{"gene":"ITGA7","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1995,"finding":"ITGA7 is encoded by a single gene in both rat and human genomes, localized to human chromosome 12q13, and its expression is developmentally regulated during skeletal muscle formation with isoforms containing different cytoplasmic and extracellular domains accompanying myogenesis.","method":"Southern blotting and in situ hybridization; phylogenetic analysis of integrin alpha chain sequences","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic mapping by Southern blot and in situ hybridization, single lab, two complementary methods","pmids":["7607681"],"is_preprint":false},{"year":1999,"finding":"The human ITGA7 gene comprises at least 27 exons spanning ~22.5 kb; major cytoplasmic variants alpha7A and alpha7B and extracellular isoforms X1 and X2 are expressed in human tissues in a developmentally regulated and tissue-specific manner, and a D variant is detectable in adult tissues.","method":"Genomic sequencing of exon/intron boundaries, RT-PCR for splice variant identification, radiation hybrid mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural characterization by sequencing and RT-PCR, single lab, multiple orthogonal methods","pmids":["10403775"],"is_preprint":false},{"year":2015,"finding":"AAV-mediated systemic overexpression of ITGA7 in mdx/utrn(-/-) mice (a severe DMD model) extended longevity, reduced kyphosis, protected against contraction-induced force loss, and increased specific force in diaphragm and EDL muscles, functioning as a laminin receptor that links the extracellular matrix to the internal actin cytoskeleton at the sarcolemma.","method":"In vivo AAV gene delivery (rAAVrh.74.MCK.ITGA7) in mdx/utrn(-/-) mice; force measurement; immunohistochemistry for sarcolemmal localization","journal":"Human gene therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gene delivery with functional force readouts and defined cellular localization, multiple phenotypic endpoints, replicates prior work on alpha7 integrin function","pmids":["26076707"],"is_preprint":false},{"year":2018,"finding":"FOXC1 directly binds to the ITGA7 promoter and transcriptionally activates ITGA7 expression; genetic epistasis confirmed that ITGA7 acts downstream of FOXC1 to promote colorectal cancer invasion and metastasis.","method":"ChIP (chromatin immunoprecipitation), transcriptional reporter assays, genetic epistasis analysis (FOXC1 overexpression/knockdown with ITGA7 manipulation), in vivo lung metastasis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and epistasis in multiple cellular and in vivo models, multiple orthogonal methods in a single rigorous study","pmids":["29884889"],"is_preprint":false},{"year":2018,"finding":"Knockdown of ITGA7 in breast cancer cell lines (MDA-MB-231 and BT-549) significantly inhibited migration and invasion, and was accompanied by upregulation of c-Met and vimentin, suggesting ITGA7 suppresses EMT-related pathways.","method":"siRNA knockdown, migration and invasion assays, Western blot","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with downstream protein readout, no mechanistic rescue","pmids":["29760566"],"is_preprint":false},{"year":2020,"finding":"Knockdown of ITGA7 in papillary thyroid carcinoma cell lines (TPC1 and KTC-1) enhanced proliferation, migration, invasion, and colony formation while decreasing apoptosis, accompanied by decreased E-cadherin and increased N-cadherin and vimentin, indicating ITGA7 suppresses epithelial-to-mesenchymal transition in thyroid cancer.","method":"siRNA knockdown, proliferation/migration/invasion assays, Western blot for EMT markers","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with phenotypic and protein readouts, no mechanistic rescue","pmids":["31942970"],"is_preprint":false},{"year":2021,"finding":"ITGA7 knockdown via siRNA in SH-SY5Y (dopaminergic) cells decreased TH expression, increased alpha-synuclein expression, decreased bcl2, and increased the bax/bcl2 ratio, indicating that ITGA7 loss promotes dopaminergic cell apoptosis and alpha-synuclein accumulation.","method":"siRNA knockdown in SH-SY5Y cells; immunohistochemistry and Western blot for TH, alpha-syn, bcl2, bax","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA approach with protein-level readouts only, no pathway rescue or mechanistic follow-up","pmids":["34884422"],"is_preprint":false},{"year":2022,"finding":"The RNA-binding protein QKI regulates alternative splicing of Itga7, controlling the mutually exclusive Itga7-X1 and -X2 isoforms in muscle stem cells; QKI loss or antisense oligonucleotide-forced shift to X1 isoform disrupts polarized localization of Itga7 and Dmd proteins, impairs asymmetric cell divisions, and reduces the myogenic progenitor population.","method":"Conditional QKI knockout mouse; transcriptomic analysis; antisense oligonucleotide splice-switching; immunofluorescence for protein polarity; quantification of asymmetric divisions","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with transcriptomic validation, antisense oligonucleotide recapitulation, and direct imaging of protein polarity across multiple orthogonal experiments","pmids":["35165120"],"is_preprint":false},{"year":2022,"finding":"ATF1 transcriptionally activates miR-214-5p, which directly targets and represses ITGA7; this ATF1/miR-214-5p/ITGA7 axis promotes osteoclastogenesis, and knockdown of miR-214-5p suppresses osteoclast differentiation through derepression of ITGA7.","method":"ChIP, luciferase reporter assay, siRNA knockdown of ATF1/miR-214-5p/ITGA7, TRAP staining for osteoclast differentiation, OVX mouse model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase validate direct regulation, functional epistasis in cells and in vivo, single lab","pmids":["35568813"],"is_preprint":false},{"year":2022,"finding":"Fixed-state nanohydroxyapatite (nHAP) upregulates ITGA7 in human bone marrow stem cells, and ITGA7 upregulation mediates activation of the PI3K-AKT signaling pathway