{"gene":"ITGB1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2003,"finding":"Galectin-3 binds to CD29 (ITGB1) on the cell surface and induces T-cell apoptosis via mitochondrial pathway, including cytochrome c release and caspase-3 activation (but not caspase-8 activation), in a carbohydrate-dependent manner.","method":"Antibody blocking, lactose inhibition assay, co-immunoprecipitation, apoptosis assays (cytochrome c release, caspase activation)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification by binding assay with sugar inhibitor controls, functional apoptosis readout, single lab","pmids":["14678989"],"is_preprint":false},{"year":1993,"finding":"CD29 (ITGB1) engagement by soluble anti-CD29 mAb K20 suppresses T-cell proliferation by reducing diacylglycerol and phosphatidic acid levels in CD3-activated T cells, without affecting PIP2 hydrolysis, cytosolic Ca2+ or inositolphosphates, and independently of IL-2 receptor engagement.","method":"Phospholipid metabolite measurement (DAG, PA, PE), proliferation assay, IL-2 rescue experiment in Jurkat and primary CD4+ T cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical measurement of phospholipid metabolism with multiple metabolites tested, single lab","pmids":["7686929"],"is_preprint":false},{"year":1995,"finding":"Mouse CD29 (ITGB1, beta1 integrin subunit) mediates cell adhesion to extracellular matrix proteins collagen, laminin, and fibronectin; blocking CD29 in combination with anti-LFA-1 inhibits T cell proliferation induced by anti-CD3 and allogeneic MLR.","method":"mAb generation, immunoprecipitation, cell adhesion blocking assay, T-cell proliferation assay","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking with defined mAb, multiple readouts (adhesion + proliferation), single lab","pmids":["7547709"],"is_preprint":false},{"year":1992,"finding":"ITGB1 (CD29) engagement by immobilized anti-CD49d (alpha4) mAb potentiates T-cell proliferation via anti-CD3; soluble anti-CD29 mAb inhibits this VLA-4-mediated co-stimulation of T cells.","method":"Immobilized mAb proliferation assay, soluble antibody inhibition","journal":"Journal of leukocyte biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay, single lab, no biochemical mechanistic follow-up","pmids":["1383369"],"is_preprint":false},{"year":2011,"finding":"CD29 (ITGB1) and CD73 mediate mechanically-induced decrease in MSC migration; specific inhibition of CD29/CD73 demonstrates their substrate-dependent involvement in post-loading migration, with FAK and Src-family kinases identified as downstream targets.","method":"Mechanical loading, specific antibody inhibition, scanning electron microscopy, phalloidin staining (actin), FAK/Src kinase analysis","journal":"European cells & materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional inhibition, morphological imaging, kinase phosphorylation), single lab","pmids":["21732280"],"is_preprint":false},{"year":2011,"finding":"CD29 (ITGB1) activation in neonatal rat cardiomyocytes induces an NOX2/p47(phox)-dependent reactive oxygen species burst and activates MEK/ERK and PI3K/Akt pro-survival pathways; NOX2-deficient cardiomyocytes lose CD29-induced pro-survival signaling.","method":"Flow cytometry (ROS), lucigenin chemiluminescence (NOX activity), adenoviral overexpression of antioxidants, NOX2 knockout mouse cardiomyocytes, pharmacological inhibition","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological inhibition, antioxidant overexpression), replicated across genetic and pharmacological approaches in the same study","pmids":["22198504"],"is_preprint":false},{"year":2012,"finding":"The CD49d/CD29 (ITGB1) integrin complex constitutively associates with CD38 in CLL cells; CD38 enhances CD49d/CD29-mediated cell adhesion to VCAM-1 and fibronectin substrates, with CD49d+CD38+ cells showing higher Vav-1 phosphorylation, more complex F-actin distribution at adhesion sites, and greater apoptosis resistance.","method":"Co-capping, co-immunoprecipitation, cell adhesion assay on CD49d-specific substrates, CD38 transfection, phospho-Vav-1 Western blot, F-actin staining","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, co-capping, functional adhesion rescue with CD38 transfectants, multiple orthogonal methods in one study","pmids":["22289918"],"is_preprint":false},{"year":2019,"finding":"TIMP-1 signals through its receptor CD63 to ITGB1 (CD29), activating FAK (and associated kinases SRC and PI3K), which drives hypermotility of Toxoplasma gondii-infected dendritic cells; shRNA silencing of ITGB1 or FAK, or antibody blockade of ITGB1, abrogated DC hypermotility.","method":"shRNA gene silencing (TIMP-1, CD63, ITGB1, FAK), antibody blockade, pharmacological inhibition of FAK/SRC/PI3K, live-cell migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal silencing approaches (shRNA + antibody blockade) with pharmacological validation, single lab, multiple genetic targets confirmed","pmids":["30635444"],"is_preprint":false},{"year":2013,"finding":"SOX10 transcriptionally regulates beta1-integrin (ITGB1) expression; compound heterozygous Sox10/beta1-integrin mutant mice show more severe intestinal aganglionosis and enteric neural crest cell migration defects (reduced speed and altered directionality) than single mutants, establishing a cooperative genetic interaction.","method":"Mouse genetic epistasis (double mutant cross), video-microscopy of neural crest cell migration, gene expression analysis in Sox10 mutant mice","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — classic genetic epistasis with double mutant phenotype exceeding single mutants, live imaging validation, in vivo","pmids":["23608456"],"is_preprint":false},{"year":2015,"finding":"CD29 (ITGB1) overexpression in hepatocellular carcinoma cells activates ILK, increases Akt Ser473 phosphorylation and mTORC1 expression, induces EMT (decreased E-cadherin, increased fibronectin and vimentin), and confers resistance to radiation and cisplatin; CD29 silencing sensitizes tumors to these treatments.","method":"Adenoviral CD29 overexpression/shRNA silencing, xenograft mouse model, Western blot (ILK, Akt, EMT markers), MTT cell viability","journal":"Medical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic gain/loss of function with in vivo xenograft, pathway protein readouts, single lab","pmids":["25805567"],"is_preprint":false},{"year":2018,"finding":"ITGB1 is an upstream regulator of Caveolin-1 (CAV1) expression in prostate cancer cells; ITGB1 and integrin-associated proteins were identified as CAV1 regulators by rationalized RNAi screening, and CAV1 upregulation downstream of ITGB1 switches TGFβ signaling from tumor-suppressive to oncogenic.","method":"RNAi screen with high-content microscopy, gene expression correlation, quantitative multiplex imaging of clinical samples, CAV1 knockdown functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNAi screen plus functional validation with multiple readouts, single lab","pmids":["29402961"],"is_preprint":false},{"year":2019,"finding":"TIMP-1/CD63/ITGB1/STAT3 form a feedback loop in breast cancer cells: TIMP-1 binds CD63 and cooperates with integrin β1 to activate STAT3 and ERK1/2; STAT3 in turn drives TIMP-1 expression; knockdown of any component abolishes CAF-induced migration and growth.","method":"siRNA knockdown of each component, recombinant TIMP-1 treatment, STAT3/ERK phosphorylation Western blot, migration assay with CAF conditioned medium","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic knockdown of each loop component with functional readout, single lab","pmids":["36291767"],"is_preprint":false},{"year":2020,"finding":"THBS4 (thrombospondin 4) physically interacts with ITGB1 (integrin β1) and activates the FAK/PI3K/AKT signaling pathway to promote HCC cell proliferation and metastasis in vitro and in vivo.","method":"Co-immunoprecipitation, Western blot, immunofluorescence, colony formation, Transwell, xenograft","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirms physical interaction plus functional in vivo validation, single lab","pmids":["32567740"],"is_preprint":false},{"year":2020,"finding":"ALKBH5 demethylates m6A on ITGB1 mRNA and suppresses YTHDF2-mediated m6A-dependent degradation of ITGB1 mRNA, resulting in increased ITGB1 protein, FAK and Src phosphorylation, and enhanced lymphangiogenesis and lymph node metastasis in ovarian cancer.","method":"RNA pulldown, RIP-qPCR, MeRIP-qPCR, co-IP, luciferase reporter, m6A dot blot, in vitro/in vivo functional