, KDM4C inhibition, EGFR/MEK/ERK western blot, in vivo diabetic wound model","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for epigenetic mark + loss/gain of function with mechanistic pathway (KDM4C→H3K9me3→ITGA1→EGFR/ERK), single lab","pmids":["40778546"],"is_preprint":false}],"current_model":"ITGA1 (CD49a) encodes the alpha1 subunit of the heterodimeric integrin VLA-1 (alpha1beta1), which binds collagen I–IV and laminin via a divalent cation-dependent (Mg2+/Mn2+-promoted, Ca2+-inhibited), non-RGD mechanism; its expression is epigenetically controlled by CpG methylation of its promoter (regulated by SRF/CArG and KDM4C/H3K9me3) and transcriptionally by E2F1, TEAD1, RUNX2/RUNX3, and GTF2B, while functionally it mediates tissue retention and locomotion of memory T cells and tissue-resident NK cells in non-lymphoid tissues, dampens TGFβR2 signaling in cartilage to protect against osteoarthritis, promotes MDSC-T cell suppressive contacts via collagen IV binding, drives inflammatory cytokine production by T and NKT cells, and activates FAK-ERK and STAT3 downstream signaling pathways to promote cancer cell invasion, EMT, and therapy resistance."},"narrative":{"teleology":[{"year":1985,"claim":"Establishing that VLA-1 is a heterodimer of distinct α1 (~210 kDa) and β1 (~130 kDa) glycoprotein subunits resolved the molecular identity of what would become the founding collagen-binding integrin.","evidence":"Immunoprecipitation, chemical cross-linking, glycosidase digestion, and peptide mapping of VLA-1 from human T cell lines","pmids":["2415516"],"confidence":"High","gaps":["No ligand identified at this stage","Post-translational modification details beyond glycosylation unknown"]},{"year":1991,"claim":"Defining VLA-1's ligand specificity — collagens I–IV and laminin via a Ca²⁺/Mg²⁺-dependent, non-RGD mechanism — distinguished it from RGD-binding integrins and established the biochemical basis for its adhesive function.","evidence":"Purified VLA-1 reconstituted into liposomes tested for binding to multiple ECM substrates with peptide inhibition and divalent cation manipulation","pmids":["2229189","1807406"],"confidence":"High","gaps":["Structural basis for collagen versus laminin selectivity not resolved","No crystal structure of the I-domain/collagen interface"]},{"year":1994,"claim":"Demonstrating that Mg²⁺/Mn²⁺ support and Ca²⁺ inhibits VLA-1-mediated adhesion, and that inside-out activation occurs via β1 stimulatory antibodies, established the regulatory logic of VLA-1 activation in living cells.","evidence":"Cell adhesion assays with divalent cation manipulation and activating/blocking monoclonal antibodies on neuroblastoma and T cell lines","pmids":["7516898","8025956"],"confidence":"Medium","gaps":["Intracellular signaling pathways triggered by outside-in VLA-1 engagement not mapped","Inside-out activation signals from TCR to VLA-1 undefined"]},{"year":2000,"claim":"The first VLA-1-null mouse revealed a non-redundant role for α1β1 in maintaining gut intraepithelial lymphocyte numbers and collagen-dependent T cell proliferation, shifting understanding from a generic adhesion receptor to one with tissue-specific immune functions.","evidence":"Itga1-knockout mouse with flow cytometric enumeration of IELs and in vitro adhesion/proliferation assays","pmids":["10805967"],"confidence":"High","gaps":["Survival versus homing contribution to IEL reduction not distinguished","Downstream intracellular signals mediating proliferative support on collagen unknown"]},{"year":2004,"claim":"Demonstrating that VLA-1 is required for tissue retention of influenza-specific CD8⁺ memory T cells in the lung — with antibody blockade and KO yielding concordant results — established α1β1 as a master regulator of tissue-resident memory (TRM) positioning.","evidence":"Anti-α1 antibody blockade and Itga1-KO mice challenged with influenza; tissue-specific T cell enumeration and heterosubtypic immunity assay","pmids":["14975239"],"confidence":"High","gaps":["Whether VLA-1 actively signals survival or merely anchors cells not resolved","Relative contribution of collagen I versus IV binding to lung retention unclear"]},{"year":2007,"claim":"Identification of CpG methylation of 19 sites in the ITGA1 promoter as the epigenetic silencing mechanism during megakaryocyte differentiation, with SRF/CArG-box involvement, revealed how ITGA1 expression is lineage-restricted.","evidence":"Bisulfite sequencing, promoter-luciferase reporter, and 5-aza-2′-deoxycytidine demethylation rescue in megakaryocytic cells","pmids":["17669516"],"confidence":"High","gaps":["Which DNA methyltransferases target the ITGA1 promoter not identified","Whether methylation-based silencing operates in lymphocyte subsets unknown"]},{"year":2010,"claim":"Extending the TRM paradigm to CD4⁺ T cells, α1-null mice showed that VLA-1 is required for airway CD4⁺ memory accumulation and rapid IFN-γ recall, broadening its role beyond CD8⁺ TRM.","evidence":"Itga1-KO mice after influenza infection; airway and lymphoid tissue T cell enumeration, intracellular cytokine staining, apoptosis marker analysis","pmids":["20200271"],"confidence":"High","gaps":["Whether VLA-1 provides a direct anti-apoptotic signal in CD4⁺ TRM not mechanistically defined"]},{"year":2017,"claim":"Two discoveries addressed ITGA1's transcriptional control and cancer biology: E2F1 was shown to directly bind and activate the ITGA1 promoter, while ITGA1 was shown to be required for collagen-induced stemness, EMT, and gemcitabine resistance in pancreatic cancer.","evidence":"ChIP and dual-luciferase reporter for E2F1-ITGA1 promoter binding; siRNA/shRNA knockdown of ITGA1 with