to promote osteogenesis; free-state nHAP produces the opposite effect.","method":"In vitro hBMSC culture with different nHAP forms; siRNA knockdown of ITGA7; PI3K-AKT pathway activity assays; ectopic osteogenesis in mouse subcutaneous model","journal":"Bioactive materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ITGA7 knockdown with pathway readout and in vivo confirmation, single lab, multiple methods","pmids":["35415300"],"is_preprint":false},{"year":2022,"finding":"ITGA7 knockdown in C2C12 cells significantly increased alpha-synuclein expression, indicating that ITGA7 normally suppresses alpha-synuclein accumulation in muscle cells.","method":"siRNA knockdown in C2C12 cells; immunofluorescence and Western blot for ITGA7 and alpha-synuclein","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with single readout, no mechanistic follow-up","pmids":["35628462"],"is_preprint":false},{"year":2023,"finding":"Knockdown of ITGA7 by siRNA in porcine ovarian granulosa cells significantly inhibited the PI3K-AKT signaling pathway, decreased PCNA expression, and increased apoptosis rates and pro-apoptotic proteins, establishing ITGA7 as an upstream activator of PI3K-AKT signaling in granulosa cells.","method":"siRNA knockdown; Western blot for PI3K-AKT pathway components; flow cytometry for apoptosis; CCK-8 proliferation assay","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA approach with downstream pathway readout, no direct binding or reconstitution","pmids":["36901882"],"is_preprint":false},{"year":2023,"finding":"ITGA7 and Dystroglycan co-localize at the nanoscale in zebrafish muscle fibers at the sarcolemma, with distinct nanoscale distributions detectable by super-resolution FPALM microscopy, consistent with their shared role in connecting the cytoskeleton to the extracellular matrix.","method":"FPALM super-resolution microscopy in intact zebrafish muscle fibers; confocal imaging validation","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by super-resolution imaging in intact tissue, single lab, two imaging modalities","pmids":["37509580"],"is_preprint":false},{"year":2024,"finding":"ITGA7 binds to CKAP4 (co-immunoprecipitation), blocking the interaction between CKAP4 and PI3K p85α, thereby suppressing PI3K/AKT/NF-κB pathway activation; loss of ITGA7 releases CKAP4 to interact with PI3K p85α, activating NF-κB nuclear translocation and transcription of MMP9, SETD7, and ADAM15 in colorectal cancer cells.","method":"Co-immunoprecipitation (CoIP), Western blot, nuclear/cytoplasmic fractionation, RNA sequencing, RT-qPCR, rescue assays; promoter methylation analysis (BSP) and 5-Aza-CdR treatment","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP establishes direct protein-protein interaction, supported by pathway rescue assays and fractionation, single lab","pmids":["38885843"],"is_preprint":false},{"year":2024,"finding":"Loss of ITGA7 in omental adipose-derived mesenchymal stem cells (ADSCs) decreased stemness properties and induced the emergence of cancer-associated fibroblast (CAF) morphology and biomarkers; conditioned medium from ITGA7-depleted ADSCs enhanced migration and invasion of ovarian cancer cells in vitro.","method":"siRNA knockdown of ITGA7 in primary ADSCs; morphological assessment; biomarker analysis; conditioned medium migration/invasion assays","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with phenotypic and biomarker readouts, no mechanistic pathway identified","pmids":["38174862"],"is_preprint":false}],"current_model":"ITGA7 encodes a laminin-binding integrin alpha subunit expressed predominantly in skeletal muscle, where it localizes to the sarcolemma and links the extracellular matrix to the internal actin cytoskeleton; its expression is transcriptionally activated by FOXC1 and repressed by ATF1/miR-214-5p, its alternative splicing (X1/X2 isoforms) is regulated by the RNA-binding protein QKI to control muscle stem cell polarity and asymmetric division, and at the molecular level ITGA7 binds CKAP4 to suppress PI3K/AKT/NF-κB signaling, while loss of ITGA7 releases CKAP4 to activate PI3K p85α, driving NF-κB nuclear translocation and upregulation of pro-invasive targets."},"narrative":{"mechanistic_narrative":"ITGA7 encodes a laminin-binding integrin alpha subunit that localizes to the skeletal muscle sarcolemma, where it functions as a laminin receptor linking the extracellular matrix to the internal actin cytoskeleton; its systemic overexpression in a severe muscular dystrophy mouse model extends longevity, reduces kyphosis, and protects against contraction-induced force loss [PMID:26076707]. The gene is developmentally regulated during myogenesis and produces multiple cytoplasmic (alpha7A/B) and extracellular (X1/X2) splice variants encoded across at least 27 exons [PMID:7607681, PMID:10403775]. Alternative splicing of the mutually exclusive X1/X2 isoforms is controlled by the RNA-binding protein QKI, and this isoform choice governs polarized localization of ITGA7 and dystrophin proteins, asymmetric muscle stem cell division, and maintenance of the myogenic progenitor population [PMID:35165120]; at the sarcolemma ITGA7 co-localizes at the nanoscale with dystroglycan, consistent with a shared role in coupling cytoskeleton to matrix [PMID:37509580]. ITGA7 expression is directly activated by FOXC1 binding to its promoter and repressed through an ATF1/miR-214-5p axis [PMID:29884889, PMID:35568813]. Mechanistically, ITGA7 binds CKAP4 to block the CKAP4–PI3K p85alpha interaction, thereby restraining PI3K/AKT/NF-kB signaling; loss of ITGA7 releases CKAP4 to activate p85alpha, driving NF-kB nuclear translocation and transcription of pro-invasive targets including MMP9, SETD7, and ADAM15 in colorectal cancer [PMID:38885843]. ITGA7 also acts as an upstream activator of PI3K-AKT signaling in non-muscle contexts such as granulosa cells and osteogenic stem cells [PMID:35415300, PMID:36901882].","teleology":[{"year":1995,"claim":"Established ITGA7 as a single-copy gene whose