{"gene":"DAG1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1997,"finding":"Dystroglycan (DAG1) is essential for the development of Reichert's membrane; homozygous Dag1-null mice show disrupted localization of laminin and collagen IV in this extra-embryonic basement membrane, demonstrating that dystroglycan is required for basement membrane organization.","method":"Knockout mouse (Dag1neo2 null allele), immunofluorescence localization of dystroglycan, laminin, and collagen IV in embryos","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with specific phenotypic readout (Reichert's membrane disruption), protein localization by immunofluorescence, replicated observations across multiple embryos","pmids":["9175728"],"is_preprint":false},{"year":2002,"finding":"Striated muscle-specific disruption of DAG1 abolishes the dystrophin-glycoprotein complex in differentiated muscle fibers; satellite cells retaining dystroglycan expression support continued efficient muscle regeneration, and dystroglycan is transiently re-expressed in regenerating muscle fibers.","method":"Muscle-specific conditional knockout (Cre-lox), immunofluorescence, histological analysis of muscle regeneration, comparison with human muscular dystrophy biopsy","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, multiple orthogonal methods (immunofluorescence, histology, human biopsy comparison), published in high-impact journal","pmids":["12230980"],"is_preprint":false},{"year":1993,"finding":"The dystrophin-associated glycoprotein A3a (43DAG) is identical to the cytoplasmic domain of dystroglycan; it is retained in Duchenne muscular dystrophy muscle despite absence of dystrophin, indicating it is not solely dependent on dystrophin for membrane localization.","method":"Internal amino acid sequencing of A3a, antibody generation against synthetic peptide, immunohistochemistry and immunoblot of DMD patient muscle (n=30)","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein sequencing identifying A3a as dystroglycan cytoplasmic domain, immunohistochemical validation in 30 DMD patients","pmids":["8113213"],"is_preprint":false},{"year":1993,"finding":"The dystrophin-associated protein 43DAG (A3a, corresponding to dystroglycan) is expressed in skeletal muscle, cardiac muscle, smooth muscle, lung, liver, CNS, and peripheral nerve in monkeys, whereas 50DAG is restricted to skeletal and cardiac muscle, indicating tissue-specific distribution of dystrophin-glycoprotein complex components.","method":"Immunoblot analysis of multiple monkey tissues with antibodies against 50DAG (A2) and 43DAG (A3a)","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single-lab immunoblot across multiple tissues, no functional manipulation, but systematic tissue survey with clear results","pmids":["8138555"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, loss of dag1 (p.V567D missense mutation causing complete absence of protein) destabilizes the dystroglycan complex, causing membrane damage at myosepta and basement membranes between myofibers; additionally, structural abnormalities in triads (t-tubules and sarcoplasmic reticulum) precede sarcolemmal damage, and a subpopulation of dystroglycan localizes to t-tubules in normal skeletal muscle.","method":"Forward genetic screen, genetic mapping, immunofluorescence, immunogold electron microscopy, analysis of t-tubule and sarcoplasmic reticulum structure in dag1 mutant fish","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function zebrafish model with multiple orthogonal readouts (immunofluorescence, immunogold EM, structural analysis), subcellular localization tied to functional consequence","pmids":["21296866"],"is_preprint":false},{"year":2014,"finding":"Compound heterozygous missense mutations in the N-terminal region of α-dystroglycan (DAG1) affect its glycosylation; mutated DAG1 cDNAs fail to rescue the phenotype in DAG1-knockout haploid human cells, confirming these mutations are pathogenic by disrupting α-dystroglycan glycosylation.","method":"Whole-exome sequencing, DAG1-knockout haploid human cell line transfection with mutant DAG1 cDNA (phenotype-rescue assay), immunoblot for α-dystroglycan expression","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based rescue assay in knockout background with defined molecular readout, single lab but uses orthogonal genetic and biochemical methods","pmids":["25503980"],"is_preprint":false},{"year":2018,"finding":"A novel homozygous missense mutation in DAG1 (c.2326C>T; p.R776C) causes significant reduction of α-dystroglycan expression in muscle tissue, establishing that this conserved residue is required for normal α-dystroglycan protein levels.","method":"Whole exome sequencing, Sanger sequencing for co-segregation, immunoblotting of muscle tissue for α-dystroglycan","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single family study, single immunoblot method, no functional rescue experiment","pmids":["30450679"],"is_preprint":false},{"year":2009,"finding":"Sp1 transcription factor directly binds to GC-box elements in the mouse Dag1 gene promoter to drive its expression; DNA methylation reduces Dag1 promoter activity, and promoter methylation decreases while expression increases during C2C12 myoblast differentiation into myotubes.","method":"Promoter deletion/transfection analysis, chromatin immunoprecipitation (ChIP) for Sp1 binding, siRNA knockdown of Sp1, 5-aza-2'-deoxycytidine and trichostatin A treatment, in vitro methylation assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct Sp1 binding, siRNA knockdown shows functional consequence, methylation experiments orthogonally confirm epigenetic regulation, single lab","pmids":["19657058"],"is_preprint":false},{"year":2023,"finding":"circ-TNRC6B sponges miR-452-5p to upregulate DAG1 expression and activity in esophageal squamous cell carcinoma cells; loss of DAG1 activity contributes to tumor cell proliferation, migration, and invasion.","method":"RNA immunoprecipitation, dual-luciferase reporter assay, overexpression and knockdown functional experiments in ESCC cells","journal":"Molecular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect evidence for DAG1 functional role through miRNA sponge mechanism; DAG1 functional role not directly tested with specific DAG1 manipulation","pmids":["37014625"],"is_preprint":false}],"current_model":"DAG1 (dystroglycan) is a central component of the dystrophin-glycoprotein complex that anchors cells to the basement membrane via interactions with laminin and other extracellular matrix components; it is required for basement membrane organization (including Reichert's membrane in early embryogenesis), localizes to the sarcolemma and t-tubules in skeletal muscle where it stabilizes the DGC, and its α-subunit undergoes critical glycosylation that is disrupted in dystroglycanopathies; DAG1 expression is transcriptionally regulated by Sp1 binding to GC-box promoter elements and by DNA methylation/histone acetylation, increasing during myoblast differentiation."