ALDH1 stem marker, EMT marker, and in vivo metastasis readouts","pmids":["28264467","28855593"],"confidence":"Medium","gaps":["Whether E2F1 regulation of ITGA1 operates in non-cancer contexts unknown","Direct versus collagen-mediated mechanism of gemcitabine resistance not dissected"]},{"year":2020,"claim":"Intravital imaging overturned the pure 'anchor' model by showing that VLA-1 facilitates T cell locomotion in tissues rather than immobilizing cells, reframing α1β1 as a motility-enabling receptor for local immune surveillance.","evidence":"In vitro motility assay and intravital two-photon imaging of virus-specific CD8⁺ T cells in lungs after influenza infection","pmids":["32439709"],"confidence":"Medium","gaps":["Molecular mechanism by which collagen engagement promotes motility not defined","Whether motility function is collagen-subtype-specific unknown"]},{"year":2021,"claim":"VLA-1-dependent binding to collagen IV was shown to sustain extended MDSC–T cell contacts required for immune suppression, identifying a collagen-subtype-specific function in immunoregulation beyond T cell–intrinsic roles.","evidence":"Itga1-KO MDSCs with intravital two-photon microscopy measuring contact duration and T cell suppression on collagen IV versus fibronectin substrates","pmids":["33584706"],"confidence":"High","gaps":["Whether other collagen-binding integrins compensate for VLA-1 loss on MDSCs not tested","Signal transduction within MDSCs downstream of VLA-1 ligation unknown"]},{"year":2023,"claim":"Three parallel advances defined new transcriptional regulators and a tissue-protective signaling role: RUNX2/3 were identified as required for IL-15/TGF-β-induced CD49a expression in TRM differentiation; genetic epistasis showed α1β1 normally dampens TGFβR2 signaling to protect cartilage from osteoarthritis; and GTF2B was shown to activate ITGA1 transcription downstream of a lncRNA/m6A axis, coupling ITGA1 to FAK-ERK signaling in pancreatic cancer.","evidence":"RUNX2/3 siRNA with ATAC-seq/RNA-seq in TRM; Itga1-KO × cartilage-specific Tgfbr2-KO double-mutant rescue in OA model; RNA pull-down and ChIP for GTF2B at ITGA1 promoter with FAK/ERK phosphorylation readout","pmids":["37269830","37649532","37293163"],"confidence":"High","gaps":["Direct physical mechanism by which α1β1 dampens TGFβR2 not identified","Whether RUNX2/3 regulation is specific to epidermal TRM or general to all TRM lineages unknown"]},{"year":2025,"claim":"Recent work extended ITGA1's roles to neuroinflammation and endothelial senescence: microglial Itga1 drives NLRP3 inflammasome activation via PGAM5 in Parkinson's disease models, ITGA1 signals through STAT3 in retinoblastoma, and KDM4C-mediated H3K9me3 demethylation at the ITGA1 promoter provides an additional epigenetic control layer in endothelial cells.","evidence":"Conditional microglial Itga1 KD with transcriptomics and NLRP3 assembly assay; ITGA1 KD with STAT3 agonist rescue in retinoblastoma; ChIP for H3K9me3 at ITGA1 promoter with KDM4C inhibition in HUVECs","pmids":["41462565","40939856","40778546"],"confidence":"Medium","gaps":["PGAM5 as a direct α1β1 effector versus indirect transcriptional target not resolved","Whether STAT3 is a general downstream effector of α1β1 across cell types unknown","KDM4C regulation of ITGA1 shown only in endothelial context"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of α1β1's dual collagen/laminin recognition; how α1β1 physically inhibits TGFβR2 signaling at the membrane; the intracellular signaling cascade linking collagen engagement to T cell motility; and whether the diverse downstream pathways (FAK-ERK, STAT3, PGAM5-NLRP3) reflect cell-type-specific rewiring or a shared proximal signaling node.","evidence":"Open questions from the cumulative literature","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of full-length α1β1 in complex with collagen","No reconstituted signaling cascade from VLA-1 ligation to TRM motility","Interplay between epigenetic regulators (CpG methylation, KDM4C/H3K9me3) and transcription factors (E2F1, RUNX2/3, TEAD1) at the ITGA1 locus not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,4,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[14,24,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,4,6]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,2,12]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,13,14,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[24,27,28]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2,8]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,6,21]}],"complexes":["α1β1 integrin (VLA-1)"],"partners":["ITGB1","FAK","STAT3","SRF","E2F1","RUNX2","RUNX3","TEAD1"],"other_free_text":[]},"mechanistic_narrative":"ITGA1 encodes the α1 subunit of the collagen- and laminin-binding integrin α1β1 (VLA-1/CD49a), a heterodimeric receptor that mediates divalent-cation-dependent (Mg²⁺/Mn²⁺-supported, Ca²⁺-inhibited), RGD-independent adhesion to collagens I–IV and laminin, coupling extracellular matrix engagement to intracellular FAK-ERK and STAT3 signaling [PMID:2229189, PMID:1807406, PMID:37293163, PMID:40939856]. In the immune system, α1β1 is essential for tissue retention, locomotion, and effector function of memory/resident T cells and NK cells in non-lymphoid organs, and it sustains MDSC–T cell suppressive contacts on collagen IV substrates [PMID:14975239, PMID:20200271, PMID:32439709, PMID:33584706]. ITGA1 transcription is controlled by CpG promoter methylation, SRF/CArG-box binding, and the transcription factors E2F1, TEAD1, RUNX2/RUNX3, and GTF2B, with KDM4C-mediated H3K9me3 demethylation providing an additional epigenetic layer [PMID:17669516, PMID:28264467, PMID:37269830, PMID:38169150, PMID:40778546]. In cartilage, α1β1 normally dampens TGFβR2 signaling to protect against osteoarthritis, as demonstrated by genetic epistasis in Itga1-null mice [PMID:37649532]."