expression is developmentally regulated during skeletal muscle formation, framing it as a myogenesis-associated integrin.","evidence":"Southern blotting, in situ hybridization, and phylogenetic analysis in rat and human genomes","pmids":["7607681"],"confidence":"Medium","gaps":["Did not define isoform function","No protein-level localization or ligand confirmed"]},{"year":1999,"claim":"Resolved the exon/intron architecture and catalogued the cytoplasmic (alpha7A/B) and extracellular (X1/X2) splice variants, defining the structural repertoire later shown to be functionally important.","evidence":"Genomic sequencing of exon boundaries, RT-PCR, radiation hybrid mapping","pmids":["10403775"],"confidence":"Medium","gaps":["Functional distinction between isoforms not established","Regulators of splicing unknown at this stage"]},{"year":2015,"claim":"Demonstrated in vivo that ITGA7 acts as a sarcolemmal laminin receptor coupling matrix to cytoskeleton, with therapeutic restoration of muscle force in a dystrophy model.","evidence":"AAV-mediated systemic ITGA7 overexpression in mdx/utrn(-/-) mice with force measurement and immunohistochemistry","pmids":["26076707"],"confidence":"High","gaps":["Molecular partners at the sarcolemma not enumerated","Signaling consequences downstream of ITGA7 not addressed"]},{"year":2018,"claim":"Identified FOXC1 as a direct transcriptional activator of ITGA7 and placed ITGA7 downstream of FOXC1 in driving cancer invasion, extending ITGA7 biology beyond muscle.","evidence":"ChIP, reporter assays, genetic epistasis, and in vivo lung metastasis model in colorectal cancer","pmids":["29884889"],"confidence":"High","gaps":["Molecular effector of ITGA7-driven invasion not yet defined","Whether muscle isoforms apply to cancer context unclear"]},{"year":2018,"claim":"Indicated a tumor-suppressive role of ITGA7 in breast cancer via repression of EMT-associated markers, an apparent contrast to its pro-invasive role elsewhere.","evidence":"siRNA knockdown with migration/invasion assays and Western blot in breast cancer lines","pmids":["29760566"],"confidence":"Low","gaps":["No mechanistic rescue","Direction of effect conflicts with colorectal findings, unresolved by context"]},{"year":2020,"claim":"Reinforced an EMT-suppressing role of ITGA7 in thyroid carcinoma, supporting a context-dependent tumor-suppressive function.","evidence":"siRNA knockdown with proliferation/invasion assays and EMT marker Western blots in papillary thyroid cell lines","pmids":["31942970"],"confidence":"Low","gaps":["No mechanistic rescue","Upstream and downstream pathway not connected"]},{"year":2021,"claim":"Linked ITGA7 loss to dopaminergic cell apoptosis and alpha-synuclein accumulation, introducing a possible neuronal role.","evidence":"siRNA knockdown in SH-SY5Y cells with Western blot for TH, alpha-synuclein, and apoptotic markers","pmids":["34884422"],"confidence":"Low","gaps":["Single readout without pathway rescue","Mechanism connecting ITGA7 to alpha-synuclein unknown"]},{"year":2022,"claim":"Showed that QKI-controlled X1/X2 splicing of Itga7 governs protein polarity, asymmetric muscle stem cell division, and progenitor maintenance, giving functional meaning to the long-known isoform diversity.","evidence":"Conditional QKI knockout mouse, transcriptomics, antisense splice-switching, and imaging of protein polarity","pmids":["35165120"],"confidence":"High","gaps":["Distinct ligand or signaling properties of X1 vs X2 not defined","How polarized ITGA7 directs the spindle/division apparatus unresolved"]},{"year":2022,"claim":"Defined an ATF1/miR-214-5p axis that directly represses ITGA7 to promote osteoclastogenesis, identifying a transcriptional/post-transcriptional repression arm.","evidence":"ChIP, luciferase reporter, siRNA epistasis, TRAP staining, and OVX mouse model","pmids":["35568813"],"confidence":"Medium","gaps":["Downstream signaling of derepressed ITGA7 in osteoclasts not detailed"]},{"year":2022,"claim":"Connected ITGA7 to PI3K-AKT activation in bone marrow stem cells responding to nanohydroxyapatite, implicating it in matrix-sensing osteogenic signaling.","evidence":"hBMSC culture with nHAP, ITGA7 siRNA knockdown, PI3K-AKT activity assays, and ectopic osteogenesis in mice","pmids":["35415300"],"confidence":"Medium","gaps":["Direct ITGA7-PI3K coupling not biochemically resolved here","Mechanism distinguishing fixed vs free nHAP effects unclear"]},{"year":2022,"claim":"Extended the ITGA7/alpha-synuclein relationship to muscle cells, supporting a conserved suppression of alpha-synuclein accumulation.","evidence":"siRNA knockdown in C2C12 cells with immunofluorescence and Western blot","pmids":["35628462"],"confidence":"Low","gaps":["Single readout, no mechanistic follow-up","Causal pathway to alpha-synuclein unknown"]},{"year":2023,"claim":"Established ITGA7 as an upstream activator of PI3K-AKT supporting proliferation and survival in granulosa cells, generalizing its pro-survival signaling role.","evidence":"siRNA knockdown with PI3K-AKT Western blots, apoptosis flow cytometry, and proliferation assays in porcine granulosa cells","pmids":["36901882"],"confidence":"Low","gaps":["No direct binding or reconstitution","Effector linking ITGA7 to PI3K not identified in this system"]},{"year":2023,"claim":"Provided nanoscale spatial evidence that ITGA7 and dystroglycan co-localize at the sarcolemma, supporting parallel matrix-cytoskeleton linkage roles.","evidence":"FPALM super-resolution microscopy with confocal validation in intact zebrafish muscle fibers","pmids":["37509580"],"confidence":"Medium","gaps":["Physical interaction between ITGA7 and dystroglycan not demonstrated","Functional consequence of distinct nanoscale distributions unclear"]},{"year":2024,"claim":"Defined the molecular mechanism by which ITGA7 restrains pro-invasive signaling: binding CKAP4 to block CKAP4-PI3K p85alpha interaction and suppress NF-kB-driven transcription of MMP9, SETD7, and ADAM15.","evidence":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, rescue