{"gene":"MAGI1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1997,"finding":"MAGI-1 was identified as a novel MAGUK scaffolding protein with an inverted domain structure: guanylate kinase (GK) domain at the N-terminus, two WW domains replacing the SH3 domain, and five PDZ domains at the C-terminus. Subcellular fractionation and immunolocalization in MDCK cells showed that the longest splice variant (MAGI-1c), which contains bipartite nuclear localization signals in its unique C-terminal sequence, localizes predominantly to the nucleus, while shorter forms lacking these signals are found in membrane and cytoplasmic fractions.","method":"cDNA cloning, subcellular fractionation, immunolocalization in MDCK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — original cloning and characterization with direct localization experiments; foundational study replicated by subsequent work","pmids":["9395497"],"is_preprint":false},{"year":1997,"finding":"MAGI-1 WW domains were identified as binding partners for PY-motif (PPxY)-containing proteins; cloning of ligand targets (COLT) screen identified MAGI-1 among novel WW domain proteins capable of binding PY-motif ligands from signaling and regulatory proteins.","method":"COLT screen (cDNA expression library screening with peptide ligands), in vitro WW domain binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single in vitro binding screen identifying WW domain ligand interaction","pmids":["9169421"],"is_preprint":false},{"year":1998,"finding":"MAGI-1 (as AIP1/AIP3) was identified as an atrophin-1 interacting protein through its WW domains; yeast two-hybrid and in vitro binding assays confirmed that atrophin-1 binds to MAGI-1 in the vicinity of its polyglutamine tract.","method":"Yeast two-hybrid screen, in vitro binding assays (GST pulldown)","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid confirmed by in vitro binding, single study","pmids":["9647693"],"is_preprint":false},{"year":2000,"finding":"MAGI-1 was identified as a binding partner of adenovirus type 9 E4-ORF1 and high-risk HPV E6 oncoproteins via PDZ domain interaction. E4-ORF1 aberrantly sequesters MAGI-1 in the cytoplasm, while high-risk HPV E6 targets MAGI-1 for degradation. Transformation-defective viral mutants are deficient for these activities, implicating MAGI-1 interaction in viral oncogenesis.","method":"Co-immunoprecipitation, immunofluorescence localization, mutational analysis of viral oncoproteins","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, localization, functional mutant analysis in multiple viral systems","pmids":["11077444"],"is_preprint":false},{"year":2000,"finding":"MAGI-1b fifth PDZ domain (PDZ5) is essential for membrane localization of MAGI-1b, and this PDZ domain binds beta-catenin. MAGI-1b forms complexes with beta-catenin and E-cadherin during formation of cell-cell junctions in MDCK cells; GFP-MAGI-1b localizes to the basolateral membrane of polarized MDCK cells.","method":"PDZ domain deletion analysis, co-immunoprecipitation, GFP-fusion localization in MDCK cells","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with deletion mutants plus co-IP and live-cell localization with functional context","pmids":["10772923"],"is_preprint":false},{"year":2002,"finding":"MAGI-1 and MAGI-3 are components of tight junctions in cultured epithelial cells and in all epithelial cell types examined in vivo. Human MAGI-1 is alternatively spliced at three sites producing isoforms with different C-termini; two brain-specific forms lack nuclear targeting signals. MAGI-1 colocalizes with ZO-1 and ZO-2 in non-polarized epithelial cells, suggesting a pre-assembled complex incorporated into tight junctions upon polarization. All alternatively spliced forms show tight junction localization independently of the GK and WW domains or extended C-terminus.","method":"Immunofluorescence colocalization, isoform-specific domain deletion analysis in cultured epithelial cells, in vivo tissue expression analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — direct localization across multiple cell types and tissues, domain deletion functional analysis, replicated with multiple isoforms","pmids":["11969287"],"is_preprint":false},{"year":2003,"finding":"JAM4 (junctional adhesion molecule 