},"narrative":{"mechanistic_narrative":"DAG1 (dystroglycan) is a core component of the dystrophin-glycoprotein complex (DGC) that links cells to the basement membrane and is required for basement membrane organization, as shown by the disrupted localization of laminin and collagen IV in the Reichert's membrane of Dag1-null embryos [PMID:9175728]. The protein is processed into a cytoplasmic dystrophin-associated subunit (43DAG/A3a) and a heavily glycosylated extracellular α-dystroglycan [PMID:8113213], with the α-subunit's glycosylation being the critical determinant of function: missense mutations in the N-terminal region or at conserved residues disrupt α-dystroglycan glycosylation and protein levels and cause dystroglycanopathy, confirmed by failure of mutant DAG1 cDNA to rescue DAG1-knockout cells [PMID:25503980, PMID:30450679]. In striated muscle, dystroglycan is required to assemble and maintain the DGC at the sarcolemma, and a subpopulation localizes to t-tubules; its loss abolishes the complex in differentiated fibers and produces membrane damage at myosepta and structural defects in triads, while satellite-cell expression supports muscle regeneration [PMID:12230980, PMID:21296866]. The 43DAG cytoplasmic subunit persists at the membrane in Duchenne dystrophy muscle lacking dystrophin, indicating its localization is not strictly dystrophin-dependent [PMID:8113213]. DAG1 transcription is driven by direct Sp1 binding to GC-box promoter elements and is repressed by DNA methylation, with promoter demethylation and increased expression accompanying myoblast-to-myotube differentiation [PMID:19657058].","teleology":[{"year":1993,"claim":"Establishing the molecular identity of the dystrophin-associated glycoproteins was needed to define the DGC architecture; sequencing showed 43DAG/A3a is the cytoplasmic domain of dystroglycan and that it persists in dystrophin-deficient muscle.","evidence":"Internal amino acid sequencing, anti-peptide antibodies, and immunohistochemistry/immunoblot of DMD patient muscle","pmids":["8113213"],"confidence":"High","gaps":["Does not define how 43DAG is anchored at the membrane in the absence of dystrophin","No structural detail on the α/β cleavage or glycosylation"]},{"year":1993,"claim":"Mapping the tissue distribution of DGC components clarified which are broadly versus restrictedly expressed; 43DAG (dystroglycan) is widely distributed across muscle, nerve, CNS and viscera, unlike the muscle-restricted 50DAG.","evidence":"Immunoblot survey of multiple monkey tissues with subunit-specific antibodies","pmids":["8138555"],"confidence":"Medium","gaps":["Descriptive expression only, no functional role assigned per tissue","Single-lab immunoblot without quantification"]},{"year":1997,"claim":"The developmental requirement for dystroglycan was unknown; knockout mice revealed it is essential for organizing the Reichert's membrane basement membrane by correctly positioning laminin and collagen IV.","evidence":"Dag1-null knockout mouse with immunofluorescence localization of dystroglycan, laminin, and collagen IV in embryos","pmids":["9175728"],"confidence":"High","gaps":["Early embryonic lethality limits analysis of later tissue roles","Does not resolve direct versus indirect ECM-binding mechanism"]},{"year":2002,"claim":"Whether dystroglycan is required cell-autonomously in mature muscle and during regeneration was unclear; muscle-specific deletion showed it is essential for the DGC in differentiated fibers, while satellite-cell expression sustains regeneration.","evidence":"Cre-lox muscle-specific conditional knockout with immunofluorescence, regeneration histology, and human muscular dystrophy biopsy comparison","pmids":["12230980"],"confidence":"High","gaps":["Does not define the signaling consequences of DGC loss beyond membrane stability","Mechanism of transient re-expression in regenerating fibers not resolved"]},{"year":2009,"claim":"How DAG1 transcription is controlled was unknown; Sp1 binding to GC-box promoter elements and epigenetic DNA methylation were shown to regulate expression, which rises during myoblast differentiation.","evidence":"Promoter deletion/transfection, ChIP for Sp1, Sp1 siRNA, methylation/HDAC inhibitor treatment, and in vitro methylation assays in C2C12 cells","pmids":["19657058"],"confidence":"Medium","gaps":["Demonstrated in mouse promoter; human regulatory architecture not addressed","Does not link transcriptional control to specific developmental signals"]},{"year":2011,"claim":"The subcellular basis of dystroglycan's role in muscle membrane integrity was incomplete; a zebrafish loss-of-function model showed it stabilizes membranes at myosepta and that t-tubule/triad defects precede sarcolemmal damage, placing a subpopulation of dystroglycan at t-tubules.","evidence":"Forward genetic screen with mapping, immunofluorescence, immunogold EM, and triad ultrastructural analysis in dag1 mutant zebrafish","pmids":["21296866"],"confidence":"High","gaps":["Molecular basis of the t-tubule localization and triad role unresolved","Whether triad defects are primary or secondary to membrane fragility not fully established"]},{"year":2014,"claim":"Whether N-terminal α-dystroglycan mutations are pathogenic was open; a knockout-cell rescue assay confirmed that such missense mutations disrupt α-dystroglycan glycosylation and cause disease.","evidence":"Whole-exome sequencing plus DAG1-knockout haploid human cell rescue assay with mutant cDNA and α-dystroglycan immunoblot","pmids":["25503980"],"confidence":"Medium","gaps":["The specific glycosyltransferase step impaired by the N-terminal mutation not pinpointed","Single-lab cell-based readout"]},{"year":2018,"claim":"Whether a conserved C-terminal residue affects α-dystroglycan levels was unknown; a homozygous p.R776C mutation was associated with reduced α-dystroglycan in patient muscle.","evidence":"Whole-exome and Sanger co-segregation sequencing with α-dystroglycan immunoblot of muscle tissue","pmids":["30450679"],"confidence":"Low","gaps":["Single family with no functional rescue experiment","Causality versus correlation not established by orthogonal methods"]},{"year":2023,"claim":"A possible role for DAG1 in epithelial cancer was tested; a circ-TNRC6B/miR-452-5p axis was reported to regulate DAG1 levels, with reduced DAG1 activity associated with ESCC proliferation, migration, and invasion.","evidence":"RNA immunoprecipitation, dual-luciferase reporter, and overexpression/knockdown assays in esophageal squamous cell carcinoma cells","pmids":["37014625"],"confidence":"Low","gaps":["DAG1's functional role inferred through the miRNA axis rather than direct DAG1 manipulation","Mechanism by which DAG1 restrains tumor cell behavior not defined"]},{"year":null,"claim":"How α-dystroglycan glycosylation is enzymatically built and how its disruption maps quantitatively to dystroglycanopathy severity, and what downstream signaling the DGC transmits beyond membrane anchorage, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of glycosylated α-dystroglycan bound to ECM ligands in the timeline","Signaling outputs of the cytoplasmic 43DAG domain not characterized","Genotype-phenotype rules for individual DAG1 mutations not systematically established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]}],"complexes":["dystrophin-glycoprotein complex"],"partners":["DMD","LAMA2","COL4A1","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14118","full_name":"Dystroglycan 