},"prefetch_data":{"uniprot":{"accession":"P56199","full_name":"Integrin alpha-1","aliases":["CD49 antigen-like family member A","Laminin and collagen receptor","VLA-1"],"length_aa":1179,"mass_kda":130.8,"function":"Integrin alpha-1/beta-1 is a receptor for laminin and collagen. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. 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The alpha1 and beta subunits each contain substantial sialic acid and N-linked carbohydrate, and are non-homologous to each other by one-dimensional peptide mapping.\",\n      \"method\": \"Immunoprecipitation, chemical cross-linking, neuraminidase/endoglycosidase F digestion, 1D peptide mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution/characterization with multiple orthogonal methods in a foundational study\",\n      \"pmids\": [\"2415516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"VLA-1 integrin purified from human smooth muscle by collagen-Sepharose affinity chromatography mediates adhesion to type I, II, III, and IV collagens, C1q, and laminin in a Ca2+/Mg2+-dependent manner, but does not bind gelatin, fibronectin, or thrombospondin, establishing the substrate specificity of ITGA1-containing integrin.\",\n      \"method\": \"Affinity chromatography purification, liposome adhesion assay, inhibition with divalent cations, immunoblotting\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified protein and functional adhesion assay, multiple substrates tested\",\n      \"pmids\": [\"2229189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Purified VLA-1 from human smooth muscle interacts via a Ca2+/Mg2+-dependent mechanism with interstitial collagens I, II, and III and basement membrane proteins (collagen IV and laminin) but not with fibronectin, thrombospondin, or albumin; denaturation of collagen I reduces binding 5-7-fold, and GRGDSP peptide does not inhibit binding, indicating a non-RGD-dependent collagen-binding mechanism.\",\n      \"method\": \"Affinity chromatography purification, liposome binding assay, substrate denaturation, peptide inhibition\",\n      \"journal\": \"Biokhimiia (Moscow, Russia)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted adhesion with purified integrin, mechanistic substrate specificity defined\",\n      \"pmids\": [\"1807406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"VLA-1-mediated adhesion of neuroblastoma NB100 cells to collagen type I is supported by Mg2+ or Mn2+ but not Ca2+ alone; Ca2+ inhibits Mg2+-supported adhesion. VLA-1 can be directly activated by the stimulatory anti-beta1 monoclonal antibody TS2/16, demonstrating inside-out and outside-in regulation of integrin activity.\",\n      \"method\": \"Cell adhesion assay with divalent cation manipulation, blocking and activating monoclonal antibodies, novel blocking anti-alpha1 mAb 5E8D9\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean functional adhesion assay with pharmacological manipulation and antibody tools, single lab\",\n      \"pmids\": [\"7516898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"VLA-1 (CD49a/alpha1beta1) on long-term activated human T lymphocytes functions as a specific collagen IV receptor; antibody blockade of CD49a inhibits adhesion to collagen IV by ~94% and collagen I by ~82%, and ligation of VLA-1 induces spreading on collagen IV in a Mg2+-dependent manner and can signal IL-2 receptor expression in gamma-delta T cells.\",\n      \"method\": \"Radiolabeled adhesion assay, blocking monoclonal antibody (1B3.1), cell spreading morphology, IL-2R induction readout\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — blocking antibody adhesion assay with defined readouts, single lab\",\n      \"pmids\": [\"8025956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Glomerular epithelial cells use VLA-1 and VLA-2 cooperatively for adhesion to laminin but rely on VLA-2 alone for collagen adhesion, whereas mesangial cells use VLA-1 for laminin adhesion and both VLA-1 and VLA-2 for collagen, demonstrating cell-type-specific modulation of VLA-1 ligand-binding specificity.\",\n      \"method\": \"Blocking monoclonal antibodies against rat VLA-1 and VLA-2, cell adhesion assay to ECM proteins, ELISA and immunocytochemistry\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional blocking antibody experiments in two cell types, single lab\",\n      \"pmids\": [\"7898055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Integrin alpha1beta1 (VLA-1) is the primary collagen receptor on human intestinal intraepithelial lymphocytes (IELs); antibody blockade of both alpha1 (CD49a) and beta1 subunits inhibited adhesion to collagen I by 82% and collagen IV by 94%, and adhesion was dependent on extracellular divalent cations (Mg2+ and Mn2+ supported; Ca2+ inhibited) and upregulated by PKC stimulation.\",\n      \"method\": \"51Cr-labelled lymphocyte adhesion assay, blocking antibodies, divalent cation manipulation, phorbol ester/staurosporine treatment\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional adhesion assay with blocking antibodies and mechanistic dissection of cation dependence\",\n      \"pmids\": [\"10457223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"VLA-1 (integrin alpha1beta1) is required for normal numbers of gut intraepithelial lymphocytes; VLA1-null mice show ~50% reduction in intestinal IELs despite normal peripheral lymphocyte distribution, and IL-2-stimulated VLA1-null splenocytes show deficient adhesion to fibrillar and basement membrane collagen and reduced proliferation on collagen substrate.