4) was identified as a novel MAGI-1 binding protein at tight junctions. JAM4 binds MAGI-1 (but not ZO-1) in vitro, co-clusters with MAGI-1 in COS-7 cells, and MAGI-1 strengthens JAM4-mediated cell-cell adhesion and epithelial barrier sealing effects. MAGI-1 also recruits ZO-1, occludin, and other tight junction proteins to JAM4-based cell contacts.","method":"In vitro GST pulldown, co-immunoprecipitation, colocalization in COS-7 cells, functional adhesion and permeability assays in L cells and CHO cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed in vitro and in cells, functional consequence (adhesion, barrier permeability) demonstrated","pmids":["12773569"],"is_preprint":false},{"year":2005,"finding":"MAGI-1 recruits Delta-like 1 (Dll1) to cadherin-based adherens junctions (AJs) and stabilizes Dll1 on the cell surface. In developing neural tube, MAGI-1 accumulates at AJs at apical termini of radial processes. MAGI-1 binds both Dll1 and N-cadherin-beta-catenin complexes. In cultured fibroblasts, MAGI-1 localizes to AJs and recruits Dll1 to these sites through direct binding, stabilizing Dll1 on the cell surface.","method":"Yeast two-hybrid, co-immunoprecipitation, in situ hybridization, immunofluorescence colocalization in vivo and in cultured fibroblasts, cell surface biotinylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, Co-IP, in vivo localization, cell-surface assay) with clear functional outcome","pmids":["15908431"],"is_preprint":false},{"year":2005,"finding":"A novel MAGI-1-associated protein (MASCOT) was identified that binds to the first WW domain of MAGI-1 via a variant LPxY motif (not the canonical PPxY). MASCOT colocalizes with MAGI-1 at tight junctions in MDCK cells and its coiled-coil domain is necessary for this junctional localization.","method":"Glomerular cDNA library screen, GST pulldown assays, co-immunoprecipitation with endogenous MAGI-1, immunofluorescence in MDCK cells, domain deletion analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 — single study with GST pulldown, Co-IP, and colocalization; LPxY motif as novel WW domain ligand is mechanistically informative","pmids":["16019084"],"is_preprint":false},{"year":2008,"finding":"MAGI-1 was identified as a candidate stereociliary scaffolding protein that binds the hair-cell-specific Cdh23(+68) splice variant of cadherin 23 via its PDZ4 domain interacting with the C-terminal PDZ-binding site of Cdh23. MAGI-1 immunoreactivity is present throughout neonatal stereocilia in a distribution similar to Cdh23, becoming punctate in adult, and is proposed to replace harmonin's PDZ2 binding at the Cdh23 C-terminus in the tip-link complex.","method":"Cochlear cDNA library screen using Cdh23 intracellular domain as bait, PDZ domain binding assays, immunofluorescence in cochlear hair cells","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — library screen and binding domain mapping confirmed by immunolocalization; functional replacement of harmonin is proposed but not directly tested","pmids":["18971469"],"is_preprint":false},{"year":2008,"finding":"TRIP6, a zyxin-family protein, was identified as a direct MAGI-1b interactor binding to its fifth PDZ domain (PDZ5). Ectopic TRIP6 expression induced invasiveness in MDCK cells in a PI3-kinase- and NF-κB-dependent manner and impaired cell-cell aggregation by uncoupling adherens junctional complexes from the cytoskeleton. A TRIP6 mutant lacking the PDZ-binding motif could not promote invasiveness or interfere with cell-cell aggregation, despite retaining NF-κB and Akt activation, demonstrating that PDZ scaffold interactions are required for these functions.","method":"Yeast two-hybrid screening, direct binding assays, ectopic expression in MDCK/MDCKts-src cells, invasion assays, cell aggregation assays, intracellular peptide delivery competition","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — Y2H confirmed by direct binding, functional rescue with competing peptides, clear mechanistic pathway placement with domain-specific mutants","pmids":["19017743"],"is_preprint":false},{"year":2009,"finding":"C. elegans MAGI-1 (ortholog of mammalian MAGI/S-SCAM) is required in specific neurons for different aspects of associative learning and memory. MAGI-1 in RIA interneurons