1","aliases":["Dystroglycan","Dystrophin-associated glycoprotein 1"],"length_aa":895,"mass_kda":97.4,"function":"The dystroglycan complex is involved in a number of signaling events and processes including laminin deposition and extracellular matrix assembly, acetylcholine receptor clustering, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, epithelial polarization, and epithelium branching morphogenesis (By similarity). Required for the formation of photoreceptor ribbon synapses, and long-term maintenance of inhibitory synapses in cerebellar Purkinje cells (By similarity). Also involved in the positive regulation of cartilage formation through agrin (AGRN) binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation (PubMed:26290588) Extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains. As a receptor for laminin is involved in extracellular matrix assembly, and activation of the PI3K/AKT pathway regulating cell apoptotic signals in muscle (By similarity). Binding of laminin LAMA1 to alpha-dystroglycan also initiates a signaling cascade in which Src kinases, c-Src or c-Fyn, phosphorylate syntrophin modifying its interaction with the adapter protein GRB2; this triggers recruitment of guanyl-nucleotide exchange factor SOS1 and activation of RAC1, finally resulting in c-Jun phosphorylation by MAPK8/JNK1 (By similarity). As a receptor for laminin LAMA1 is also involved in epithelium branching morphogenesis in salivary glang and lung (By similarity). Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells (By similarity). Also acts as a receptor for laminin LAMA5 (By similarity). In muscle cells, it is a receptor for laminin-1 (also known as laminin-111 or EHS laminin) and is involved in the stimulation of agrin-induced acetylcholine receptor (AChR) clustering, and formation of the synaptic basement membrane. It is required for acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ) through its binding with perlecan (HSPG2) and is, therefore, involved in the down-regulation of colinergic synaptic transmission (By similarity). In the retina, it is required for the formation of photoreceptor ribbon synapses through its interaction with pikachurin (EGFLAM) (By similarity). Involved in the positive regulation of cartilage formation through agrin (AGRN) binding and up-regulation of SOX9, a transcription factor that plays a key role in chondrocytes differentiation (PubMed:26290588) Transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus glycoprotein and class C new-world arenaviruses (PubMed:16254364, PubMed:17360738, PubMed:19324387). Acts as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy, but only in the presence of the G-domain of LAMA2 (PubMed:9851927)","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton; Nucleus, nucleoplasm; Cell membrane, sarcolemma; Synapse; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14118/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DAG1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATP6V1D","stoichiometry":4.0},{"gene":"UTRN","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/DAG1","total_profiled":1310},"omim":[{"mim_id":"620793","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 29; LGMDR29","url":"https://www.omim.org/entry/620793"},{"mim_id":"620166","title":"MUSCULAR DYSTROPHY, CONGENITAL, WITH OR WITHOUT SEIZURES; MYOS","url":"https://www.omim.org/entry/620166"},{"mim_id":"618992","title":"MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 15; MDDGB15","url":"https://www.omim.org/entry/618992"},{"mim_id":"618135","title":"MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 8; MDDGC8","url":"https://www.omim.org/entry/618135"},{"mim_id":"617683","title":"EGF-LIKE, FIBRONECTIN TYPE III, AND LAMININ G DOMAINS-CONTAINING PROTEIN; EGFLAM","url":"https://www.omim.org/entry/617683"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DAG1"},"hgnc":{"alias_symbol":["A3a","156DAG","AGRNR","DAG"],"prev_symbol":[]},"alphafold":{"accession":"Q14118","domains":[{"cath_id":"2.60.40.10","chopping":"71-163","consensus_level":"high","plddt":88.5119,"start":71,"end":163},{"cath_id":"3.30.70.1040","chopping":"185-303","consensus_level":"high","plddt":92.6344,"start":185,"end":303},{"cath_id":"2.60.40.10","chopping":"499-597","consensus_level":"high","plddt":90.5727,"start":499,"end":597},{"cath_id":"-","chopping":"607-720","consensus_level":"high","plddt":85.9118,"start":607,"end":720}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14118","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14118-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14118-F1-predicted_aligned_error_v6.png","plddt_mean":68.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DAG1","jax_strain_url":"https://www.jax.org/strain/search?query=DAG1"},"sequence":{"accession":"Q14118","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14118.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14118/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14118"}},"corpus_meta":[{"pmid":"14610053","id":"PMC_14610053","title":"Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14610053","citation_count":826,"is_preprint":false},{"pmid":"9175728","id":"PMC_9175728","title":"Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9175728","citation_count":445,"is_preprint":false},{"pmid":"10571228","id":"PMC_10571228","title":"Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta: DAG binding to UNC-13 is required to stimulate acetylcholine release.","date":"1999","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/10571228","citation_count":275,"is_preprint":false},{"pmid":"16678913","id":"PMC_16678913","title":"PKD at the crossroads of DAG and PKC signaling.","date":"2006","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16678913","citation_count":274,"is_preprint":false},{"pmid":"26153463","id":"PMC_26153463","title":"DAG tales: the multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.","date":"2015","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/26153463","citation_count":237,"is_preprint":false},{"pmid":"12230980","id":"PMC_12230980","title":"Disruption of DAG1 in differentiated skeletal muscle reveals a role for dystroglycan in muscle regeneration.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12230980","citation_count":232,"is_preprint":false},{"pmid":"11158925","id":"PMC_11158925","title":"DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells.","date":"2001","source":"American journal of physiology. 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How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?","date":"2000","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10715158","citation_count":70,"is_preprint":false},{"pmid":"16418272","id":"PMC_16418272","title":"Goalpha regulates olfactory adaptation by antagonizing Gqalpha-DAG signaling in Caenorhabditis elegans.