studies","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal RNA biology methods (pulldown, RIP, MeRIP, luciferase) plus in vivo validation confirming m6A-ITGB1-FAK axis","pmids":["36632222"],"is_preprint":false},{"year":2021,"finding":"KAT1 activates YTHDF2 transcription via histone acetylation; YTHDF2 then triggers m6A-dependent ITGB1 mRNA degradation, suppressing ITGB1 expression and downstream FAK/PI3K/AKT signaling in retinal cells, reducing diabetic retinopathy progression.","method":"Histone acetylation assay, YTHDF2 promoter reporter, sh-YTHDF2/sh-ITGB1 knockdown, Western blot (FAK/PI3K/AKT), in vivo STZ mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic mechanism with functional rescue experiments, in vivo model, single lab","pmids":["34098071"],"is_preprint":false},{"year":2023,"finding":"PD-L1 directly binds ITGB1 on NSCLC cell membranes; this PD-L1/ITGB1 interaction activates NF-κB signaling to confer chemoresistance. USP51 deubiquitinates and stabilizes PD-L1, enabling this interaction. DHM inhibits USP51, reducing PD-L1 and re-sensitizing cells to chemotherapy.","method":"Co-immunoprecipitation, pulldown assay, protein deubiquitination assay, SPR, cellular thermal shift assay, NF-κB pathway analysis, tissue microarray, mouse models","journal":"Cancer communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding confirmed by pulldown + SPR + co-IP, deubiquitinase activity assay, and in vivo validation, multiple orthogonal methods","pmids":["37386737"],"is_preprint":false},{"year":2021,"finding":"ITGB1 knockdown in NSCLC cells enhances radiation-induced DNA damage, increases G2/M arrest, and suppresses YAP1 expression and nuclear translocation; ITGB1 promotes radioresistance via DNA repair modulation and YAP1-induced EMT.","method":"shRNA knockdown, colony formation, flow cytometry, immunofluorescence (γH2AX), Western blot (YAP1, EMT markers)","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular readouts and pathway marker analysis, single lab","pmids":["33613118"],"is_preprint":false},{"year":2021,"finding":"ITGB1 drives HCC progression through the ITGB1/PXN (paxillin)/YWHAZ (14-3-3ζ)/AKT axis; ITGB1 siRNA knockdown decreases PXN and YWHAZ expression, impairs HCC cell migration, drug resistance, and colony formation, and delays cell cycle progression.","method":"siRNA knockdown, Western blot, immunostaining, xenograft, cell cycle analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined downstream pathway proteins and in vivo validation, single lab","pmids":["34977001"],"is_preprint":false},{"year":2019,"finding":"FRK (Fyn-related kinase) decreases ITGB1 expression at both mRNA and protein levels in glioma cells, suppressing FAK and AKT activity; ITGB1 overexpression partially rescues FRK-induced glioma growth suppression, positioning ITGB1 downstream of FRK in the FRK–ITGB1–FAK signaling axis.","method":"FRK overexpression, ITGB1 overexpression rescue, Western blot (ITGB1, FAK, AKT), intracranial xenograft, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment plus in vivo model, single lab","pmids":["31395336"],"is_preprint":false},{"year":2020,"finding":"MUC5AC physically interacts with CD44 and ITGB1 (CD29), promoting CD44/ITGB1 clustering and Rac1 activation, which drives migration of adipose-derived mesenchymal stem cells toward pancreatic tumors; pharmacological inhibition of Rac1 blocks this migration.","method":"Mass spectrometry interactome, ELISA, live-cell imaging, flow cytometry, Rac1 pharmacological inhibition, autochthonous murine PC models","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus functional validation with genetic and pharmacological tools in autochthonous models, single lab","pmids":["35219699"],"is_preprint":false},{"year":2019,"finding":"SIPA1 (GTPase-activating protein) promotes invasion and migration in oral squamous cell carcinoma through regulation of ITGB1 and MMP7; SIPA1 knockdown increases ITGB1 expression while decreasing MMP7, identifying ITGB1 as a downstream effector of SIPA1 in cancer metastasis.","method":"shRNA knockdown, Western blot, invasion/migration assay, immunohistochemistry","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown approach showing inverse regulation, no direct interaction demonstrated, single lab","pmids":["28237246"],"is_preprint":false},{"year":2022,"finding":"ITGB1 mediates DDR2-regulated periostin (POSTN) expression in ovarian cancer-associated fibroblasts; DDR2 controls periostin through ITGB1, and POSTN-ITGB1 signaling promotes mesothelial clearance and tumor invasion.","method":"Co-culture experiments, DDR2/POSTN knockdown and overexpression, tumor burden assay in mouse, functional invasion assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss/gain of function in both in vitro and in vivo settings, single lab","pmids":["35884543"],"is_preprint":false},{"year":2018,"finding":"Dynamins 2 and 3 (DNM2/DNM3) regulate ITGB1 activity in megakaryocytes; inhibition or knockdown of DNM2/DNM3, or expression of dominant-negative/GTPase-defective dynamin, diminishes ITGB1 (beta1 integrin) activity and impairs directional megakaryocyte migration toward SDF-1α gradients.","method":"DNM2/DNM3 shRNA knockdown, dominant-negative/GTPase-dead dynamin expression, ITGB1 activity assay, directional migration assay","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic approaches (shRNA + dominant-negative) converging on ITGB1 activity readout, single lab","pmids":["30538113"],"is_preprint":false},{"year":2020,"finding":"SPARCL1 physically interacts with ITGB1 (confirmed by co-immunoprecipitation and mass spectrometry); SPARCL1 promotes bovine satellite cell migration and early differentiation through ITGB1-mediated regulation of p-FAK, p-paxillin, vinculin, Cdc42, and Arp2/3.","method":"Immunoprecipitation + mass spectrometry, co-immunoprecipitation, cell scratch assay, desmin staining, Western blot (FAK, paxillin, vinculin, Cdc42, Arp2/3)","journal":"Animals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction confirmed by co-IP/MS plus downstream pathway readouts, single lab","pmids":["32781616"],"is_preprint":false},{"year":2022,"finding":"miR-134-5p directly targets Itgb1 mRNA (confirmed by luciferase reporter assay); Itgb1 knockdown reverses miR-134-5p antagomir-promoted osteoclastogenesis; the miR-134-5p/Itgb1 axis modulates the MAPK pathway (p-p38 and p-ERK levels) to regulate osteoclast differentiation.","method":"Luciferase reporter assay, miR-134-5p agomir/antagomir transfection, Itgb1 siRNA co-transfection, OVX mouse model, MAPK pathway Western blot","journal":"Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase + genetic rescue with Itgb1 siRNA + in vivo OVX model, single lab","pmids":["35691339"],"is_preprint":false},{"year":2019,"finding":"ITGB1 (CD29) is required for CNS accumulation of plasmacytoid dendritic cells during EAE neuroinflammation; adoptive transfer experiments showed pDC entry into the CNS was strongly inhibited in the absence of CD29, while CD18 (β2 integrin) was not required; blocking CD49d (α4) also diminished CNS-pDC numbers.","method":"Adoptive transfer experiments, CD29-knockout pDCs, antibody blockade of CD49d, flow cytometry","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (KO) and pharmacological (antibody blocking) approaches in vivo, single lab","pmids":["31318439"],"is_preprint":false},{"year":2001,"finding":"α4β1 (VLA-4, CD49d/CD29) and α5β1 (VLA-5, CD49e/CD29) integrins mediate β2-integrin-independent neutrophil recruitment to LPS-induced lung inflammation; combined blocking of α4 + β2 inhibited parenchymal PMNL accumulation by 56%, adding α5 blockade increased inhibition to 79%; α5β1 also mediates pulmonary vascular and epithelial permeability.","method":"Blocking mAb administration in Lewis rat LPS lung inflammation model, myeloperoxidase assay, BALF protein measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo blocking with multiple mAb combinations, quantitative tissue readout, single lab","pmids":["11254723"],"is_preprint":false},{"year":2024,"finding":"RPS7 stabilizes LOXL2 mRNA by binding AUUUA motifs in the 3'UTR of LOXL2, increasing LOXL2 expression; LOXL2 then maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling to promote HCC metastasis.","method":"RNA-seq, RIP, RNA pulldown, dual luciferase reporter, nascent RNA capture, RNA decay assay, CRISPR-Cas9 KO, Western blot","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal RNA biology methods confirm RPS7–LOXL2 mRNA binding; LOXL2–ITGB1 protein stability link demonstrated; pathway