assays, and promoter methylation analysis in colorectal cancer cells","pmids":["38885843"],"confidence":"Medium","gaps":["CoIP from single lab without reciprocal structural validation","Reconciliation with FOXC1-driven pro-invasive role not fully integrated"]},{"year":2024,"claim":"Implicated ITGA7 in maintaining stromal stem cell identity, where its loss drives cancer-associated fibroblast conversion and a pro-metastatic secretome.","evidence":"siRNA knockdown in primary omental ADSCs with morphology, biomarker, and conditioned-medium migration assays","pmids":["38174862"],"confidence":"Low","gaps":["No mechanistic pathway identified","Secreted factors driving cancer cell invasion not defined"]},{"year":null,"claim":"It remains unresolved how ITGA7 produces opposite effects across contexts — acting as a PI3K-AKT activator and pro-invasive effector in some tissues while suppressing PI3K/AKT/NF-kB and EMT in others.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model reconciling activating vs suppressing roles","Isoform-specific signaling differences not mapped to cancer/stem cell phenotypes","No structural model of the ITGA7-CKAP4 interface"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,11,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,13]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["CKAP4","DAG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13683","full_name":"Integrin alpha-7","aliases":[],"length_aa":1181,"mass_kda":128.9,"function":"Integrin alpha-7/beta-1 is the primary laminin receptor on skeletal myoblasts and adult myofibers. During myogenic differentiation, it may induce changes in the shape and mobility of myoblasts, and facilitate their localization at laminin-rich sites of secondary fiber formation. It is involved in the maintenance of the myofibers cytoarchitecture as well as for their anchorage, viability and functional integrity. Isoform Alpha-7X2B and isoform Alpha-7X1B promote myoblast migration on laminin 1 and laminin 2/4, but isoform Alpha-7X1B is less active on laminin 1 (In vitro). Acts as a Schwann cell receptor for laminin-2. Acts as a receptor of COMP and mediates its effect on vascular smooth muscle cells (VSMCs) maturation (By similarity). Required to promote contractile phenotype acquisition in differentiated airway smooth muscle (ASM) cells","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13683/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ITGA7","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ITGA7","total_profiled":1310},"omim":[{"mim_id":"613204","title":"MUSCULAR DYSTROPHY, CONGENITAL, DUE TO INTEGRIN ALPHA-7 DEFICIENCY","url":"https://www.omim.org/entry/613204"},{"mim_id":"608625","title":"PEPTIDYL-tRNA HYDROLASE 2; PTRH2","url":"https://www.omim.org/entry/608625"},{"mim_id":"602714","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 12; ADAM12","url":"https://www.omim.org/entry/602714"},{"mim_id":"600536","title":"INTEGRIN, ALPHA-7; ITGA7","url":"https://www.omim.org/entry/600536"},{"mim_id":"310200","title":"MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD","url":"https://www.omim.org/entry/310200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":138.6},{"tissue":"skeletal muscle","ntpm":135.6}],"url":"https://www.proteinatlas.org/search/ITGA7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13683","domains":[{"cath_id":"2.130.10.130","chopping":"40-234_245-268_303-516","consensus_level":"medium","plddt":92.5963,"start":40,"end":516},{"cath_id":"2.60.40.1460","chopping":"519-645_661-677","consensus_level":"high","plddt":88.979,"start":519,"end":677},{"cath_id":"2.60.40.1510","chopping":"692-848","consensus_level":"high","plddt":86.8339,"start":692,"end":848},{"cath_id":"2.60.40.1530","chopping":"852-946_989-1071","consensus_level":"high","plddt":81.1022,"start":852,"end":1071}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13683","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13683-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13683-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ITGA7","jax_strain_url":"https://www.jax.org/strain/search?query=ITGA7"},"sequence":{"accession":"Q13683","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13683.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13683/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13683"}},"corpus_meta":[{"pmid":"29943828","id":"PMC_29943828","title":"Circular RNA circITGA7 inhibits colorectal cancer growth and metastasis by modulating the Ras pathway and upregulating transcription of its host gene ITGA7.","date":"2018","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29943828","citation_count":220,"is_preprint":false},{"pmid":"31372051","id":"PMC_31372051","title":"Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31372051","citation_count":63,"is_preprint":false},{"pmid":"29884889","id":"PMC_29884889","title":"Forkhead box C1 promotes colorectal cancer metastasis through transactivating ITGA7 and FGFR4 expression.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29884889","citation_count":50,"is_preprint":false},{"pmid":"7607681","id":"PMC_7607681","title":"Localization of the alpha 7 integrin gene (ITGA7) on human chromosome 12q13: clustering of integrin and Hox genes implies parallel evolution of these gene families.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7607681","citation_count":36,"is_preprint":false},{"pmid":"29760566","id":"PMC_29760566","title":"ITGA7 functions as a tumor suppressor and regulates migration and invasion in breast cancer.","date":"2018","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/29760566","citation_count":35,"is_preprint":false},{"pmid":"23317273","id":"PMC_23317273","title":"Quantitative real-time RT-PCR of ITGA7, SVEP1, TNS1, LPHN3, SEMA3G, KLB and MMP13 mRNA expression in breast cancer.","date":"2012","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/23317273","citation_count":24,"is_preprint":false},{"pmid":"26076707","id":"PMC_26076707","title":"Human α7 Integrin Gene (ITGA7) Delivered by Adeno-Associated Virus Extends Survival of Severely Affected Dystrophin/Utrophin-Deficient 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MPTP-Induced Mouse Model of Parkinson's Disease.