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16418272","citation_count":69,"is_preprint":false},{"pmid":"11576950","id":"PMC_11576950","title":"Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway.","date":"2001","source":"American journal of kidney diseases : the official journal of the National Kidney 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neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15361878","citation_count":58,"is_preprint":false},{"pmid":"8281158","id":"PMC_8281158","title":"Genetic heterogeneity for Duchenne-like muscular dystrophy (DLMD) based on linkage and 50 DAG analysis.","date":"1993","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8281158","citation_count":57,"is_preprint":false},{"pmid":"8180245","id":"PMC_8180245","title":"Vitamin E suppresses diacylglycerol (DAG) level in thrombin-stimulated endothelial cells through an increase of DAG kinase activity.","date":"1994","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/8180245","citation_count":56,"is_preprint":false},{"pmid":"36525963","id":"PMC_36525963","title":"Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis.","date":"2022","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36525963","citation_count":50,"is_preprint":false},{"pmid":"16741513","id":"PMC_16741513","title":"TRPC7 is a receptor-operated DAG-activated channel in human keratinocytes.","date":"2006","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16741513","citation_count":49,"is_preprint":false},{"pmid":"3443853","id":"PMC_3443853","title":"The agarase gene (dag A) of Streptomyces coelicolor A3(2): affinity purification and characterization of the cloned gene product.","date":"1987","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/3443853","citation_count":49,"is_preprint":false},{"pmid":"8138555","id":"PMC_8138555","title":"Distribution of dystrophin isoforms and dystrophin-associated proteins 43DAG (A3a) and 50DAG (A2) in various monkey tissues.","date":"1993","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8138555","citation_count":44,"is_preprint":false},{"pmid":"10588371","id":"PMC_10588371","title":"d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity.","date":"1999","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/10588371","citation_count":44,"is_preprint":false},{"pmid":"2605168","id":"PMC_2605168","title":"Conformation of DNA modified at a d(GG) or a d(AG) site by the antitumor drug cis-diamminedichloroplatinum(II).","date":"1989","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2605168","citation_count":44,"is_preprint":false},{"pmid":"35159379","id":"PMC_35159379","title":"Carboxypeptidase A3-A Key Component of the Protease Phenotype of Mast Cells.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35159379","citation_count":42,"is_preprint":false},{"pmid":"12724346","id":"PMC_12724346","title":"Receptor-coupled, DAG-gated Ca2+-permeable cationic channels in LNCaP human prostate cancer epithelial cells.","date":"2003","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12724346","citation_count":42,"is_preprint":false},{"pmid":"21986573","id":"PMC_21986573","title":"Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway.","date":"2011","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/21986573","citation_count":42,"is_preprint":false},{"pmid":"31210638","id":"PMC_31210638","title":"A FRET sensor of C-terminal movement reveals VRAC activation by plasma membrane DAG signaling rather than ionic strength.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31210638","citation_count":37,"is_preprint":false},{"pmid":"20837870","id":"PMC_20837870","title":"DAG lipase involvement in depolarization-induced suppression of inhibition: does endocannabinoid biosynthesis always meet the demand?","date":"2010","source":"The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/20837870","citation_count":36,"is_preprint":false},{"pmid":"21264296","id":"PMC_21264296","title":"Paradoxical increase in TAG and DAG content parallel the insulin sensitizing effect of unilateral DGAT1 overexpression in rat skeletal muscle.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21264296","citation_count":36,"is_preprint":false},{"pmid":"29846015","id":"PMC_29846015","title":"AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells.","date":"2018","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29846015","citation_count":35,"is_preprint":false},{"pmid":"26582574","id":"PMC_26582574","title":"Novel Features of DAG-Activated PKC Isozymes Reveal a Conserved 3-D Architecture.","date":"2015","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26582574","citation_count":35,"is_preprint":false},{"pmid":"23833248","id":"PMC_23833248","title":"Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23833248","citation_count":35,"is_preprint":false},{"pmid":"17532549","id":"PMC_17532549","title":"Activation of TRPC6 calcium channels by diacylglycerol (DAG)-containing arachidonic acid: a comparative study with DAG-containing docosahexaenoic acid.","date":"2006","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/17532549","citation_count":35,"is_preprint":false},{"pmid":"15104178","id":"PMC_15104178","title":"Activation, subunit composition and physiological relevance of DAG-sensitive TRPC proteins.","date":"2004","source":"Novartis Foundation symposium","url":"https://pubmed.ncbi.nlm.nih.gov/15104178","citation_count":34,"is_preprint":false},{"pmid":"10395290","id":"PMC_10395290","title":"Role of diacylglycerol (DAG) in hormonal induction of S phase in hepatocytes: the DAG-dependent protein kinase C pathway is not activated by epidermal growth factor (EGF), but is involved in mediating the enhancement of responsiveness to EGF by vasopressin, angiotensin II, and norepinephrine.","date":"1999","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10395290","citation_count":34,"is_preprint":false},{"pmid":"25503980","id":"PMC_25503980","title":"DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of α-dystroglycan.","date":"2014","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25503980","citation_count":33,"is_preprint":false},{"pmid":"31548309","id":"PMC_31548309","title":"CDP-DAG synthase 1 and 2 regulate lipid droplet growth through distinct mechanisms.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31548309","citation_count":33,"is_preprint":false},{"pmid":"28276191","id":"PMC_28276191","title":"Deleting the DAG kinase Dgk1 augments yeast vacuole fusion through increased Ypt7 activity and altered membrane fluidity.","date":"2017","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/28276191","citation_count":31,"is_preprint":false},{"pmid":"8113213","id":"PMC_8113213","title":"A dystrophin-associated glycoprotein, A3a (one of 43DAG doublets), is retained in Duchenne muscular dystrophy muscle.","date":"1993","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8113213","citation_count":30,"is_preprint":false},{"pmid":"14662735","id":"PMC_14662735","title":"Phospholipase C, but not InsP3 or DAG, -dependent activation of the muscarinic receptor-operated cation current in guinea-pig ileal smooth muscle cells.","date":"2003","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/14662735","citation_count":30,"is_preprint":false},{"pmid":"26791243","id":"PMC_26791243","title":"Reduced expression of CDP-DAG synthase changes lipid composition and leads to male sterility in Drosophila.","date":"2016","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/26791243","citation_count":28,"is_preprint":false},{"pmid":"29860222","id":"PMC_29860222","title":"Acylated ghrelin induces but deacylated ghrelin prevents hepatic steatosis and insulin resistance in lean rats: Effects on DAG/ PKC/JNK pathway.