validated in vivo","pmids":["38326908"],"is_preprint":false},{"year":2023,"finding":"CD248 promotes the interaction between ITGB1 and ECM proteins CYR61 and fibronectin, activating the FAK-paxillin pathway and formation of focal adhesions to drive osteosarcoma migration and metastasis; CD248 knockdown inhibits lung metastasis in vivo.","method":"RNA-seq, Western blot, immunofluorescence, co-immunoprecipitation (CD248 KD cells), lung metastasis nude mouse model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirming interaction plus in vivo metastasis validation, single lab","pmids":["36997926"],"is_preprint":false},{"year":2024,"finding":"COL10A1 (Type X collagen) directly interacts with ITGB1 and activates PI3K/AKT signaling to promote TNBC cell proliferation, migration, invasion, and in vivo tumor growth; knockdown of either COL10A1 or ITGB1 reverses these effects.","method":"Co-immunoprecipitation (COL10A1-ITGB1 interaction), COL10A1/ITGB1 knockdown, PI3K/AKT pathway analysis, in vivo tumor and lung metastasis models","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction by co-IP, genetic validation of both binding partners with in vivo readout, single lab","pmids":["38866293"],"is_preprint":false},{"year":2024,"finding":"GMFG, a paracrine signal from ERS-CAFs (via IER2/GMFG axis), directly binds ITGB1 on tumor cells to promote chordoma progression; ITGB1 inhibition attenuates tumor malignant progression, which is partially reversed by exogenous GMFG.","method":"Single-cell RNA-seq, spatial transcriptomics, DIA proteomics, multiplexed immunofluorescence, ITGB1 inhibition with GMFG rescue experiment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding claim supported by rescue experiment; multimodal -omics context; single lab","pmids":["39207055"],"is_preprint":false},{"year":2025,"finding":"CircRNF13 interacts with m6A reader IGF2BP1, inhibiting its ubiquitin-mediated degradation and promoting IGF2BP1 phase separation; this increases ITGB1 mRNA stability in an m6A-dependent manner, promoting cisplatin resistance in oral cancer.","method":"circRNA expression analysis, co-IP (circRNF13–IGF2BP1), ubiquitination assay, phase separation assay, m6A modification assay, in vitro and in vivo cisplatin resistance experiments","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-RNA interaction confirmed by co-IP and functional assays, m6A mechanism validated, single lab","pmids":["39891203"],"is_preprint":false},{"year":2022,"finding":"Maspin suppresses gastric cancer invasion and angiogenesis by blocking the ITGB1/FAK pathway; Maspin expression is negatively correlated with ITGB1 and p-FAK levels in tumor tissues; Maspin CRISPR activation plus ITGB1 siRNA increases E-cadherin and reduces Vimentin and VEGF.","method":"Immunohistochemistry (tissue), CRISPR activation, siRNA knockdown, Transwell, wound healing, tube formation assay, Western blot","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR and siRNA functional tools with multiple assays, single lab","pmids":["32409959"],"is_preprint":false},{"year":2023,"finding":"ITGB1 overexpression activates the cAMP signaling pathway in chondrocytes, suppressing cartilage inflammation (TNF-α, IL-1β, IL-6) and apoptosis in an osteoarthritis model; a cAMP pathway inhibitor reverses the protective effects of ITGB1 overexpression.","method":"Bioinformatics, OA rat model, ITGB1 overexpression, Western blot (cAMP pathway), ELISA (cytokines), CCK-8, flow cytometry","journal":"Journal of orthopaedic surgery and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression approach with pharmacological pathway inhibitor, no direct cAMP measurement or mechanistic link elucidated, single lab","pmids":["37941009"],"is_preprint":false},{"year":2009,"finding":"Cell-permeable ceramides (C2- and C6-ceramide) suppress CD29 (ITGB1)-mediated monocytic U937 cell-cell and cell-fibronectin adhesion in a dose-dependent manner; C6-ceramide inhibits CD29 phosphorylation induced by MEM101A and downregulates surface levels of CD29, CD98, and CD147.","method":"Cell adhesion assay, ceramide/sphingolipid dose-response, CD29 phosphorylation Western blot, surface expression flow cytometry","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical (phosphorylation inhibition) plus functional (adhesion) readouts with defined pharmacological agents, single lab","pmids":["19576658"],"is_preprint":false},{"year":2016,"finding":"CD29 (ITGB1), CD98, and CD147 form a molecular complex at the cell surface of U937 monocytes that jointly mediates cell-cell adhesion; co-IP and confocal microscopy confirm molecular association between all three molecules and the actin cytoskeleton; antibody blockade of any single component reduces adhesion similarly.","method":"Co-immunoprecipitation, confocal microscopy, aggregation-activating/blocking antibodies, enzyme inhibitor sensitivity profiling","journal":"Korean journal of physiology & pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + confocal co-localization, functional blocking with multiple antibodies, single lab","pmids":["27610038"],"is_preprint":false}],"current_model":"ITGB1 (CD29, β1 integrin) functions as a transmembrane adhesion receptor that heterodimerizes with various α-integrin subunits to mediate cell adhesion to ECM proteins (fibronectin, laminin, collagen); upon activation—by ligands (galectin-3, TIMP-1, MUC5AC, periostin, GMFG, SPARCL1, COL10A1, THBS4), by mechanical stimulation, or by co-receptor complexes (with CD38, CD63, CD98, CD147, PD-L1)—ITGB1 activates intracellular signaling cascades including FAK/Src/PI3K/AKT, MEK/ERK, ILK/Akt, NF-κB, and MAPK to regulate cell survival, migration, invasion, EMT, radioresistance, and chemoresistance; ITGB1 mRNA stability and expression are post-transcriptionally controlled by m6A modification (writers METTL3, erasers ALKBH5, readers YTHDF2/IGF2BP1), and ITGB1 activity is modulated by dynamin-dependent endocytic recycling and by upstream transcription factors including SOX10; in the immune system, ITGB1 on T cells, dendritic cells, and regulatory T cells controls tissue migration and cytotoxic effector function."},"narrative":{"mechanistic_narrative":"ITGB1 (CD29, β1 integrin) is a transmembrane adhesion receptor that mediates cell attachment to extracellular matrix proteins—collagen, laminin, and fibronectin—and translates engagement into intracellular signaling that governs adhesion, migration, survival, and tumor progression [PMID:7547709]. As a β subunit it heterodimerizes with α partners (VLA-4/CD49d and VLA-5/CD49e) to drive integrin-dependent leukocyte costimulation and recruitment [PMID:1383369, PMID:11254723], and its adhesive output is amplified within surface co-receptor complexes containing CD38, CD98, CD147, CD63, CD248, and PD-L1 [PMID:22289918, PMID:27610038, PMID:30635444, PMID:36997926, PMID:37386737]. The dominant downstream module is FAK/Src signaling, which—together with PI3K/AKT, ILK, MEK/ERK, NF-κB and MAPK arms—is activated by ECM-derived and matricellular ligands including TIMP-1, periostin, THBS4, SPARCL1, COL10A1, GMFG and MUC5AC, and confers proliferation, EMT, radioresistance, and chemoresistance in multiple cancers [PMID:30635444, PMID:32567740, PMID:32781616, PMID:38866293, PMID:25805567, PMID:33613118]. ITGB1 abundance is set transcriptionally by SOX10, which cooperates with β1 integrin to guide enteric neural crest cell migration [PMID:23608456], and post-transcriptionally by an m6A axis in which ALKBH5 erasure and IGF2BP1 reading stabilize ITGB1 mRNA while YTHDF2 reading drives its degradation [PMID:36632222, PMID:34098071, PMID:39891203]. ITGB1 surface activity is further tuned by dynamin-dependent trafficking and by integrin-associated regulators that feed back on FAK/AKT signaling [PMID:30538113, PMID:31395336]. In the immune system, β1 integrin controls T-cell signaling and CNS entry of dendritic cells, and galectin-3 binding to CD29 triggers mitochondrial T-cell apoptosis [PMID:31318439, PMID:14678989].","teleology":[{"year":1993,"claim":"Established that CD29 engagement is not merely structural but feeds into T-cell signaling, by showing antibody ligation modulates lipid second-messenger metabolism during CD3 activation.","evidence":"Phospholipid metabolite measurement and proliferation/IL-2 rescue assays in Jurkat and primary CD4+ T cells","pmids":["7686929"],"confidence":"Medium","gaps":["Antibody ligation may not mimic physiological ECM engagement","No defined α partner or downstream kinase identified","Mechanism linking integrin to DAG/PA