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35628462","citation_count":7,"is_preprint":false},{"pmid":"34552617","id":"PMC_34552617","title":"Case Report: A Boy From a Consanguineous Family Diagnosed With Congenital Muscular Dystrophy Caused by Integrin Alpha 7 (ITGA7) Mutation.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34552617","citation_count":7,"is_preprint":false},{"pmid":"34884422","id":"PMC_34884422","title":"Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson's Disease Mouse Model and SH-SY5Y Cells.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34884422","citation_count":6,"is_preprint":false},{"pmid":"38885843","id":"PMC_38885843","title":"Promoter hypermethylation-induced downregulation of ITGA7 promotes colorectal cancer proliferation and migration by activating the PI3K/AKT/NF-κB pathway.","date":"2024","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38885843","citation_count":5,"is_preprint":false},{"pmid":"40210748","id":"PMC_40210748","title":"Molecular typing of gliomas on the basis of integrin family genes and a functional study of ITGA7.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40210748","citation_count":4,"is_preprint":false},{"pmid":"39719569","id":"PMC_39719569","title":"Analysis of the basement membrane-related genes ITGA7 and its regulatory role in periodontitis via machine learning: a retrospective study.","date":"2024","source":"BMC oral health","url":"https://pubmed.ncbi.nlm.nih.gov/39719569","citation_count":4,"is_preprint":false},{"pmid":"36694626","id":"PMC_36694626","title":"circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma.","date":"2023","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36694626","citation_count":3,"is_preprint":false},{"pmid":"38174862","id":"PMC_38174862","title":"ITGA7 loss drives the differentiation of adipose-derived mesenchymal stem cells to cancer-associated fibroblasts.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38174862","citation_count":3,"is_preprint":false},{"pmid":"34743543","id":"PMC_34743543","title":"ITGA7 relates to disease risk, pathological feature, treatment response and survival in Ph- acute lymphoblastic leukemia.","date":"2021","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34743543","citation_count":1,"is_preprint":false},{"pmid":"37509580","id":"PMC_37509580","title":"Super-Resolution Imaging Reveals the Nanoscale Distributions of Dystroglycan and Integrin Itga7 in Zebrafish Muscle Fibers.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/37509580","citation_count":1,"is_preprint":false},{"pmid":"33655887","id":"PMC_33655887","title":"miRNAs regulating the expressions of NTF3, GNG2 and ITGA7 are involved in the pathogenesis of abdominal aortic aneurysm in mice.","date":"2021","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33655887","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.19.613933","title":"A Machine Learning-Based Investigation of Integrin Expression Patterns in Cancer and Metastasis","date":"2024-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.19.613933","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14756,"output_tokens":3657,"usd":0.049562,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11391,"output_tokens":4390,"usd":0.083352,"stage2_stop_reason":"end_turn"},"total_usd":0.132914,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"ITGA7 is encoded by a single gene in both rat and human genomes, localized to human chromosome 12q13, and its expression is developmentally regulated during skeletal muscle formation with isoforms containing different cytoplasmic and extracellular domains accompanying myogenesis.\",\n      \"method\": \"Southern blotting and in situ hybridization; phylogenetic analysis of integrin alpha chain sequences\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic mapping by Southern blot and in situ hybridization, single lab, two complementary methods\",\n      \"pmids\": [\"7607681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human ITGA7 gene comprises at least 27 exons spanning ~22.5 kb; major cytoplasmic variants alpha7A and alpha7B and extracellular isoforms X1 and X2 are expressed in human tissues in a developmentally regulated and tissue-specific manner, and a D variant is detectable in adult tissues.\",\n      \"method\": \"Genomic sequencing of exon/intron boundaries, RT-PCR for splice variant identification, radiation hybrid mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural characterization by sequencing and RT-PCR, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"10403775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AAV-mediated systemic overexpression of ITGA7 in mdx/utrn(-/-) mice (a severe DMD model) extended longevity, reduced kyphosis, protected against contraction-induced force loss, and increased specific force in diaphragm and EDL muscles, functioning as a laminin receptor that links the extracellular matrix to the internal actin cytoskeleton at the sarcolemma.\",\n      \"method\": \"In vivo AAV gene delivery (rAAVrh.74.MCK.ITGA7) in mdx/utrn(-/-) mice; force measurement; immunohistochemistry for sarcolemmal localization\",\n      \"journal\": \"Human gene therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gene delivery with functional force readouts and defined cellular localization, multiple phenotypic endpoints, replicates prior work on alpha7 integrin function\",\n      \"pmids\": [\"26076707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXC1 directly binds to the ITGA7 promoter and transcriptionally activates ITGA7 expression; genetic epistasis confirmed that ITGA7 acts downstream of FOXC1 to promote colorectal cancer invasion and metastasis.