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/29860222","citation_count":27,"is_preprint":false},{"pmid":"26210852","id":"PMC_26210852","title":"Enzymatic selective synthesis of 1,3-DAG based on deep eutectic solvent acting as substrate and solvent.","date":"2015","source":"Bioprocess and biosystems engineering","url":"https://pubmed.ncbi.nlm.nih.gov/26210852","citation_count":27,"is_preprint":false},{"pmid":"12699375","id":"PMC_12699375","title":"Differential binding modes of diacylglycerol (DAG) and DAG lactones to protein kinase C (PK-C).","date":"2003","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12699375","citation_count":26,"is_preprint":false},{"pmid":"26633375","id":"PMC_26633375","title":"DAG/PKCδ and IP3/Ca²⁺/CaMK IIβ Operate in Parallel to Each Other in PLCγ1-Driven Cell Proliferation and Migration of Human Gastric Adenocarcinoma Cells, through Akt/mTOR/S6 Pathway.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26633375","citation_count":26,"is_preprint":false},{"pmid":"16374778","id":"PMC_16374778","title":"Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCgamma activate myelin phagocytosis by both.","date":"2006","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/16374778","citation_count":26,"is_preprint":false},{"pmid":"23193081","id":"PMC_23193081","title":"DAG-sensitive and Ca(2+) permeable TRPC6 channels are expressed in dentate granule cells and interneurons in the hippocampal formation.","date":"2012","source":"Hippocampus","url":"https://pubmed.ncbi.nlm.nih.gov/23193081","citation_count":26,"is_preprint":false},{"pmid":"36125261","id":"PMC_36125261","title":"Progressive enhancement of kinetic proofreading in T cell antigen discrimination from receptor activation to DAG generation.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36125261","citation_count":25,"is_preprint":false},{"pmid":"8380777","id":"PMC_8380777","title":"Early cell cycle diacylglycerol (DAG) content and protein kinase C (PKC) activity enhancement potentiates prostaglandin F2 alpha (PGF2 alpha) induced mitogenesis in Swiss 3T3 cells.","date":"1993","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8380777","citation_count":25,"is_preprint":false},{"pmid":"15621338","id":"PMC_15621338","title":"Genotoxicity studies on dietary diacylglycerol (DAG) oil.","date":"2005","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/15621338","citation_count":25,"is_preprint":false},{"pmid":"33768402","id":"PMC_33768402","title":"Compounds DRG and DAG, Two Phenol Glycosides, Inhibit TNF-α-stimulated Inflammatory Response through Blocking NF-kB/AKT/JNK Signaling Pathways in MH7A Cells.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/33768402","citation_count":24,"is_preprint":false},{"pmid":"39302831","id":"PMC_39302831","title":"Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39302831","citation_count":23,"is_preprint":false},{"pmid":"25064446","id":"PMC_25064446","title":"Independent and interactive effects of DOF affecting germination 1 (DAG1) and the Della proteins GA insensitive (GAI) and Repressor of ga1-3 (RGA) in embryo development and seed germination.","date":"2014","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/25064446","citation_count":23,"is_preprint":false},{"pmid":"10966739","id":"PMC_10966739","title":"Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C.","date":"2000","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10966739","citation_count":22,"is_preprint":false},{"pmid":"25362646","id":"PMC_25362646","title":"A novel DAG-dependent mechanism links PKCɑ and Cyclin B1 regulating cell cycle progression.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25362646","citation_count":21,"is_preprint":false},{"pmid":"9873742","id":"PMC_9873742","title":"Conformationally constrained analogues of diacylglycerol (DAG). 15. The indispensable role of the sn-1 and sn-2 carbonyls in the binding of DAG-lactones to protein kinase C (PK-C).","date":"1998","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/9873742","citation_count":21,"is_preprint":false},{"pmid":"17466270","id":"PMC_17466270","title":"ATP promotes NCX-reversal in aortic smooth muscle cells by DAG-activated Na+ entry.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17466270","citation_count":21,"is_preprint":false},{"pmid":"19657058","id":"PMC_19657058","title":"Identification of Sp1 and GC-boxes as transcriptional regulators of mouse Dag1 gene promoter.","date":"2009","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19657058","citation_count":20,"is_preprint":false},{"pmid":"34848707","id":"PMC_34848707","title":"Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34848707","citation_count":20,"is_preprint":false},{"pmid":"28707153","id":"PMC_28707153","title":"Medium-Chain Enriched Diacylglycerol (MCE-DAG) Oil Decreases Body Fat Mass in Mice by Increasing Lipolysis and Thermogenesis in Adipose Tissue.","date":"2017","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/28707153","citation_count":20,"is_preprint":false},{"pmid":"17284021","id":"PMC_17284021","title":"Conformationally constrained analogues of diacylglycerol (DAG). 27. Modulation of membrane translocation of protein kinase C (PKC) isozymes alpha and delta by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups.","date":"2007","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17284021","citation_count":19,"is_preprint":false},{"pmid":"31178220","id":"PMC_31178220","title":"Structures of the Mitochondrial CDP-DAG Synthase Tam41 Suggest a Potential Lipid Substrate Pathway from Membrane to the Active Site.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/31178220","citation_count":19,"is_preprint":false},{"pmid":"37014625","id":"PMC_37014625","title":"Circular RNA circ-TNRC6B inhibits the proliferation and invasion of esophageal squamous cell carcinoma cells by regulating the miR-452-5p/DAG1 axis.","date":"2023","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37014625","citation_count":18,"is_preprint":false},{"pmid":"30367178","id":"PMC_30367178","title":"Genome-wide RNA-seq analysis indicates that the DAG1 transcription factor promotes hypocotyl elongation acting on ABA, ethylene and auxin signaling.