changes unresolved"]},{"year":1995,"claim":"Defined the core adhesive function of β1 integrin—binding collagen, laminin and fibronectin—and its contribution to T-cell proliferation alongside LFA-1.","evidence":"mAb generation, immunoprecipitation, adhesion blocking and proliferation assays in mouse","pmids":["7547709"],"confidence":"Medium","gaps":["Did not resolve which αβ1 heterodimers bind which ligands","No intracellular signaling mechanism","Costimulation role inferred from combined blockade"]},{"year":2003,"claim":"Showed CD29 can act as a death-signaling receptor in T cells, with galectin-3 binding triggering the mitochondrial apoptotic pathway in a glycan-dependent manner.","evidence":"Carbohydrate-inhibition binding, co-IP and apoptosis readouts (cytochrome c, caspase-3)","pmids":["14678989"],"confidence":"Medium","gaps":["Direct vs. indirect coupling of CD29 to mitochondria not defined","Caspase-8 independence leaves upstream trigger unclear","Single lab"]},{"year":2012,"claim":"Demonstrated that β1 integrin adhesive output is modulated within surface co-receptor complexes, as CD38 associates with CD49d/CD29 and enhances adhesion and survival in CLL.","evidence":"Reciprocal co-IP, co-capping, CD38-transfectant adhesion rescue and phospho-Vav-1 analysis","pmids":["22289918"],"confidence":"High","gaps":["Stoichiometry and structural basis of the complex unknown","Whether CD38 alters integrin conformation directly untested"]},{"year":2011,"claim":"Connected CD29 engagement to pro-survival signaling, showing it drives a NOX2-dependent ROS burst that activates MEK/ERK and PI3K/Akt in cardiomyocytes.","evidence":"ROS flow cytometry, NOX activity assay, NOX2-knockout cardiomyocytes and antioxidant overexpression","pmids":["22198504"],"confidence":"High","gaps":["Link between integrin clustering and NOX2 activation undefined","Generality beyond cardiomyocytes untested"]},{"year":2013,"claim":"Placed ITGB1 under transcriptional control of SOX10 and showed a cooperative genetic requirement for enteric neural crest cell migration in vivo.","evidence":"Mouse genetic epistasis with double mutants and live-imaging of neural crest migration","pmids":["23608456"],"confidence":"High","gaps":["Direct SOX10 binding to ITGB1 regulatory regions not shown","Migration defect mechanism (speed vs directionality) only partly resolved"]},{"year":2019,"claim":"Identified a TIMP-1/CD63/ITGB1/FAK signaling cascade controlling dendritic cell motility, defining a defined ligand-receptor route into integrin signaling.","evidence":"shRNA silencing of multiple components, antibody blockade and FAK/SRC/PI3K inhibition with live-cell migration","pmids":["30635444"],"confidence":"High","gaps":["Whether TIMP-1/CD63 engages ITGB1 directly or via clustering unclear","α partner not specified"]},{"year":2020,"claim":"Established m6A control of ITGB1 mRNA, with ALKBH5 demethylation antagonizing YTHDF2-mediated decay to elevate ITGB1 and FAK/Src signaling and drive metastasis.","evidence":"RNA pulldown, RIP/MeRIP-qPCR, luciferase reporter and in vivo ovarian cancer models","pmids":["36632222"],"confidence":"High","gaps":["Site-specific m6A residues on ITGB1 not fully mapped","How upstream signals set ALKBH5/YTHDF2 balance unknown"]},{"year":2021,"claim":"Extended m6A regulation by showing a KAT1→YTHDF2 axis represses ITGB1 and downstream FAK/PI3K/AKT, with disease relevance in diabetic retinopathy.","evidence":"Histone acetylation and promoter reporter assays, sh-YTHDF2/sh-ITGB1 knockdown and STZ mouse model","pmids":["34098071"],"confidence":"Medium","gaps":["Direct KAT1 occupancy at YTHDF2 promoter inferred","Generality of the axis beyond retina untested"]},{"year":2025,"claim":"Implicated the m6A reader IGF2BP1 in ITGB1 stabilization via phase separation, broadening the post-transcriptional control network in chemoresistance.","evidence":"circRNA co-IP, ubiquitination and phase-separation assays with cisplatin-resistance models","pmids":["39891203"],"confidence":"Medium","gaps":["Direct IGF2BP1 binding to ITGB1 transcript vs indirect effect not fully separated","Role of phase separation in mRNA stability mechanistically unresolved"]},{"year":2023,"claim":"Revealed an immune-checkpoint cross-talk in which PD-L1 directly binds ITGB1 to activate NF-κB and confer chemoresistance, with USP51 stabilizing PD-L1.","evidence":"Pulldown, SPR, co-IP, deubiquitination assay and mouse models","pmids":["37386737"],"confidence":"High","gaps":["Binding interface on ITGB1 not mapped","Whether interaction alters integrin adhesion function untested"]},{"year":2024,"claim":"Expanded the matricellular ligand repertoire, showing COL10A1 and GMFG directly bind ITGB1 to activate PI3K/AKT and promote tumor progression.","evidence":"Co-IP, knockdown/rescue and in vivo tumor and metastasis models","pmids":["38866293","39207055"],"confidence":"Medium","gaps":["Binding sites and α partner specificity undefined","Direct vs co-receptor-mediated binding not fully resolved"]},{"year":null,"claim":"How the many ligands, co-receptors, and m6A/transcriptional inputs are integrated into context-specific α-subunit pairing and conformational activation of ITGB1 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ligand/co-receptor engagement on ITGB1 in the corpus","α partner specificity for most ligands not defined","Inside-out vs outside-in activation hierarchy not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,26,35]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,12,15,29]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,15,19,35]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,29,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12,9,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,25,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16,9]}],"complexes":["VLA-4 (CD49d/CD29 integrin)","VLA-5 (CD49e/CD29 integrin)","CD29/CD98/CD147 surface complex","CD49d/CD29/CD38 complex"],"partners":["CD38","CD63","CD98","CD147","CD248","PD-L1","THBS4","COL10A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P05556","full_name":"Integrin beta-1","aliases":["Fibronectin receptor subunit beta","Glycoprotein IIa","GPIIA","VLA-4 subunit beta"],"length_aa":798,"mass_kda":88.4,"function":"Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion (By similarity). Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. When associated with alpha-7 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGA4:ITGB1 and ITGA5:ITGB1 bind to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 acts as a receptor for fibronectin FN1 and mediates R-G-D-dependent cell adhesion to FN1 (PubMed:33962943). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973). Plays an important role in myoblast differentiation and fusion during skeletal myogenesis (By similarity). ITGA9:ITGB1 may play a crucial role in SVEP1/polydom-mediated myoblast cell adhesion (By similarity). Integrins ITGA9:ITGB1 and ITGA4:ITGB1 repress PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells via their interaction with SVEP1, thereby inhibit vasocontraction (PubMed:35802072) Interferes with isoform 1 resulting in a dominant negative effect on cell adhesion and migration (in vitro) Isoform 5 displaces isoform 1 in striated muscles (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8 (Microbial infection) Acts as a receptor for Cytomegalovirus/HHV-5 (Microbial infection) Acts as a receptor for Epstein-Barr virus/HHV-4 (Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human parvovirus B19 (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus (Microbial infection) Acts as a receptor for Mammalian reovirus (Microbial infection) In case of HIV-1 infection, integrin ITGA5:ITGB1 binding to extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions (Microbial infection) Interacts with CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:32487760). Integrin ITGA3:ITGB1 may act as a receptor for R.delemar CotH7 in alveolar epithelial cells, which may be an early step in pulmonary mucormycosis disease progression (PubMed:32487760) (Microbial infection) May serve as a receptor for adhesin A (nadA) of N.meningitidis (Microbial infection) Facilitates rabies infection in a fibronectin-dependent manner and participates in rabies virus traffic after internalization","subcellular_location":"Cell membrane, sarcolemma; Cell junction","url":"https://www.uniprot.org/uniprotkb/P05556/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGB1","classification":"Not 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SCAI","url":"https://www.omim.org/entry/619222"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ITGB1"},"hgnc":{"alias_symbol":["CD29","GPIIA"],"prev_symbol":["FNRB","MSK12","MDF2"]},"alphafold":{"accession":"P05556","domains":[{"cath_id":"3.30.1680.10","chopping":"20-83","consensus_level":"medium","plddt":85.2981,"start":20,"end":83},{"cath_id":"2.60.40.1510","chopping":"87-99_108-138_382-460","consensus_level":"high","plddt":91.3941,"start":87,"end":460},{"cath_id":"3.40.50.410","chopping":"142-380","consensus_level":"high","plddt":93.2087,"start":142,"end":380},{"cath_id":"2.10.25.10","chopping":"561-592","consensus_level":"medium","plddt":88.7856,"start":561,"end":592},{"cath_id":"4.10.1240.30","chopping":"638-717","consensus_level":"high","plddt":81.5761,"start":638,"end":717}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05556","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05556-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05556-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGB1","jax_strain_url":"https://www.jax.org/strain/search?query=ITGB1"},"sequence":{"accession":"P05556","fasta_url":"https://rest.uniprot.org/uniprotkb/P05556.