\",\n      \"method\": \"Genetic knockout mouse (VLA1-null), flow cytometry, adhesion assay, proliferation assay\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific cellular phenotype and in vitro adhesion/proliferation readouts\",\n      \"pmids\": [\"10805967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VLA-1 (alpha1beta1 integrin) mediates both glomerular and interstitial fibrosis in crescentic glomerulonephritis; delayed antibody blockade of VLA-1 reduced glomerular and tubulointerstitial scarring, decreased type IV collagen and ED-A fibronectin deposition, and increased MMP-9 expression in the glomeruli of treated rats.\",\n      \"method\": \"Anti-VLA-1 antibody treatment (Ha31/8) in rat nephrotoxic nephritis model, immunohistochemistry, serum creatinine, Kaplan-Meier renal survival\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo antibody blockade with defined fibrosis phenotype and MMP-9 mechanistic readout, single lab\",\n      \"pmids\": [\"12368200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VLA-1 (alpha1beta1 integrin) expression marks a stable phenotypic subset of human CD4+ memory T cells enriched for Th1 cytokine production; VLA-1+ CD4+ T cells are selectively enriched for recall antigen-responsive cells, and depletion of the small VLA-1+ fraction from CD4+ PBLs significantly abrogated the proliferative response to recall antigens.\",\n      \"method\": \"Flow cytometry, T cell depletion and reconstitution, recall antigen proliferation assay, cytokine polarization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — depletion experiment with defined functional readout (recall antigen proliferation), single lab\",\n      \"pmids\": [\"14597770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The collagen-binding alpha1beta1 integrin (VLA-1/CD49a) is responsible for retention of influenza-specific CD8 memory T cells in the lung and other nonlymphoid tissues; antibody blockade or genetic deficiency of VLA-1 decreased virus-specific CTL in lung/nonlymphoid tissues and increased them in spleen, and impaired secondary heterosubtypic immunity.\",\n      \"method\": \"Antibody blockade and genetic KO mouse model, flow cytometry of tissue-specific T cells, heterosubtypic challenge model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent approaches (antibody and KO) with defined tissue retention and immunity phenotypes\",\n      \"pmids\": [\"14975239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The ITGA1 promoter contains a CArG box bound by serum response factor (SRF). Selective CpG methylation of a CpG-rich ITGA1 promoter region is the epigenetic mechanism suppressing ITGA1 expression during megakaryocyte differentiation; 5-aza-2'-deoxycytidine (but not trichostatin A) induced de novo ITGA1 expression in megakaryocytic cells, and progressive CpG methylation at 19 CpG sites occurs during thrombopoietin-induced megakaryocyte differentiation.\",\n      \"method\": \"Sodium bisulfite genomic sequencing, promoter-LUC reporter transfection, 5-aza-CdR treatment, mRNA expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequencing of methylation status combined with functional reporter assay and pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"17669516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CD49a (alpha1beta1) and CD49b (alpha2beta1) show reciprocal expression on CD8 and CD4 T cells in influenza-infected lung, correlating with distinct spatial localizations: CD8+ T cells associate with collagen IV-rich basement membranes of airways/blood vessels, while CD4+ T cells localize in collagen I-rich interstitial spaces.\",\n      \"method\": \"Flow cytometry, immunofluorescent tissue analysis of collagen distribution and T cell localization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — correlative localization with defined spatial mechanistic implication, single lab\",\n      \"pmids\": [\"17372009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"VLA-1 (CD49a/alpha1beta1) is required for the accumulation and maintenance of a tissue-memory CD4+ T cell population in the airways after influenza infection; alpha1-/- mice showed fewer memory/effector CD4+ T cells in airways (but not lymphoid tissues), and CD49a+ airway CD4+ T cells were enriched for early IFN-gamma secretion upon secondary challenge and showed reduced apoptosis markers.\",\n      \"method\": \"Alpha1-/- knockout mice, flow cytometry, intracellular cytokine staining, apoptosis markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with tissue-specific phenotype and functional effector readout, clean experimental design\",\n      \"pmids\": [\"20200271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CD49a promotes T-cell-mediated hepatitis; CD49a-/- mice were protected from ConA-induced hepatitis with significantly reduced serum ALT and decreased IFN-gamma and IL-17A production. CD49a blockade in vivo ameliorated hepatitis with reduced inflammatory cytokine production by CD4+ T and invariant NKT cells.\",\n      \"method\": \"CD49a-/- knockout mouse, ConA-induced hepatitis model, serum ALT, intracellular cytokine staining, in vivo antibody blockade\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and antibody blockade with defined inflammatory phenotype, two orthogonal approaches\",\n      \"pmids\": [\"24164540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TGF-beta and IL-12 induce CD49a expression by CD8+ T cells in vitro; CD49a is expressed early following T cell activation in vivo but is not required for generation of a primary CD8+ T cell response to cutaneous HSV infection or migration across epidermal basement membrane. Rather, CD49a supports CD8+ TRM persistence in skin, regulates epidermal TRM dendritic extensions, and increases the frequency of IFN-gamma+ CD8+ TRM following local antigen challenge.