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation), transcriptional reporter assays, genetic epistasis analysis (FOXC1 overexpression/knockdown with ITGA7 manipulation), in vivo lung metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and epistasis in multiple cellular and in vivo models, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"29884889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of ITGA7 in breast cancer cell lines (MDA-MB-231 and BT-549) significantly inhibited migration and invasion, and was accompanied by upregulation of c-Met and vimentin, suggesting ITGA7 suppresses EMT-related pathways.\",\n      \"method\": \"siRNA knockdown, migration and invasion assays, Western blot\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with downstream protein readout, no mechanistic rescue\",\n      \"pmids\": [\"29760566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of ITGA7 in papillary thyroid carcinoma cell lines (TPC1 and KTC-1) enhanced proliferation, migration, invasion, and colony formation while decreasing apoptosis, accompanied by decreased E-cadherin and increased N-cadherin and vimentin, indicating ITGA7 suppresses epithelial-to-mesenchymal transition in thyroid cancer.\",\n      \"method\": \"siRNA knockdown, proliferation/migration/invasion assays, Western blot for EMT markers\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with phenotypic and protein readouts, no mechanistic rescue\",\n      \"pmids\": [\"31942970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ITGA7 knockdown via siRNA in SH-SY5Y (dopaminergic) cells decreased TH expression, increased alpha-synuclein expression, decreased bcl2, and increased the bax/bcl2 ratio, indicating that ITGA7 loss promotes dopaminergic cell apoptosis and alpha-synuclein accumulation.\",\n      \"method\": \"siRNA knockdown in SH-SY5Y cells; immunohistochemistry and Western blot for TH, alpha-syn, bcl2, bax\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA approach with protein-level readouts only, no pathway rescue or mechanistic follow-up\",\n      \"pmids\": [\"34884422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The RNA-binding protein QKI regulates alternative splicing of Itga7, controlling the mutually exclusive Itga7-X1 and -X2 isoforms in muscle stem cells; QKI loss or antisense oligonucleotide-forced shift to X1 isoform disrupts polarized localization of Itga7 and Dmd proteins, impairs asymmetric cell divisions, and reduces the myogenic progenitor population.\",\n      \"method\": \"Conditional QKI knockout mouse; transcriptomic analysis; antisense oligonucleotide splice-switching; immunofluorescence for protein polarity; quantification of asymmetric divisions\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with transcriptomic validation, antisense oligonucleotide recapitulation, and direct imaging of protein polarity across multiple orthogonal experiments\",\n      \"pmids\": [\"35165120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATF1 transcriptionally activates miR-214-5p, which directly targets and represses ITGA7; this ATF1/miR-214-5p/ITGA7 axis promotes osteoclastogenesis, and knockdown of miR-214-5p suppresses osteoclast differentiation through derepression of ITGA7.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown of ATF1/miR-214-5p/ITGA7, TRAP staining for osteoclast differentiation, OVX mouse model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase validate direct regulation, functional epistasis in cells and in vivo, single lab\",\n      \"pmids\": [\"35568813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fixed-state nanohydroxyapatite (nHAP) upregulates ITGA7 in human bone marrow stem cells, and ITGA7 upregulation mediates activation of the PI3K-AKT signaling pathway to promote osteogenesis; free-state nHAP produces the opposite effect.\",\n      \"method\": \"In vitro hBMSC culture with different nHAP forms; siRNA knockdown of ITGA7; PI3K-AKT pathway activity assays; ectopic osteogenesis in mouse subcutaneous model\",\n      \"journal\": \"Bioactive materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ITGA7 knockdown with pathway readout and in vivo confirmation, single lab, multiple methods\",\n      \"pmids\": [\"35415300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGA7 knockdown in C2C12 cells significantly increased alpha-synuclein expression, indicating that ITGA7 normally suppresses alpha-synuclein accumulation in muscle cells.\",\n      \"method\": \"siRNA knockdown in C2C12 cells; immunofluorescence and Western blot for ITGA7 and alpha-synuclein\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with single readout, no mechanistic follow-up\",\n      \"pmids\": [\"35628462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Knockdown of ITGA7 by siRNA in porcine ovarian granulosa cells significantly inhibited the PI3K-AKT signaling pathway, decreased PCNA expression, and increased apoptosis rates and pro-apoptotic proteins, establishing ITGA7 as an upstream activator of PI3K-AKT signaling in granulosa cells.\",\n      \"method\": \"siRNA knockdown; Western blot for PI3K-AKT pathway components; flow cytometry for apoptosis; CCK-8 proliferation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA approach with downstream pathway readout, no direct binding or reconstitution\",\n      \"pmids\": [\"36901882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ITGA7 and Dystroglycan co-localize at the nanoscale in zebrafish muscle fibers at the sarcolemma, with distinct nanoscale distributions detectable by super-resolution FPALM microscopy, consistent with their shared role in connecting the cytoskeleton to the extracellular matrix.