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30367178","citation_count":18,"is_preprint":false},{"pmid":"21966255","id":"PMC_21966255","title":"Fast synthesis of 1,3-DAG by Lecitase® Ultra-catalyzed esterification in solvent-free system.","date":"2011","source":"European journal of lipid science and technology : EJLST","url":"https://pubmed.ncbi.nlm.nih.gov/21966255","citation_count":17,"is_preprint":false},{"pmid":"25624232","id":"PMC_25624232","title":"Enzyme-assisted process for DAG synthesis in edible oils.","date":"2014","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25624232","citation_count":17,"is_preprint":false},{"pmid":"32229289","id":"PMC_32229289","title":"MicroRNA-184 alleviates insulin resistance in cardiac myocytes and high fat diet-induced cardiac dysfunction in mice through the LPP3/DAG pathway.","date":"2020","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32229289","citation_count":16,"is_preprint":false},{"pmid":"24666138","id":"PMC_24666138","title":"Modeling studies on the structural determinants for the DAG/phorbol ester binding to C1 domain.","date":"2014","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/24666138","citation_count":16,"is_preprint":false},{"pmid":"22238145","id":"PMC_22238145","title":"Synthetic caged DAG-lactones for photochemically controlled activation of protein kinase C.","date":"2011","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/22238145","citation_count":16,"is_preprint":false},{"pmid":"22265739","id":"PMC_22265739","title":"Impact of DAG stimulation on mineral synthesis, mineral structure and osteogenic differentiation of human cord blood stem cells.","date":"2011","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/22265739","citation_count":16,"is_preprint":false},{"pmid":"35784730","id":"PMC_35784730","title":"CD73-Adenosine A1R Axis Regulates the Activation and Apoptosis of Hepatic Stellate Cells Through the PLC-IP3-Ca2+/DAG-PKC Signaling Pathway.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35784730","citation_count":15,"is_preprint":false},{"pmid":"16134942","id":"PMC_16134942","title":"Conformationally constrained analogues of diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C.","date":"2005","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16134942","citation_count":15,"is_preprint":false},{"pmid":"25749469","id":"PMC_25749469","title":"Biochemical properties and structure analysis of a DAG-Like lipase from Malassezia globosa.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25749469","citation_count":15,"is_preprint":false},{"pmid":"24794745","id":"PMC_24794745","title":"Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP.","date":"2014","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24794745","citation_count":15,"is_preprint":false},{"pmid":"20416320","id":"PMC_20416320","title":"Vitellogenesis in Oncopeltus fasciatus: PLC/IP(3), DAG/PK-C pathway triggered by CaM.","date":"2010","source":"Journal of insect physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20416320","citation_count":15,"is_preprint":false},{"pmid":"29155849","id":"PMC_29155849","title":"Unusual occurrence of a DAG motif in the Ipomovirus Cassava brown streak virus and implications for its vector transmission.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29155849","citation_count":15,"is_preprint":false},{"pmid":"39436710","id":"PMC_39436710","title":"MOGAT3-mediated DAG accumulation drives acquired resistance to anti-BRAF/anti-EGFR therapy in BRAFV600E-mutant metastatic colorectal cancer.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39436710","citation_count":14,"is_preprint":false},{"pmid":"28025123","id":"PMC_28025123","title":"Structured DAG oil ameliorates renal injury in streptozotocin-induced diabetic rats through inhibition of NF-κB and activation of Nrf2 pathway.","date":"2016","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/28025123","citation_count":14,"is_preprint":false},{"pmid":"18247369","id":"PMC_18247369","title":"L- and N-current but not M-current inhibition by M1 muscarinic receptors requires DAG lipase activity.","date":"2008","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18247369","citation_count":14,"is_preprint":false},{"pmid":"20385136","id":"PMC_20385136","title":"Plasmodium CDP-DAG synthase: an atypical gene with an essential N-terminal extension.","date":"2010","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/20385136","citation_count":14,"is_preprint":false},{"pmid":"9421197","id":"PMC_9421197","title":"A novel 15-hydroxyeicosatrienoic acid-substituted diacylglycerol (15-HETrE-DAG) selectively inhibits epidermal protein kinase C-beta.","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9421197","citation_count":14,"is_preprint":false},{"pmid":"31832062","id":"PMC_31832062","title":"Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) Are Associated with Poorer Outcome after Single Mismatch Unrelated Donor Stem Cell Transplantation: A Study of the Cooperative Transplant Study Group (KTS) of the German Group for Bone Marrow and Stem Cell Transplantation (DAG-KBT).","date":"2019","source":"Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie","url":"https://pubmed.ncbi.nlm.nih.gov/31832062","citation_count":13,"is_preprint":false},{"pmid":"8122397","id":"PMC_8122397","title":"Nucleotide sequence of a Singapore isolate of zucchini yellow mosaic virus coat protein gene revealed an altered DAG motif.","date":"1993","source":"Virus genes","url":"https://pubmed.ncbi.nlm.nih.gov/8122397","citation_count":13,"is_preprint":false},{"pmid":"9161034","id":"PMC_9161034","title":"Tam3 produces a suppressible allele of the DAG locus of Antirrhinum majus similar to Mu-suppressible alleles of maize.","date":"1997","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9161034","citation_count":13,"is_preprint":false},{"pmid":"37224601","id":"PMC_37224601","title":"Synthesis and evaluation of DAG-lactone derivatives with HIV-1 latency reversing activity.","date":"2023","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37224601","citation_count":11,"is_preprint":false},{"pmid":"37499844","id":"PMC_37499844","title":"Total flavonoids of Hippophae rhamnoides L. improves type 2 diabetes symptoms in rats through down-regulating of the DAG/PRKCA/MAPK10/p65/TNF-α signalling pathway.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37499844","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49822,"output_tokens":2523,"usd":0.093656,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9455,"output_tokens":3351,"usd":0.065525,"stage2_stop_reason":"end_turn"},"total_usd":0.159181,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical DAG1 gene (dystroglycan) and extract mechanistic findings. Let me classify each paper:\n\n- Papers about DAG1/dystroglycan (the mammalian gene): PMIDs 9175728, 12230980, 8138555, 8113213, 21296866, 30450679, 25503980, 19657058, 37014625\n- Papers about diacylglycerol (DAG, the lipid second messenger): Most other papers - these are about the lipid, not the gene DAG1\n- Papers about plant DAG1 (Arabidopsis DOF transcription factor): PMIDs 19874540, 25064446, 30367178 - these are plant orthologs/symbol collisions\n- Virus/other papers: PMIDs 10567662, 8122397, 29155849, 37316672, etc. - symbol collisions\n\nLet me focus on the dystroglycan (DAG1 protein) papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Dystroglycan (DAG1) is essential for the development of Reichert's membrane; homozygous Dag1-null mice show disrupted localization of laminin and collagen IV in this extra-embryonic basement membrane, demonstrating that dystroglycan is required for basement membrane organization.\",\n      \"method\": \"Knockout mouse (Dag1neo2 null allele), immunofluorescence localization of dystroglycan, laminin, and collagen IV in embryos\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with specific phenotypic readout (Reichert's membrane disruption), protein localization by immunofluorescence, replicated observations across multiple embryos\",\n      \"pmids\": [\"9175728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Striated muscle-specific disruption of DAG1 abolishes the dystrophin-glycoprotein complex in differentiated muscle fibers; satellite cells retaining dystroglycan expression support continued efficient muscle regeneration, and dystroglycan is transiently re-expressed in regenerating muscle fibers.