\",\n      \"method\": \"In vitro cytokine stimulation, CD49a KO mouse, cutaneous HSV infection model, flow cytometry, intravital imaging of dendritic extensions\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple defined functional readouts (persistence, morphology, antigen recall), single lab with orthogonal methods\",\n      \"pmids\": [\"32877667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ITGA1 is required for collagen-induced tumorigenic potential in pancreatic ductal adenocarcinoma cells; ITGA1 depletion revealed it promotes survival of ALDH1-positive stem-like cells, cooperates with TGF-beta to drive gemcitabine resistance, and is required for TGF-beta/collagen-induced EMT and metastasis.\",\n      \"method\": \"ITGA1 siRNA/shRNA knockdown, collagen adhesion/invasion assays, ALDH1 stem cell marker analysis, gemcitabine resistance assay, EMT marker western blot, in vivo metastasis model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple defined phenotypic readouts, single lab\",\n      \"pmids\": [\"28855593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E2F1 transcription factor directly upregulates ITGA1 expression; dual luciferase reporter assay and chromatin immunoprecipitation showed E2F1 binds the ITGA1 promoter to activate transcription, and d-ICD treatment inhibits E2F1 expression, thereby reducing ITGA1 levels and suppressing HCC cell migration and invasion.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), qRT-PCR, western blot, wound healing and transwell invasion assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — ChIP and reporter assay demonstrate direct E2F1-ITGA1 promoter interaction, single lab\",\n      \"pmids\": [\"28264467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD49a on decidual NK cells regulates their cytotoxic activity, migration, and adhesion; neutralization of CD49a with blocking antibody increased perforin, granzyme B, and IFN-gamma expression, increased killing activity in 51Cr release assay, and decreased migration and adhesion of dNK cells. A newly identified lncRNA (lnc-49a) was identified as a positive regulator of CD49a expression in primary human NK cells.\",\n      \"method\": \"CD49a neutralizing antibody, flow cytometry, 51Cr release cytotoxicity assay, migration and adhesion assay, lncRNA microarray analysis\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade with multiple functional readouts and identification of upstream lncRNA regulator\",\n      \"pmids\": [\"30756436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD49a (VLA-1) facilitates locomotion of virus-specific CD8 T cells both in vitro and in vivo in the pulmonary system after influenza infection, contrary to an expected pure retention function; CD49a facilitates T cell motility rather than immobilizing cells, potentially contributing to local surveillance.\",\n      \"method\": \"In vitro motility assay, intravital imaging (in vivo), flow cytometry of TRM phenotype development\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct motility measurement in vitro and in vivo, single lab\",\n      \"pmids\": [\"32439709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD49a expression on tumor-infiltrating CD8+ T cells increases their motility in the tumor microenvironment, particularly in proximity to tumor cells, suggesting CD49a may interfere with productive TCR engagement of tumor cells; expression of CD49a was driven by antigen-independent elements in the TME and further increased by TCR stimulation.\",\n      \"method\": \"Live tumor slice imaging of T cell motility, flow cytometry, Nur77 reporter for TCR engagement, short-term CD49a blockade\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct live imaging of motility with mechanistic dissection, single lab\",\n      \"pmids\": [\"33619119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"VLA-1 binding to collagen IV provides the substrate for extended contact times between myeloid-derived suppressor cells (MDSCs) and effector CD4+ T cells required for T cell suppression; Itga1-/- A-MDSCs showed equivalent splenic homing but shorter interaction times with Teff on collagen IV (but not fibronectin) and reduced suppressive capacity, as measured by T cell proliferation inhibition and apoptosis induction.\",\n      \"method\": \"Itga1-/- genetic KO, in vitro suppression assay on collagen IV vs. fibronectin substrate, intravital two-photon microscopy, T cell proliferation and apoptosis assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + intravital two-photon microscopy with quantitative interaction time measurement, mechanistic link to suppression\",\n      \"pmids\": [\"33584706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RUNX2 and RUNX3 transcription factors are required for IL-15/TGF-beta-induced CD49a expression and the cytotoxic transcriptional profile in circulating CD8+ T cells differentiating toward epidermal TRM cells; RUNX-binding motifs are enriched in epidermal CD8+CD103+CD49a+ TRM cells and RUNX2/RUNX3 protein is highly expressed in this population.