\",\n      \"method\": \"FPALM super-resolution microscopy in intact zebrafish muscle fibers; confocal imaging validation\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by super-resolution imaging in intact tissue, single lab, two imaging modalities\",\n      \"pmids\": [\"37509580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ITGA7 binds to CKAP4 (co-immunoprecipitation), blocking the interaction between CKAP4 and PI3K p85α, thereby suppressing PI3K/AKT/NF-κB pathway activation; loss of ITGA7 releases CKAP4 to interact with PI3K p85α, activating NF-κB nuclear translocation and transcription of MMP9, SETD7, and ADAM15 in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (CoIP), Western blot, nuclear/cytoplasmic fractionation, RNA sequencing, RT-qPCR, rescue assays; promoter methylation analysis (BSP) and 5-Aza-CdR treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP establishes direct protein-protein interaction, supported by pathway rescue assays and fractionation, single lab\",\n      \"pmids\": [\"38885843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of ITGA7 in omental adipose-derived mesenchymal stem cells (ADSCs) decreased stemness properties and induced the emergence of cancer-associated fibroblast (CAF) morphology and biomarkers; conditioned medium from ITGA7-depleted ADSCs enhanced migration and invasion of ovarian cancer cells in vitro.\",\n      \"method\": \"siRNA knockdown of ITGA7 in primary ADSCs; morphological assessment; biomarker analysis; conditioned medium migration/invasion assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with phenotypic and biomarker readouts, no mechanistic pathway identified\",\n      \"pmids\": [\"38174862\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ITGA7 encodes a laminin-binding integrin alpha subunit expressed predominantly in skeletal muscle, where it localizes to the sarcolemma and links the extracellular matrix to the internal actin cytoskeleton; its expression is transcriptionally activated by FOXC1 and repressed by ATF1/miR-214-5p, its alternative splicing (X1/X2 isoforms) is regulated by the RNA-binding protein QKI to control muscle stem cell polarity and asymmetric division, and at the molecular level ITGA7 binds CKAP4 to suppress PI3K/AKT/NF-κB signaling, while loss of ITGA7 releases CKAP4 to activate PI3K p85α, driving NF-κB nuclear translocation and upregulation of pro-invasive targets.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ITGA7 encodes a laminin-binding integrin alpha subunit that localizes to the skeletal muscle sarcolemma, where it functions as a laminin receptor linking the extracellular matrix to the internal actin cytoskeleton; its systemic overexpression in a severe muscular dystrophy mouse model extends longevity, reduces kyphosis, and protects against contraction-induced force loss [#2]. The gene is developmentally regulated during myogenesis and produces multiple cytoplasmic (alpha7A/B) and extracellular (X1/X2) splice variants encoded across at least 27 exons [#0, #1]. Alternative splicing of the mutually exclusive X1/X2 isoforms is controlled by the RNA-binding protein QKI, and this isoform choice governs polarized localization of ITGA7 and dystrophin proteins, asymmetric muscle stem cell division, and maintenance of the myogenic progenitor population [#7]; at the sarcolemma ITGA7 co-localizes at the nanoscale with dystroglycan, consistent with a shared role in coupling cytoskeleton to matrix [#12]. ITGA7 expression is directly activated by FOXC1 binding to its promoter and repressed through an ATF1/miR-214-5p axis [#3, #8]. Mechanistically, ITGA7 binds CKAP4 to block the CKAP4–PI3K p85alpha interaction, thereby restraining PI3K/AKT/NF-kB signaling; loss of ITGA7 releases CKAP4 to activate p85alpha, driving NF-kB nuclear translocation and transcription of pro-invasive targets including MMP9, SETD7, and ADAM15 in colorectal cancer [#13]. ITGA7 also acts as an upstream activator of PI3K-AKT signaling in non-muscle contexts such as granulosa cells and osteogenic stem cells [#9, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established ITGA7 as a single-copy gene whose expression is developmentally regulated during skeletal muscle formation, framing it as a myogenesis-associated integrin.\",\n      \"evidence\": \"Southern blotting, in situ hybridization, and phylogenetic analysis in rat and human genomes\",\n      \"pmids\": [\"7607681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define isoform function\", \"No protein-level localization or ligand confirmed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the exon/intron architecture and catalogued the cytoplasmic (alpha7A/B) and extracellular (X1/X2) splice variants, defining the structural repertoire later shown to be functionally important.\",\n      \"evidence\": \"Genomic sequencing of exon boundaries, RT-PCR, radiation hybrid mapping\",\n      \"pmids\": [\"10403775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional distinction between isoforms not established\", \"Regulators of splicing unknown at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that ITGA7 acts as a sarcolemmal laminin receptor coupling matrix to cytoskeleton, with therapeutic restoration of muscle force in a dystrophy model.\",\n      \"evidence\": \"AAV-mediated systemic ITGA7 overexpression in mdx/utrn(-/-) mice with force measurement and immunohistochemistry\",\n      \"pmids\": [\"26076707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners at the sarcolemma not enumerated\", \"Signaling consequences downstream of ITGA7 not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified FOXC1 as a direct transcriptional activator of ITGA7 and placed ITGA7 downstream of FOXC1 in driving cancer invasion, extending ITGA7 biology beyond muscle.\",\n      \"evidence\": \"ChIP, reporter assays, genetic epistasis, and in vivo lung metastasis model in colorectal cancer\",\n      \"pmids\": [\"29884889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector of ITGA7-driven invasion not yet defined\", \"Whether muscle isoforms apply to cancer context unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Indicated a tumor-suppressive role of ITGA7 in breast cancer via repression of EMT-associated markers, an apparent contrast to its pro-invasive role elsewhere.