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05556/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05556"}},"corpus_meta":[{"pmid":"14678989","id":"PMC_14678989","title":"CD29 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caspase activation)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification by binding assay with sugar inhibitor controls, functional apoptosis readout, single lab\",\n      \"pmids\": [\"14678989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"CD29 (ITGB1) engagement by soluble anti-CD29 mAb K20 suppresses T-cell proliferation by reducing diacylglycerol and phosphatidic acid levels in CD3-activated T cells, without affecting PIP2 hydrolysis, cytosolic Ca2+ or inositolphosphates, and independently of IL-2 receptor engagement.\",\n      \"method\": \"Phospholipid metabolite measurement (DAG, PA, PE), proliferation assay, IL-2 rescue experiment in Jurkat and primary CD4+ T cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical measurement of phospholipid metabolism with multiple metabolites tested, single lab\",\n      \"pmids\": [\"7686929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Mouse CD29 (ITGB1, beta1 integrin subunit) mediates cell adhesion to extracellular matrix proteins collagen, laminin, and fibronectin; blocking CD29 in combination with anti-LFA-1 inhibits T cell proliferation induced by anti-CD3 and allogeneic MLR.\",\n      \"method\": \"mAb generation, immunoprecipitation, cell adhesion blocking assay, T-cell proliferation assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking with defined mAb, multiple readouts (adhesion + proliferation), single lab\",\n      \"pmids\": [\"7547709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"ITGB1 (CD29) engagement by immobilized anti-CD49d (alpha4) mAb potentiates T-cell proliferation via anti-CD3; soluble anti-CD29 mAb inhibits this VLA-4-mediated co-stimulation of T cells.\",\n      \"method\": \"Immobilized mAb proliferation assay, soluble antibody inhibition\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay, single lab, no biochemical mechanistic follow-up\",\n      \"pmids\": [\"1383369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD29 (ITGB1) and CD73 mediate mechanically-induced decrease in MSC migration; specific inhibition of CD29/CD73 demonstrates their substrate-dependent involvement in post-loading migration, with FAK and Src-family kinases identified as downstream targets.\",\n      \"method\": \"Mechanical loading, specific antibody inhibition, scanning electron microscopy, phalloidin staining (actin), FAK/Src kinase analysis\",\n      \"journal\": \"European cells & materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional inhibition, morphological imaging, kinase phosphorylation), single lab\",\n      \"pmids\": [\"21732280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD29 (ITGB1) activation in neonatal rat cardiomyocytes induces an NOX2/p47(phox)-dependent reactive oxygen species burst and activates MEK/ERK and PI3K/Akt pro-survival pathways; NOX2-deficient cardiomyocytes lose CD29-induced pro-survival signaling.\",\n      \"method\": \"Flow cytometry (ROS), lucigenin chemiluminescence (NOX activity), adenoviral overexpression of antioxidants, NOX2 knockout mouse cardiomyocytes, pharmacological inhibition\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological inhibition, antioxidant overexpression), replicated across genetic and pharmacological approaches in the same study\",\n      \"pmids\": [\"22198504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The CD49d/CD29 (ITGB1) integrin complex constitutively associates with CD38 in CLL cells; CD38 enhances CD49d/CD29-mediated cell adhesion to VCAM-1 and fibronectin substrates, with CD49d+CD38+ cells showing higher Vav-1 phosphorylation, more complex F-actin distribution at adhesion sites, and greater apoptosis resistance.\",\n      \"method\": \"Co-capping, co-immunoprecipitation, cell adhesion assay on CD49d-specific substrates, CD38 transfection, phospho-Vav-1 Western blot, F-actin staining\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, co-capping, functional adhesion rescue with CD38 transfectants, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22289918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIMP-1 signals through its receptor CD63 to ITGB1 (CD29), activating FAK (and associated kinases SRC and PI3K), which drives hypermotility of Toxoplasma gondii-infected dendritic cells; shRNA silencing of ITGB1 or FAK, or antibody blockade of ITGB1, abrogated DC hypermotility.\",\n      \"method\": \"shRNA gene silencing (TIMP-1, CD63, ITGB1, FAK), antibody blockade, pharmacological inhibition of FAK/SRC/PI3K, live-cell migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal silencing approaches (shRNA + antibody blockade) with pharmacological validation, single lab, multiple genetic targets confirmed\",\n      \"pmids\": [\"30635444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SOX10 transcriptionally regulates beta1-integrin (ITGB1) expression; compound heterozygous Sox10/beta1-integrin mutant mice show more severe intestinal aganglionosis and enteric neural crest cell migration defects (reduced speed and altered directionality) than single mutants, establishing a cooperative genetic interaction.\",\n      \"method\": \"Mouse genetic epistasis (double mutant cross), video-microscopy of neural crest cell migration, gene expression analysis in Sox10 mutant mice\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — classic genetic epistasis with double mutant phenotype exceeding single mutants, live imaging validation, in vivo\",\n      \"pmids\": [\"23608456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD29 (ITGB1) overexpression in hepatocellular carcinoma cells activates ILK, increases Akt Ser473 phosphorylation and mTORC1 expression, induces EMT (decreased E-cadherin, increased fibronectin and vimentin), and confers resistance to radiation and cisplatin; CD29 silencing sensitizes tumors to these treatments.\",\n      \"method\": \"Adenoviral CD29 overexpression/shRNA silencing, xenograft mouse model, Western blot (ILK, Akt, EMT markers), MTT cell viability\",\n      \"journal\": \"Medical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic gain/loss of function with in vivo xenograft, pathway protein readouts, single lab\",\n      \"pmids\": [\"25805567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ITGB1 is an upstream regulator of Caveolin-1 (CAV1) expression in prostate cancer cells; ITGB1 and integrin-associated proteins were identified as CAV1 regulators by rationalized RNAi screening, and CAV1 upregulation downstream of ITGB1 switches TGFβ signaling from tumor-suppressive to oncogenic.\",\n      \"method\": \"RNAi screen with high-content microscopy, gene expression correlation, quantitative multiplex imaging of clinical samples, CAV1 knockdown functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNAi screen plus functional validation with multiple readouts, single lab\",\n      \"pmids\": [\"29402961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIMP-1/CD63/ITGB1/STAT3 form a feedback loop in breast cancer cells: TIMP-1 binds CD63 and cooperates with integrin β1 to activate STAT3 and ERK1/2; STAT3 in turn drives TIMP-1 expression; knockdown of any component abolishes CAF-induced migration and growth.