\",\n      \"method\": \"Muscle-specific conditional knockout (Cre-lox), immunofluorescence, histological analysis of muscle regeneration, comparison with human muscular dystrophy biopsy\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, multiple orthogonal methods (immunofluorescence, histology, human biopsy comparison), published in high-impact journal\",\n      \"pmids\": [\"12230980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The dystrophin-associated glycoprotein A3a (43DAG) is identical to the cytoplasmic domain of dystroglycan; it is retained in Duchenne muscular dystrophy muscle despite absence of dystrophin, indicating it is not solely dependent on dystrophin for membrane localization.\",\n      \"method\": \"Internal amino acid sequencing of A3a, antibody generation against synthetic peptide, immunohistochemistry and immunoblot of DMD patient muscle (n=30)\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein sequencing identifying A3a as dystroglycan cytoplasmic domain, immunohistochemical validation in 30 DMD patients\",\n      \"pmids\": [\"8113213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The dystrophin-associated protein 43DAG (A3a, corresponding to dystroglycan) is expressed in skeletal muscle, cardiac muscle, smooth muscle, lung, liver, CNS, and peripheral nerve in monkeys, whereas 50DAG is restricted to skeletal and cardiac muscle, indicating tissue-specific distribution of dystrophin-glycoprotein complex components.\",\n      \"method\": \"Immunoblot analysis of multiple monkey tissues with antibodies against 50DAG (A2) and 43DAG (A3a)\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single-lab immunoblot across multiple tissues, no functional manipulation, but systematic tissue survey with clear results\",\n      \"pmids\": [\"8138555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, loss of dag1 (p.V567D missense mutation causing complete absence of protein) destabilizes the dystroglycan complex, causing membrane damage at myosepta and basement membranes between myofibers; additionally, structural abnormalities in triads (t-tubules and sarcoplasmic reticulum) precede sarcolemmal damage, and a subpopulation of dystroglycan localizes to t-tubules in normal skeletal muscle.\",\n      \"method\": \"Forward genetic screen, genetic mapping, immunofluorescence, immunogold electron microscopy, analysis of t-tubule and sarcoplasmic reticulum structure in dag1 mutant fish\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function zebrafish model with multiple orthogonal readouts (immunofluorescence, immunogold EM, structural analysis), subcellular localization tied to functional consequence\",\n      \"pmids\": [\"21296866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Compound heterozygous missense mutations in the N-terminal region of α-dystroglycan (DAG1) affect its glycosylation; mutated DAG1 cDNAs fail to rescue the phenotype in DAG1-knockout haploid human cells, confirming these mutations are pathogenic by disrupting α-dystroglycan glycosylation.\",\n      \"method\": \"Whole-exome sequencing, DAG1-knockout haploid human cell line transfection with mutant DAG1 cDNA (phenotype-rescue assay), immunoblot for α-dystroglycan expression\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based rescue assay in knockout background with defined molecular readout, single lab but uses orthogonal genetic and biochemical methods\",\n      \"pmids\": [\"25503980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A novel homozygous missense mutation in DAG1 (c.2326C>T; p.R776C) causes significant reduction of α-dystroglycan expression in muscle tissue, establishing that this conserved residue is required for normal α-dystroglycan protein levels.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing for co-segregation, immunoblotting of muscle tissue for α-dystroglycan\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single family study, single immunoblot method, no functional rescue experiment\",\n      \"pmids\": [\"30450679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Sp1 transcription factor directly binds to GC-box elements in the mouse Dag1 gene promoter to drive its expression; DNA methylation reduces Dag1 promoter activity, and promoter methylation decreases while expression increases during C2C12 myoblast differentiation into myotubes.\",\n      \"method\": \"Promoter deletion/transfection analysis, chromatin immunoprecipitation (ChIP) for Sp1 binding, siRNA knockdown of Sp1, 5-aza-2'-deoxycytidine and trichostatin A treatment, in vitro methylation assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct Sp1 binding, siRNA knockdown shows functional consequence, methylation experiments orthogonally confirm epigenetic regulation, single lab\",\n      \"pmids\": [\"19657058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"circ-TNRC6B sponges miR-452-5p to upregulate DAG1 expression and activity in esophageal squamous cell carcinoma cells; loss of DAG1 activity contributes to tumor cell proliferation, migration, and invasion.\",\n      \"method\": \"RNA immunoprecipitation, dual-luciferase reporter assay, overexpression and knockdown functional experiments in ESCC cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect evidence for DAG1 functional role through miRNA sponge mechanism; DAG1 functional role not directly tested with specific DAG1 manipulation\",\n      \"pmids\": [\"37014625\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DAG1 (dystroglycan) is a central component of the dystrophin-glycoprotein complex that anchors cells to the basement membrane via interactions with laminin and other extracellular matrix components; it is required for basement membrane organization (including Reichert's membrane in early embryogenesis), localizes to the sarcolemma and t-tubules in skeletal muscle where it stabilizes the DGC, and its α-subunit undergoes critical glycosylation that is disrupted in dystroglycanopathies; DAG1 expression is transcriptionally regulated by Sp1 binding to GC-box promoter elements and by DNA methylation/histone acetylation, increasing during myoblast differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DAG1 (dystroglycan) is a core component of the dystrophin-glycoprotein complex (DGC) that links cells to the basement membrane and is required for basement membrane organization, as shown by the disrupted localization of laminin and collagen IV in the Reichert's membrane of Dag1-null embryos [#0]. The protein is processed into a cytoplasmic dystrophin-associated subunit (43DAG/A3a) and a heavily glycosylated extracellular α-dystroglycan [#2], with the α-subunit's glycosylation being the critical determinant of function: missense mutations in the N-terminal region or at conserved residues disrupt α-dystroglycan glycosylation and protein levels and cause dystroglycanopathy, confirmed