\",\n      \"evidence\": \"siRNA knockdown with migration/invasion assays and Western blot in breast cancer lines\",\n      \"pmids\": [\"29760566\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic rescue\", \"Direction of effect conflicts with colorectal findings, unresolved by context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced an EMT-suppressing role of ITGA7 in thyroid carcinoma, supporting a context-dependent tumor-suppressive function.\",\n      \"evidence\": \"siRNA knockdown with proliferation/invasion assays and EMT marker Western blots in papillary thyroid cell lines\",\n      \"pmids\": [\"31942970\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic rescue\", \"Upstream and downstream pathway not connected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ITGA7 loss to dopaminergic cell apoptosis and alpha-synuclein accumulation, introducing a possible neuronal role.\",\n      \"evidence\": \"siRNA knockdown in SH-SY5Y cells with Western blot for TH, alpha-synuclein, and apoptotic markers\",\n      \"pmids\": [\"34884422\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single readout without pathway rescue\", \"Mechanism connecting ITGA7 to alpha-synuclein unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that QKI-controlled X1/X2 splicing of Itga7 governs protein polarity, asymmetric muscle stem cell division, and progenitor maintenance, giving functional meaning to the long-known isoform diversity.\",\n      \"evidence\": \"Conditional QKI knockout mouse, transcriptomics, antisense splice-switching, and imaging of protein polarity\",\n      \"pmids\": [\"35165120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct ligand or signaling properties of X1 vs X2 not defined\", \"How polarized ITGA7 directs the spindle/division apparatus unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an ATF1/miR-214-5p axis that directly represses ITGA7 to promote osteoclastogenesis, identifying a transcriptional/post-transcriptional repression arm.\",\n      \"evidence\": \"ChIP, luciferase reporter, siRNA epistasis, TRAP staining, and OVX mouse model\",\n      \"pmids\": [\"35568813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling of derepressed ITGA7 in osteoclasts not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ITGA7 to PI3K-AKT activation in bone marrow stem cells responding to nanohydroxyapatite, implicating it in matrix-sensing osteogenic signaling.\",\n      \"evidence\": \"hBMSC culture with nHAP, ITGA7 siRNA knockdown, PI3K-AKT activity assays, and ectopic osteogenesis in mice\",\n      \"pmids\": [\"35415300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ITGA7-PI3K coupling not biochemically resolved here\", \"Mechanism distinguishing fixed vs free nHAP effects unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the ITGA7/alpha-synuclein relationship to muscle cells, supporting a conserved suppression of alpha-synuclein accumulation.\",\n      \"evidence\": \"siRNA knockdown in C2C12 cells with immunofluorescence and Western blot\",\n      \"pmids\": [\"35628462\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single readout, no mechanistic follow-up\", \"Causal pathway to alpha-synuclein unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established ITGA7 as an upstream activator of PI3K-AKT supporting proliferation and survival in granulosa cells, generalizing its pro-survival signaling role.\",\n      \"evidence\": \"siRNA knockdown with PI3K-AKT Western blots, apoptosis flow cytometry, and proliferation assays in porcine granulosa cells\",\n      \"pmids\": [\"36901882\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or reconstitution\", \"Effector linking ITGA7 to PI3K not identified in this system\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided nanoscale spatial evidence that ITGA7 and dystroglycan co-localize at the sarcolemma, supporting parallel matrix-cytoskeleton linkage roles.\",\n      \"evidence\": \"FPALM super-resolution microscopy with confocal validation in intact zebrafish muscle fibers\",\n      \"pmids\": [\"37509580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physical interaction between ITGA7 and dystroglycan not demonstrated\", \"Functional consequence of distinct nanoscale distributions unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the molecular mechanism by which ITGA7 restrains pro-invasive signaling: binding CKAP4 to block CKAP4-PI3K p85alpha interaction and suppress NF-kB-driven transcription of MMP9, SETD7, and ADAM15.\",\n      \"evidence\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, rescue assays, and promoter methylation analysis in colorectal cancer cells\",\n      \"pmids\": [\"38885843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CoIP from single lab without reciprocal structural validation\", \"Reconciliation with FOXC1-driven pro-invasive role not fully integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated ITGA7 in maintaining stromal stem cell identity, where its loss drives cancer-associated fibroblast conversion and a pro-metastatic secretome.\",\n      \"evidence\": \"siRNA knockdown in primary omental ADSCs with morphology, biomarker, and conditioned-medium migration assays\",\n      \"pmids\": [\"38174862\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanistic pathway identified\", \"Secreted factors driving cancer cell invasion not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how ITGA7 produces opposite effects across contexts — acting as a PI3K-AKT activator and pro-invasive effector in some tissues while suppressing PI3K/AKT/NF-kB and EMT in others.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model reconciling activating vs suppressing roles\", \"Isoform-specific signaling differences not mapped to cancer/stem cell phenotypes\", \"No structural model of the ITGA7-CKAP4 interface\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 13]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CKAP4\", \"DAG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}