\",\n      \"method\": \"siRNA knockdown of each component, recombinant TIMP-1 treatment, STAT3/ERK phosphorylation Western blot, migration assay with CAF conditioned medium\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic knockdown of each loop component with functional readout, single lab\",\n      \"pmids\": [\"36291767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"THBS4 (thrombospondin 4) physically interacts with ITGB1 (integrin β1) and activates the FAK/PI3K/AKT signaling pathway to promote HCC cell proliferation and metastasis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, immunofluorescence, colony formation, Transwell, xenograft\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirms physical interaction plus functional in vivo validation, single lab\",\n      \"pmids\": [\"32567740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALKBH5 demethylates m6A on ITGB1 mRNA and suppresses YTHDF2-mediated m6A-dependent degradation of ITGB1 mRNA, resulting in increased ITGB1 protein, FAK and Src phosphorylation, and enhanced lymphangiogenesis and lymph node metastasis in ovarian cancer.\",\n      \"method\": \"RNA pulldown, RIP-qPCR, MeRIP-qPCR, co-IP, luciferase reporter, m6A dot blot, in vitro/in vivo functional studies\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal RNA biology methods (pulldown, RIP, MeRIP, luciferase) plus in vivo validation confirming m6A-ITGB1-FAK axis\",\n      \"pmids\": [\"36632222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAT1 activates YTHDF2 transcription via histone acetylation; YTHDF2 then triggers m6A-dependent ITGB1 mRNA degradation, suppressing ITGB1 expression and downstream FAK/PI3K/AKT signaling in retinal cells, reducing diabetic retinopathy progression.\",\n      \"method\": \"Histone acetylation assay, YTHDF2 promoter reporter, sh-YTHDF2/sh-ITGB1 knockdown, Western blot (FAK/PI3K/AKT), in vivo STZ mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic mechanism with functional rescue experiments, in vivo model, single lab\",\n      \"pmids\": [\"34098071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PD-L1 directly binds ITGB1 on NSCLC cell membranes; this PD-L1/ITGB1 interaction activates NF-κB signaling to confer chemoresistance. USP51 deubiquitinates and stabilizes PD-L1, enabling this interaction. DHM inhibits USP51, reducing PD-L1 and re-sensitizing cells to chemotherapy.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, protein deubiquitination assay, SPR, cellular thermal shift assay, NF-κB pathway analysis, tissue microarray, mouse models\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding confirmed by pulldown + SPR + co-IP, deubiquitinase activity assay, and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37386737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGB1 knockdown in NSCLC cells enhances radiation-induced DNA damage, increases G2/M arrest, and suppresses YAP1 expression and nuclear translocation; ITGB1 promotes radioresistance via DNA repair modulation and YAP1-induced EMT.\",\n      \"method\": \"shRNA knockdown, colony formation, flow cytometry, immunofluorescence (γH2AX), Western blot (YAP1, EMT markers)\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular readouts and pathway marker analysis, single lab\",\n      \"pmids\": [\"33613118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGB1 drives HCC progression through the ITGB1/PXN (paxillin)/YWHAZ (14-3-3ζ)/AKT axis; ITGB1 siRNA knockdown decreases PXN and YWHAZ expression, impairs HCC cell migration, drug resistance, and colony formation, and delays cell cycle progression.\",\n      \"method\": \"siRNA knockdown, Western blot, immunostaining, xenograft, cell cycle analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined downstream pathway proteins and in vivo validation, single lab\",\n      \"pmids\": [\"34977001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FRK (Fyn-related kinase) decreases ITGB1 expression at both mRNA and protein levels in glioma cells, suppressing FAK and AKT activity; ITGB1 overexpression partially rescues FRK-induced glioma growth suppression, positioning ITGB1 downstream of FRK in the FRK–ITGB1–FAK signaling axis.\",\n      \"method\": \"FRK overexpression, ITGB1 overexpression rescue, Western blot (ITGB1, FAK, AKT), intracranial xenograft, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment plus in vivo model, single lab\",\n      \"pmids\": [\"31395336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MUC5AC physically interacts with CD44 and ITGB1 (CD29), promoting CD44/ITGB1 clustering and Rac1 activation, which drives migration of adipose-derived mesenchymal stem cells toward pancreatic tumors; pharmacological inhibition of Rac1 blocks this migration.\",\n      \"method\": \"Mass spectrometry interactome, ELISA, live-cell imaging, flow cytometry, Rac1 pharmacological inhibition, autochthonous murine PC models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus functional validation with genetic and pharmacological tools in autochthonous models, single lab\",\n      \"pmids\": [\"35219699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIPA1 (GTPase-activating protein) promotes invasion and migration in oral squamous cell carcinoma through regulation of ITGB1 and MMP7; SIPA1 knockdown increases ITGB1 expression while decreasing MMP7, identifying ITGB1 as a downstream effector of SIPA1 in cancer metastasis.\",\n      \"method\": \"shRNA knockdown, Western blot, invasion/migration assay, immunohistochemistry\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown approach showing inverse regulation, no direct interaction demonstrated, single lab\",\n      \"pmids\": [\"28237246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB1 mediates DDR2-regulated periostin (POSTN) expression in ovarian cancer-associated fibroblasts; DDR2 controls periostin through ITGB1, and POSTN-ITGB1 signaling promotes mesothelial clearance and tumor invasion.\",\n      \"method\": \"Co-culture experiments, DDR2/POSTN knockdown and overexpression, tumor burden assay in mouse, functional invasion assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss/gain of function in both in vitro and in vivo settings, single lab\",\n      \"pmids\": [\"35884543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dynamins 2 and 3 (DNM2/DNM3) regulate ITGB1 activity in megakaryocytes; inhibition or knockdown of DNM2/DNM3, or expression of dominant-negative/GTPase-defective dynamin, diminishes ITGB1 (beta1 integrin) activity and impairs directional megakaryocyte migration toward SDF-1α gradients.\",\n      \"method\": \"DNM2/DNM3 shRNA knockdown, dominant-negative/GTPase-dead dynamin expression, ITGB1 activity assay, directional migration assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic approaches (shRNA + dominant-negative) converging on ITGB1 activity readout, single lab\",\n      \"pmids\": [\"30538113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPARCL1 physically interacts with ITGB1 (confirmed by co-immunoprecipitation and mass spectrometry); SPARCL1 promotes bovine satellite cell migration and early differentiation through ITGB1-mediated regulation of p-FAK, p-paxillin, vinculin, Cdc42, and Arp2/3.\",\n      \"method\": \"Immunoprecipitation + mass spectrometry, co-immunoprecipitation, cell scratch assay, desmin staining, Western blot (FAK, paxillin, vinculin, Cdc42, Arp2/3)\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction confirmed by co-IP/MS plus downstream pathway readouts, single lab\",\n      \"pmids\": [\"32781616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-134-5p directly targets Itgb1 mRNA (confirmed by luciferase reporter assay); Itgb1 knockdown reverses miR-134-5p antagomir-promoted osteoclastogenesis; the miR-134-5p/Itgb1 axis modulates the MAPK pathway (p-p38 and p-ERK levels) to regulate osteoclast differentiation.\",\n      \"method\": \"Luciferase reporter assay, miR-134-5p agomir/antagomir transfection, Itgb1 siRNA co-transfection, OVX mouse model, MAPK pathway Western blot\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase + genetic rescue with Itgb1 siRNA + in vivo OVX model, single lab\",\n      \"pmids\": [\"35691339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ITGB1 (CD29) is required for CNS accumulation of plasmacytoid dendritic cells during EAE neuroinflammation; adoptive transfer experiments showed pDC entry into the CNS was strongly inhibited in the absence of CD29, while CD18 (β2 integrin) was not required; blocking CD49d (α4) also diminished CNS-pDC numbers.