by failure of mutant DAG1 cDNA to rescue DAG1-knockout cells [#5, #6]. In striated muscle, dystroglycan is required to assemble and maintain the DGC at the sarcolemma, and a subpopulation localizes to t-tubules; its loss abolishes the complex in differentiated fibers and produces membrane damage at myosepta and structural defects in triads, while satellite-cell expression supports muscle regeneration [#1, #4]. The 43DAG cytoplasmic subunit persists at the membrane in Duchenne dystrophy muscle lacking dystrophin, indicating its localization is not strictly dystrophin-dependent [#2]. DAG1 transcription is driven by direct Sp1 binding to GC-box promoter elements and is repressed by DNA methylation, with promoter demethylation and increased expression accompanying myoblast-to-myotube differentiation [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the molecular identity of the dystrophin-associated glycoproteins was needed to define the DGC architecture; sequencing showed 43DAG/A3a is the cytoplasmic domain of dystroglycan and that it persists in dystrophin-deficient muscle.\",\n      \"evidence\": \"Internal amino acid sequencing, anti-peptide antibodies, and immunohistochemistry/immunoblot of DMD patient muscle\",\n      \"pmids\": [\"8113213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how 43DAG is anchored at the membrane in the absence of dystrophin\", \"No structural detail on the α/β cleavage or glycosylation\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Mapping the tissue distribution of DGC components clarified which are broadly versus restrictedly expressed; 43DAG (dystroglycan) is widely distributed across muscle, nerve, CNS and viscera, unlike the muscle-restricted 50DAG.\",\n      \"evidence\": \"Immunoblot survey of multiple monkey tissues with subunit-specific antibodies\",\n      \"pmids\": [\"8138555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive expression only, no functional role assigned per tissue\", \"Single-lab immunoblot without quantification\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"The developmental requirement for dystroglycan was unknown; knockout mice revealed it is essential for organizing the Reichert's membrane basement membrane by correctly positioning laminin and collagen IV.\",\n      \"evidence\": \"Dag1-null knockout mouse with immunofluorescence localization of dystroglycan, laminin, and collagen IV in embryos\",\n      \"pmids\": [\"9175728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Early embryonic lethality limits analysis of later tissue roles\", \"Does not resolve direct versus indirect ECM-binding mechanism\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether dystroglycan is required cell-autonomously in mature muscle and during regeneration was unclear; muscle-specific deletion showed it is essential for the DGC in differentiated fibers, while satellite-cell expression sustains regeneration.\",\n      \"evidence\": \"Cre-lox muscle-specific conditional knockout with immunofluorescence, regeneration histology, and human muscular dystrophy biopsy comparison\",\n      \"pmids\": [\"12230980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the signaling consequences of DGC loss beyond membrane stability\", \"Mechanism of transient re-expression in regenerating fibers not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"How DAG1 transcription is controlled was unknown; Sp1 binding to GC-box promoter elements and epigenetic DNA methylation were shown to regulate expression, which rises during myoblast differentiation.\",\n      \"evidence\": \"Promoter deletion/transfection, ChIP for Sp1, Sp1 siRNA, methylation/HDAC inhibitor treatment, and in vitro methylation assays in C2C12 cells\",\n      \"pmids\": [\"19657058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in mouse promoter; human regulatory architecture not addressed\", \"Does not link transcriptional control to specific developmental signals\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The subcellular basis of dystroglycan's role in muscle membrane integrity was incomplete; a zebrafish loss-of-function model showed it stabilizes membranes at myosepta and that t-tubule/triad defects precede sarcolemmal damage, placing a subpopulation of dystroglycan at t-tubules.\",\n      \"evidence\": \"Forward genetic screen with mapping, immunofluorescence, immunogold EM, and triad ultrastructural analysis in dag1 mutant zebrafish\",\n      \"pmids\": [\"21296866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the t-tubule localization and triad role unresolved\", \"Whether triad defects are primary or secondary to membrane fragility not fully established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether N-terminal α-dystroglycan mutations are pathogenic was open; a knockout-cell rescue assay confirmed that such missense mutations disrupt α-dystroglycan glycosylation and cause disease.\",\n      \"evidence\": \"Whole-exome sequencing plus DAG1-knockout haploid human cell rescue assay with mutant cDNA and α-dystroglycan immunoblot\",\n      \"pmids\": [\"25503980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific glycosyltransferase step impaired by the N-terminal mutation not pinpointed\", \"Single-lab cell-based readout\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether a conserved C-terminal residue affects α-dystroglycan levels was unknown; a homozygous p.R776C mutation was associated with reduced α-dystroglycan in patient muscle.\",\n      \"evidence\": \"Whole-exome and Sanger co-segregation sequencing with α-dystroglycan immunoblot of muscle tissue\",\n      \"pmids\": [\"30450679\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single family with no functional rescue experiment\", \"Causality versus correlation not established by orthogonal methods\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A possible role for DAG1 in epithelial cancer was tested; a circ-TNRC6B/miR-452-5p axis was reported to regulate DAG1 levels, with reduced DAG1 activity associated with ESCC proliferation, migration, and invasion.\",\n      \"evidence\": \"RNA immunoprecipitation, dual-luciferase reporter, and overexpression/knockdown assays in esophageal squamous cell carcinoma cells\",\n      \"pmids\": [\"37014625\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"DAG1's functional role inferred through the miRNA axis rather than direct DAG1 manipulation\", \"Mechanism by which DAG1 restrains tumor cell behavior not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How α-dystroglycan glycosylation is enzymatically built and how its disruption maps quantitatively to dystroglycanopathy severity, and what downstream signaling the DGC transmits beyond membrane anchorage, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of glycosylated α-dystroglycan bound to ECM ligands in the timeline\", \"Signaling outputs of the cytoplasmic 43DAG domain not characterized\", \"Genotype-phenotype rules for individual DAG1 mutations not systematically established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"dystrophin-glycoprotein complex\"],\n    \"partners\": [\"DMD\", \"LAMA2\", \"COL4A1\", \"SP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}