\",\n      \"method\": \"RUNX2/3 siRNA knockdown, in vitro stimulation with IL-15+TGF-beta, flow cytometry, RNA-seq transcriptional profiling, ATAC-seq motif enrichment, single-cell paired skin/blood clonotype analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — loss-of-function (siRNA) + transcriptomics + chromatin accessibility, multiple orthogonal methods\",\n      \"pmids\": [\"37269830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGA1 loss in cartilage increases TGFBR2 signaling, and this enhanced TGFBR2 signaling drives early and more severe knee osteoarthritis in itga1-null mice; cartilage-specific depletion of TGFBR2 in itga1-null mice attenuated OA progression, establishing an epistatic relationship where integrin alpha1beta1 normally dampens TGFBR2 signaling to protect against OA.\",\n      \"method\": \"Itga1-/- global KO mouse, tamoxifen-inducible cartilage-specific TGFBR2 depletion (double-mutant epistasis), histological OA scoring, behavioral pain assessment, longitudinal study\",\n      \"journal\": \"Osteoarthritis and cartilage open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis (double-mutant rescue) with defined tissue-specific phenotype\",\n      \"pmids\": [\"37649532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Linc00662 recruits GTF2B to activate ITGA1 transcription in a m6A-dependent manner; ITGA1 then initiates focal adhesion formation through the ITGA1-FAK-ERK pathway, promoting malignant behavior in pancreatic cancer cells. FAK inhibitor Y15 suppressed tumor progression in Linc00662-overexpressing cells.\",\n      \"method\": \"RNA pull-down, co-IP, ChIP showing GTF2B at ITGA1 promoter, western blot for FAK/ERK phosphorylation, in vitro invasion/migration, in vivo xenograft\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and co-IP with defined downstream signaling readout, single lab\",\n      \"pmids\": [\"37293163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TEAD1 is a key transcriptional regulator of ITGA1 (and ITGA2) expression in prostate cancer cells; TEAD1 loss phenocopies dual ITGA1/ITGA2 deletion in promoting EMT via enhanced TGF-beta1 secretion/autocrine activation and nuclear YAP1 targeting. Genomic deletion of both ITGA1 and ITGA2 activates EMT and converts benign prostate epithelial cells into tumorigenic cells in vivo.\",\n      \"method\": \"TEAD1 siRNA knockdown, ITGA1/ITGA2 genomic deletion, genome-wide co-expression analysis, EMT assay, TGF-beta1 ELISA, YAP1 nuclear localization, in vivo tumorigenicity assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with mechanistic pathway dissection (TEAD1→ITGA1→TGFβ1→YAP1→EMT), single lab\",\n      \"pmids\": [\"38169150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Microglial CD49a (Itga1) drives neuroinflammation in Parkinson's disease models through PGAM5 as a central regulatory node; microglial Itga1 knockdown attenuates hyperreactivity, ameliorates mitochondrial dysfunction, suppresses NLRP3 inflammasome assembly via PGAM5 downregulation, and preserves dopaminergic neurons. The disintegrin polypeptide obtustatin specifically antagonizes microglial CD49a, suppressing neuroinflammation and improving motor deficits.\",\n      \"method\": \"Conditional microglial Itga1 knockdown, transcriptomic profiling of isolated microglia, mitochondrial function assay, NLRP3 inflammasome assembly assay, PD mouse models, obtustatin pharmacological antagonism\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KD with transcriptomics and multiple mechanistic readouts (PGAM5, NLRP3, mitochondria), single lab\",\n      \"pmids\": [\"41462565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ITGA1 knockdown or pharmacological inhibition with obtustatin impairs retinoblastoma cell proliferation, migration, and clonogenicity; STAT3 was identified as a key downstream mediator of ITGA1 signaling, and a STAT3 agonist (ML115) partially rescued the inhibitory effects of ITGA1 suppression. ITGA1 partners with ITGB1 in retinoblastoma cells.\",\n      \"method\": \"Lentiviral ITGA1 knockdown, obtustatin treatment, transcriptome analysis, western blot, STAT3 agonist rescue, in vivo xenograft model\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with rescue experiment identifying downstream signaling pathway, single lab\",\n      \"pmids\": [\"40939856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Luteolin suppresses ITGA1 transcription in endothelial cells by inhibiting KDM4C-mediated demethylation of H3K9me3 at the ITGA1 promoter; ITGA1 knockdown improved AGEs-induced senescent HUVEC functional impairments (proliferation, migration, tube formation) and reduced senescence markers, while ITGA1 overexpression abrogated luteolin's protective effects. The EGFR/MEK/ERK pathway is downstream of ITGA1 in this context.\",\n      \"method\": \"ITGA1 siRNA knockdown, ITGA1 overexpression, ChIP for H3K9me3 at ITGA1 promoter, KDM4C inhibition, EGFR/MEK/ERK western blot, in vivo diabetic wound model\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for epigenetic mark + loss/gain of function with mechanistic pathway (KDM4C→H3K9me3→ITGA1→EGFR/ERK), single lab\",\n      \"pmids\": [\"40778546\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA1 (CD49a) encodes the alpha1 subunit of the heterodimeric integrin VLA-1 (alpha1beta1), which binds collagen I–IV and laminin via a divalent cation-dependent (Mg2+/Mn2+-promoted, Ca2+-inhibited), non-RGD mechanism; its expression is epigenetically controlled by CpG methylation of its promoter (regulated by SRF/CArG and KDM4C/H3K9me3) and transcriptionally by E2F1, TEAD1, RUNX2/RUNX3, and GTF2B, while functionally it mediates tissue retention and locomotion of memory T cells and tissue-resident NK cells in non-lymphoid tissues, dampens TGFβR2 signaling in cartilage to protect against osteoarthritis, promotes MDSC-T cell suppressive contacts via collagen IV binding, drives inflammatory