\",\n      \"method\": \"Adoptive transfer experiments, CD29-knockout pDCs, antibody blockade of CD49d, flow cytometry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (KO) and pharmacological (antibody blocking) approaches in vivo, single lab\",\n      \"pmids\": [\"31318439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"α4β1 (VLA-4, CD49d/CD29) and α5β1 (VLA-5, CD49e/CD29) integrins mediate β2-integrin-independent neutrophil recruitment to LPS-induced lung inflammation; combined blocking of α4 + β2 inhibited parenchymal PMNL accumulation by 56%, adding α5 blockade increased inhibition to 79%; α5β1 also mediates pulmonary vascular and epithelial permeability.\",\n      \"method\": \"Blocking mAb administration in Lewis rat LPS lung inflammation model, myeloperoxidase assay, BALF protein measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo blocking with multiple mAb combinations, quantitative tissue readout, single lab\",\n      \"pmids\": [\"11254723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPS7 stabilizes LOXL2 mRNA by binding AUUUA motifs in the 3'UTR of LOXL2, increasing LOXL2 expression; LOXL2 then maintains ITGB1 protein stability and activates ITGB1-mediated FAK/SRC signaling to promote HCC metastasis.\",\n      \"method\": \"RNA-seq, RIP, RNA pulldown, dual luciferase reporter, nascent RNA capture, RNA decay assay, CRISPR-Cas9 KO, Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal RNA biology methods confirm RPS7–LOXL2 mRNA binding; LOXL2–ITGB1 protein stability link demonstrated; pathway validated in vivo\",\n      \"pmids\": [\"38326908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD248 promotes the interaction between ITGB1 and ECM proteins CYR61 and fibronectin, activating the FAK-paxillin pathway and formation of focal adhesions to drive osteosarcoma migration and metastasis; CD248 knockdown inhibits lung metastasis in vivo.\",\n      \"method\": \"RNA-seq, Western blot, immunofluorescence, co-immunoprecipitation (CD248 KD cells), lung metastasis nude mouse model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirming interaction plus in vivo metastasis validation, single lab\",\n      \"pmids\": [\"36997926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"COL10A1 (Type X collagen) directly interacts with ITGB1 and activates PI3K/AKT signaling to promote TNBC cell proliferation, migration, invasion, and in vivo tumor growth; knockdown of either COL10A1 or ITGB1 reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation (COL10A1-ITGB1 interaction), COL10A1/ITGB1 knockdown, PI3K/AKT pathway analysis, in vivo tumor and lung metastasis models\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction by co-IP, genetic validation of both binding partners with in vivo readout, single lab\",\n      \"pmids\": [\"38866293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GMFG, a paracrine signal from ERS-CAFs (via IER2/GMFG axis), directly binds ITGB1 on tumor cells to promote chordoma progression; ITGB1 inhibition attenuates tumor malignant progression, which is partially reversed by exogenous GMFG.\",\n      \"method\": \"Single-cell RNA-seq, spatial transcriptomics, DIA proteomics, multiplexed immunofluorescence, ITGB1 inhibition with GMFG rescue experiment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding claim supported by rescue experiment; multimodal -omics context; single lab\",\n      \"pmids\": [\"39207055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CircRNF13 interacts with m6A reader IGF2BP1, inhibiting its ubiquitin-mediated degradation and promoting IGF2BP1 phase separation; this increases ITGB1 mRNA stability in an m6A-dependent manner, promoting cisplatin resistance in oral cancer.\",\n      \"method\": \"circRNA expression analysis, co-IP (circRNF13–IGF2BP1), ubiquitination assay, phase separation assay, m6A modification assay, in vitro and in vivo cisplatin resistance experiments\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-RNA interaction confirmed by co-IP and functional assays, m6A mechanism validated, single lab\",\n      \"pmids\": [\"39891203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Maspin suppresses gastric cancer invasion and angiogenesis by blocking the ITGB1/FAK pathway; Maspin expression is negatively correlated with ITGB1 and p-FAK levels in tumor tissues; Maspin CRISPR activation plus ITGB1 siRNA increases E-cadherin and reduces Vimentin and VEGF.\",\n      \"method\": \"Immunohistochemistry (tissue), CRISPR activation, siRNA knockdown, Transwell, wound healing, tube formation assay, Western blot\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR and siRNA functional tools with multiple assays, single lab\",\n      \"pmids\": [\"32409959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGB1 overexpression activates the cAMP signaling pathway in chondrocytes, suppressing cartilage inflammation (TNF-α, IL-1β, IL-6) and apoptosis in an osteoarthritis model; a cAMP pathway inhibitor reverses the protective effects of ITGB1 overexpression.\",\n      \"method\": \"Bioinformatics, OA rat model, ITGB1 overexpression, Western blot (cAMP pathway), ELISA (cytokines), CCK-8, flow cytometry\",\n      \"journal\": \"Journal of orthopaedic surgery and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression approach with pharmacological pathway inhibitor, no direct cAMP measurement or mechanistic link elucidated, single lab\",\n      \"pmids\": [\"37941009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cell-permeable ceramides (C2- and C6-ceramide) suppress CD29 (ITGB1)-mediated monocytic U937 cell-cell and cell-fibronectin adhesion in a dose-dependent manner; C6-ceramide inhibits CD29 phosphorylation induced by MEM101A and downregulates surface levels of CD29, CD98, and CD147.\",\n      \"method\": \"Cell adhesion assay, ceramide/sphingolipid dose-response, CD29 phosphorylation Western blot, surface expression flow cytometry\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical (phosphorylation inhibition) plus functional (adhesion) readouts with defined pharmacological agents, single lab\",\n      \"pmids\": [\"19576658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD29 (ITGB1), CD98, and CD147 form a molecular complex at the cell surface of U937 monocytes that jointly mediates cell-cell adhesion; co-IP and confocal microscopy confirm molecular association between all three molecules and the actin cytoskeleton; antibody blockade of any single component reduces adhesion similarly.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, aggregation-activating/blocking antibodies, enzyme inhibitor sensitivity profiling\",\n      \"journal\": \"Korean journal of physiology & pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + confocal co-localization, functional blocking with multiple antibodies, single lab\",\n      \"pmids\": [\"27610038\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGB1 (CD29, β1 integrin) functions as a transmembrane adhesion receptor that heterodimerizes with various α-integrin subunits to mediate cell adhesion to ECM proteins (fibronectin, laminin, collagen); upon activation—by ligands (galectin-3, TIMP-1, MUC5AC, periostin, GMFG, SPARCL1, COL10A1, THBS4), by mechanical stimulation, or by co-receptor complexes (with CD38, CD63, CD98, CD147, PD-L1)—ITGB1 activates intracellular signaling cascades including FAK/Src/PI3K/AKT, MEK/ERK, ILK/Akt, NF-κB, and MAPK to regulate cell survival, migration, invasion, EMT, radioresistance, and chemoresistance; ITGB1 mRNA stability and expression are post-transcriptionally controlled by m6A modification (writers METTL3, erasers ALKBH5, readers YTHDF2/IGF2BP1), and ITGB1 activity is modulated by dynamin-dependent endocytic recycling and by upstream transcription factors including SOX10; in the immune system, ITGB1 on T cells, dendritic cells, and regulatory T cells controls tissue migration and cytotoxic effector function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGB1 (CD29, β1 integrin) is a transmembrane adhesion receptor that mediates cell attachment to extracellular matrix proteins—collagen, laminin, and fibronectin—and translates engagement into intracellular signaling that governs adhesion, migration, survival, and tumor progression [#2]. As a β subunit it heterodimerizes with α partners (VLA-4/CD49d and VLA-5/CD49e) to drive integrin-dependent leukocyte costimulation and recruitment [#3, #26], and its adhesive output is amplified within surface co-receptor complexes containing CD38, CD98, CD147, CD63, CD248, and PD-L1 [#6, #35, #7, #28, #15]. The dominant downstream module is FAK/Src signaling, which—together with PI3K/AKT, ILK, MEK/ERK, NF-κB and MAPK arms—is activated by ECM-derived and matricellular ligands including TIMP-1, periostin, THBS4, SPARCL1, COL10A1, GMFG and MUC5AC, and confers proliferation, EMT, radioresistance, and chemoresistance in multiple cancers [#7, #12, #23, #29, #9, #16]. ITGB1 abundance is set transcriptionally by SOX10, which cooperates with β1 integrin to guide enteric neural crest cell migration [#8], and post-transcriptionally by an m6A axis in which ALKBH5 erasure and IGF2BP1 reading stabilize ITGB1 mRNA while YTHDF2 reading drives its degradation [#13, #14, #31]. ITGB1 surface activity is further tuned by dynamin-dependent trafficking and by integrin-associated regulators that feed back on FAK/AKT signaling [#22, #18]. In the immune system, β1 integrin controls T-cell signaling and CNS entry of dendritic cells, and galectin-3 binding to CD29 triggers mitochondrial T-cell apoptosis [#25, #0].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that CD29 engagement is not merely structural but feeds into T-cell signaling, by showing antibody ligation modulates lipid second-messenger metabolism during CD3 activation.\",\n      \"evidence\": \"Phospholipid metabolite measurement and proliferation/IL-2 rescue assays in Jurkat and primary CD4+ T cells\",\n      \"pmids\": [\"7686929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody ligation may not mimic physiological ECM engagement\", \"No defined α partner or downstream kinase identified\", \"Mechanism linking integrin to DAG/PA changes unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the core adhesive function of β1 integrin—binding collagen, laminin and fibronectin—and its contribution to T-cell proliferation alongside LFA-1.\",\n      \"evidence\": \"mAb generation, immunoprecipitation, adhesion blocking and proliferation assays in mouse\",\n      \"pmids\": [\"7547709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve which αβ1 heterodimers bind which ligands\", \"No intracellular signaling mechanism\", \"Costimulation role inferred from combined blockade\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CD29 can act as a death-signaling receptor in T cells, with galectin-3 binding triggering the mitochondrial apoptotic pathway in a glycan-dependent manner.\",\n      \"evidence\": \"Carbohydrate-inhibition binding, co-IP and apoptosis readouts (cytochrome c, caspase-3)\",\n      \"pmids\": [\"14678989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect coupling of CD29 to mitochondria not defined\", \"Caspase-8 independence leaves upstream trigger unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that β1 integrin adhesive output is modulated within surface co-receptor complexes, as CD38 associates with CD49d/CD29 and enhances adhesion and survival in CLL.\",\n      \"evidence\": \"Reciprocal co-IP, co-capping, CD38-transfectant adhesion rescue and phospho-Vav-1 analysis\",\n      \"pmids\": [\"22289918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the complex unknown\", \"Whether CD38 alters integrin conformation directly untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected CD29 engagement to pro-survival signaling, showing it drives a NOX2-dependent ROS burst that activates MEK/ERK and PI3K/Akt in cardiomyocytes.\",\n      \"evidence\": \"ROS flow cytometry, NOX activity assay, NOX2-knockout cardiomyocytes and antioxidant overexpression\",\n      \"pmids\": [\"22198504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between integrin clustering and NOX2 activation undefined\", \"Generality beyond cardiomyocytes untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed ITGB1 under transcriptional control of SOX10 and showed a cooperative genetic requirement for enteric neural crest cell migration in vivo.\",\n      \"evidence\": \"Mouse genetic epistasis with double mutants and live-imaging of neural crest migration\",\n      \"pmids\": [\"23608456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SOX10 binding to ITGB1 regulatory regions not shown\", \"Migration defect mechanism (speed vs directionality) only partly resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a TIMP-1/CD63/ITGB1/FAK signaling cascade controlling dendritic cell motility, defining a defined ligand-receptor route into integrin signaling.\",\n      \"evidence\": \"shRNA silencing of multiple components, antibody blockade and FAK/SRC/PI3K inhibition with live-cell migration\",\n      \"pmids\": [\"30635444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TIMP-1/CD63 engages ITGB1 directly or via clustering unclear\", \"α partner not specified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established m6A control of ITGB1 mRNA, with ALKBH5 demethylation antagonizing YTHDF2-mediated decay to elevate ITGB1 and FAK/Src signaling and drive metastasis.\",\n      \"evidence\": \"RNA pulldown, RIP/MeRIP-qPCR, luciferase reporter and in vivo ovarian cancer models\",\n      \"pmids\": [\"36632222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific m6A residues on ITGB1 not fully mapped\", \"How upstream signals set ALKBH5/YTHDF2 balance unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended m6A regulation by showing a KAT1→YTHDF2 axis represses ITGB1 and downstream FAK/PI3K/AKT, with disease relevance in diabetic retinopathy.\",\n      \"evidence\": \"Histone acetylation and promoter reporter assays, sh-YTHDF2/sh-ITGB1 knockdown and STZ mouse model\",\n      \"pmids\": [\"34098071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KAT1 occupancy at YTHDF2 promoter inferred\", \"Generality of the axis beyond retina untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated the m6A reader IGF2BP1 in ITGB1 stabilization via phase separation, broadening the post-transcriptional control network in chemoresistance.\",\n      \"evidence\": \"circRNA co-IP, ubiquitination and phase-separation assays with cisplatin-resistance models\",\n      \"pmids\": [\"39891203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IGF2BP1 binding to ITGB1 transcript vs indirect effect not fully separated\", \"Role of phase separation in mRNA stability mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an immune-checkpoint cross-talk in which PD-L1 directly binds ITGB1 to activate NF-κB and confer chemoresistance, with USP51 stabilizing PD-L1.\",\n      \"evidence\": \"Pulldown, SPR, co-IP, deubiquitination assay and mouse models\",\n      \"pmids\": [\"37386737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on ITGB1 not mapped\", \"Whether interaction alters integrin adhesion function untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded the matricellular ligand repertoire, showing COL10A1 and GMFG directly bind ITGB1 to activate PI3K/AKT and promote tumor progression.\",\n      \"evidence\": \"Co-IP, knockdown/rescue and in vivo tumor and metastasis models\",\n      \"pmids\": [\"38866293\", \"39207055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding sites and α partner specificity undefined\", \"Direct vs co-receptor-mediated binding not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many ligands, co-receptors, and m6A/transcriptional inputs are integrated into context-specific α-subunit pairing and conformational activation of ITGB1 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ligand/co-receptor engagement on ITGB1 in the corpus\", \"α partner specificity for most ligands not defined\", \"Inside-out vs outside-in activation hierarchy not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 26, 35]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 12, 15, 29]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 15, 19, 35]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 29, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12, 9, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 25, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 9]}\n    ],\n    \"complexes\": [\n      \"VLA-4 (CD49d/CD29 integrin)\",\n      \"VLA-5 (CD49e/CD29 integrin)\",\n      \"CD29/CD98/CD147 surface complex\",\n      \"CD49d/CD29/CD38 complex\"\n    ],\n    \"partners\": [\n      \"CD38\",\n      \"CD63\",\n      \"CD98\",\n      \"CD147\",\n      \"CD248\",\n      \"PD-L1\",\n      \"THBS4\",\n      \"COL10A1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}