cytokine production by T and NKT cells, and activates FAK-ERK and STAT3 downstream signaling pathways to promote cancer cell invasion, EMT, and therapy resistance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ITGA1 encodes the α1 subunit of the collagen- and laminin-binding integrin α1β1 (VLA-1/CD49a), a heterodimeric receptor that mediates divalent-cation-dependent (Mg²⁺/Mn²⁺-supported, Ca²⁺-inhibited), RGD-independent adhesion to collagens I–IV and laminin, coupling extracellular matrix engagement to intracellular FAK-ERK and STAT3 signaling [PMID:2229189, PMID:1807406, PMID:37293163, PMID:40939856]. In the immune system, α1β1 is essential for tissue retention, locomotion, and effector function of memory/resident T cells and NK cells in non-lymphoid organs, and it sustains MDSC–T cell suppressive contacts on collagen IV substrates [PMID:14975239, PMID:20200271, PMID:32439709, PMID:33584706]. ITGA1 transcription is controlled by CpG promoter methylation, SRF/CArG-box binding, and the transcription factors E2F1, TEAD1, RUNX2/RUNX3, and GTF2B, with KDM4C-mediated H3K9me3 demethylation providing an additional epigenetic layer [PMID:17669516, PMID:28264467, PMID:37269830, PMID:38169150, PMID:40778546]. In cartilage, α1β1 normally dampens TGFβR2 signaling to protect against osteoarthritis, as demonstrated by genetic epistasis in Itga1-null mice [PMID:37649532].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing that VLA-1 is a heterodimer of distinct α1 (~210 kDa) and β1 (~130 kDa) glycoprotein subunits resolved the molecular identity of what would become the founding collagen-binding integrin.\",\n      \"evidence\": \"Immunoprecipitation, chemical cross-linking, glycosidase digestion, and peptide mapping of VLA-1 from human T cell lines\",\n      \"pmids\": [\"2415516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand identified at this stage\", \"Post-translational modification details beyond glycosylation unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Defining VLA-1's ligand specificity — collagens I–IV and laminin via a Ca²⁺/Mg²⁺-dependent, non-RGD mechanism — distinguished it from RGD-binding integrins and established the biochemical basis for its adhesive function.\",\n      \"evidence\": \"Purified VLA-1 reconstituted into liposomes tested for binding to multiple ECM substrates with peptide inhibition and divalent cation manipulation\",\n      \"pmids\": [\"2229189\", \"1807406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for collagen versus laminin selectivity not resolved\", \"No crystal structure of the I-domain/collagen interface\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that Mg²⁺/Mn²⁺ support and Ca²⁺ inhibits VLA-1-mediated adhesion, and that inside-out activation occurs via β1 stimulatory antibodies, established the regulatory logic of VLA-1 activation in living cells.\",\n      \"evidence\": \"Cell adhesion assays with divalent cation manipulation and activating/blocking monoclonal antibodies on neuroblastoma and T cell lines\",\n      \"pmids\": [\"7516898\", \"8025956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular signaling pathways triggered by outside-in VLA-1 engagement not mapped\", \"Inside-out activation signals from TCR to VLA-1 undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The first VLA-1-null mouse revealed a non-redundant role for α1β1 in maintaining gut intraepithelial lymphocyte numbers and collagen-dependent T cell proliferation, shifting understanding from a generic adhesion receptor to one with tissue-specific immune functions.\",\n      \"evidence\": \"Itga1-knockout mouse with flow cytometric enumeration of IELs and in vitro adhesion/proliferation assays\",\n      \"pmids\": [\"10805967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Survival versus homing contribution to IEL reduction not distinguished\", \"Downstream intracellular signals mediating proliferative support on collagen unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that VLA-1 is required for tissue retention of influenza-specific CD8⁺ memory T cells in the lung — with antibody blockade and KO yielding concordant results — established α1β1 as a master regulator of tissue-resident memory (TRM) positioning.\",\n      \"evidence\": \"Anti-α1 antibody blockade and Itga1-KO mice challenged with influenza; tissue-specific T cell enumeration and heterosubtypic immunity assay\",\n      \"pmids\": [\"14975239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VLA-1 actively signals survival or merely anchors cells not resolved\", \"Relative contribution of collagen I versus IV binding to lung retention unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of CpG methylation of 19 sites in the ITGA1 promoter as the epigenetic silencing mechanism during megakaryocyte differentiation, with SRF/CArG-box involvement, revealed how ITGA1 expression is lineage-restricted.\",\n      \"evidence\": \"Bisulfite sequencing, promoter-luciferase reporter, and 5-aza-2′-deoxycytidine demethylation rescue in megakaryocytic cells\",\n      \"pmids\": [\"17669516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which DNA methyltransferases target the ITGA1 promoter not identified\", \"Whether methylation-based silencing operates in lymphocyte subsets unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extending the TRM paradigm to CD4⁺ T cells, α1-null mice showed that VLA-1 is required for airway CD4⁺ memory accumulation and rapid IFN-γ recall, broadening its role beyond CD8⁺ TRM.\",\n      \"evidence\": \"Itga1-KO mice after influenza infection; airway and lymphoid tissue T cell enumeration, intracellular cytokine staining, apoptosis marker analysis\",\n      \"pmids\": [\"20200271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VLA-1 provides a direct anti-apoptotic signal in CD4⁺ TRM not mechanistically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two discoveries addressed ITGA1's transcriptional control and cancer biology: E2F1 was shown to directly bind and activate the ITGA1 promoter, while ITGA1 was shown to be required for collagen-induced stemness, EMT, and gemcitabine resistance in pancreatic cancer.\",\n      \"evidence\": \"ChIP and dual-luciferase reporter for E2F1-ITGA1 promoter binding; siRNA/shRNA knockdown of ITGA1 with ALDH1 stem marker, EMT marker, and in vivo metastasis readouts\",\n      \"pmids\": [\"28264467\", \"28855593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether E2F1 regulation of ITGA1 operates in non-cancer contexts unknown\", \"Direct versus collagen-mediated mechanism of gemcitabine resistance not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Intravital imaging overturned the pure 'anchor' model by showing that VLA-1 facilitates T cell locomotion in tissues rather than immobilizing cells, reframing α1β1 as a motility-enabling receptor for local immune surveillance.\",\n      \"evidence\": \"In vitro motility assay and intravital two-photon imaging of virus-specific CD8⁺ T cells in lungs after influenza infection\",\n      \"pmids\": [\"32439709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which collagen engagement promotes motility not defined\", \"Whether motility function is collagen-subtype-specific unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"VLA-1-dependent binding to collagen IV was shown to sustain extended MDSC–T cell contacts required for immune suppression, identifying a collagen-subtype-specific function in immunoregulation beyond T cell–intrinsic roles.\",\n      \"evidence\": \"Itga1-KO MDSCs with intravital two-photon microscopy measuring contact duration and T cell suppression on collagen IV versus fibronectin substrates\",\n      \"pmids\": [\"33584706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other collagen-binding integrins compensate for VLA-1 loss on MDSCs not tested\", \"Signal transduction within MDSCs downstream of VLA-1 ligation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Three parallel advances defined new transcriptional regulators and a tissue-protective signaling role: RUNX2/3 were identified as required for IL-15/TGF-β-induced CD49a expression in TRM differentiation; genetic epistasis showed α1β1 normally dampens TGFβR2 signaling to protect cartilage from osteoarthritis; and GTF2B was shown to activate ITGA1 transcription downstream of a lncRNA/m6A axis, coupling ITGA1 to FAK-ERK signaling in pancreatic cancer.\",\n      \"evidence\": \"RUNX2/3 siRNA with ATAC-seq/RNA-seq in TRM; Itga1-KO × cartilage-specific Tgfbr2-KO double-mutant rescue in OA model; RNA pull-down and ChIP for GTF2B at ITGA1 promoter with FAK/ERK phosphorylation readout\",\n      \"pmids\": [\"37269830\", \"37649532\", \"37293163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical mechanism by which α1β1 dampens TGFβR2 not identified\", \"Whether RUNX2/3 regulation is specific to epidermal TRM or general to all TRM lineages unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work extended ITGA1's roles to neuroinflammation and endothelial senescence: microglial Itga1 drives NLRP3 inflammasome activation via PGAM5 in Parkinson's disease models, ITGA1 signals through STAT3 in retinoblastoma, and KDM4C-mediated H3K9me3 demethylation at the ITGA1 promoter provides an additional epigenetic control layer in endothelial cells.\",\n      \"evidence\": \"Conditional microglial Itga1 KD with transcriptomics and NLRP3 assembly assay; ITGA1 KD with STAT3 agonist rescue in retinoblastoma; ChIP for H3K9me3 at ITGA1 promoter with KDM4C inhibition in HUVECs\",\n      \"pmids\": [\"41462565\", \"40939856\", \"40778546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PGAM5 as a direct α1β1 effector versus indirect transcriptional target not resolved\", \"Whether STAT3 is a general downstream effector of α1β1 across cell types unknown\", \"KDM4C regulation of ITGA1 shown only in endothelial context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of α1β1's dual collagen/laminin recognition; how α1β1 physically inhibits TGFβR2 signaling at the membrane; the intracellular signaling cascade linking collagen engagement to T cell motility; and whether the diverse downstream pathways (FAK-ERK, STAT3, PGAM5-NLRP3) reflect cell-type-specific rewiring or a shared proximal signaling node.\",\n      \"evidence\": \"Open questions from the cumulative literature\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of full-length α1β1 in complex with collagen\", \"No reconstituted signaling cascade from VLA-1 ligation to TRM motility\", \"Interplay between epigenetic regulators (CpG methylation, KDM4C/H3K9me3) and transcription factors (E2F1, RUNX2/3, TEAD1) at the ITGA1 locus not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 4, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [14, 24, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 6]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 13, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [24, 27, 28]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 6, 21]}\n    ],\n    \"complexes\": [\n      \"α1β1 integrin (VLA-1)\"\n    ],\n    \"partners\": [\n      \"ITGB1\",\n      \"FAK\",\n      \"STAT3\",\n      \"SRF\",\n      \"E2F1\",\n      \"RUNX2\",\n      \"RUNX3\",\n      \"TEAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}