controls, in a cell non-autonomous manner, the dynamic remodeling of AVA/AVD/AVE synapses containing ionotropic glutamate receptor (iGluR) GLR-1 during learning. During memory consolidation, MAGI-1 controls GLR-1 clustering in AVA and AVD interneurons cell-autonomously, dependent on interaction with beta-catenin HMP-2.","method":"Genetic analysis of magi-1 mutants, neuron-specific rescue experiments, fluorescence imaging of GLR-1::GFP synaptic clusters, epistasis analysis with hmp-2 (beta-catenin)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean genetic loss-of-function with cell-type-specific rescue and mechanistic pathway placement via epistasis; ortholog in C. elegans with conserved domain function","pmids":["19551147"],"is_preprint":false},{"year":2010,"finding":"MAGI-1 is a major degradation target of both HPV-16 and HPV-18 E6 oncoproteins in cervical cancer cells. E6 preferentially targets MAGI-1 within the nucleus and at membrane sites. MAGI-1 degradation directly causes loss of tight junction integrity (mislocalization of ZO-1), and restoration of tight junctions after E6 ablation is dependent on the presence of MAGI-1.","method":"siRNA knockdown of E6 in CaSKi (HPV-16+) and HeLa (HPV-18+) cells, Western blot quantification of PDZ substrates, immunofluorescence of ZO-1, MAGI-1 rescue experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — systematic comparison of multiple PDZ substrates in two HPV+ cell lines, direct rescue demonstrating MAGI-1's causal role in tight junction integrity","pmids":["21123374"],"is_preprint":false},{"year":2010,"finding":"Surface plasmon resonance (SPR) quantification established that high-risk HPV E6 C-terminal peptides bind the PDZ1 domain of MAGI-1 with dissociation constants in the micromolar range, comparable to cellular PDZ1 ligands (LPP, Tax). MAGI-1 PDZ1 shows preference for C-termini with valine at position 0 and a negative charge at position -3. Mutagenesis identified K499 of MAGI-1 PDZ1 as a novel determinant of binding specificity; charged residues upstream of the PDZ-binding motif strongly contribute to binding selectivity.","method":"Surface plasmon resonance (SPR) with GST-fusion peptides, site-directed mutagenesis of HPV16 E6 C-terminal peptide and MAGI-1 PDZ1","journal":"Journal of molecular recognition","confidence":"High","confidence_rationale":"Tier 1 — quantitative biophysical binding measurements with mutagenesis defining binding determinants","pmids":["20842623"],"is_preprint":false},{"year":2011,"finding":"MAGI-1 binds glutamate transporter GLT-1 (EAAT2) as shown by GST pulldown and co-immunoprecipitation; the two proteins co-distribute in astrocytes. Co-expression of MAGI-1 with GLT-1 in C6 glioma cells significantly reduces GLT-1 surface expression as measured by cell-surface biotinylation. Conversely, partial knockdown of endogenous MAGI-1 in differentiated astrocytes increases glutamate uptake and surface expression of GLT-1, demonstrating that MAGI-1 negatively regulates GLT-1 surface expression and GLT-1-mediated glutamate uptake.","method":"GST pulldown, co-immunoprecipitation, immunofluorescence, cell-surface biotinylation, siRNA knockdown, glutamate uptake assay","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pulldown, Co-IP, biotinylation, functional uptake assay) with both gain- and loss-of-function in relevant cell types","pmids":["21426345"],"is_preprint":false},{"year":2011,"finding":"NMR solution structure of MAGI-1 PDZ1 domain (with noncanonical extended boundaries) was solved alone and in complex with HPV16 E6 C-terminal peptide. E6 peptide binding induces quenching of high-frequency backbone motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical binding motif. Mutations in the C-terminal flanking region of PDZ1 significantly decrease binding affinity for E6 peptides, revealing a global conformational response to binding with effects propagated to distal sites.","method":"NMR spectroscopy (3D structure determination), backbone dynamics analysis, site-directed mutagenesis with binding affinity measurements","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — atomic resolution NMR structure with dynamics analysis and mutagenesis validation","pmids":["21238461"],"is_preprint":false},{"year":2012,"finding":"Biochemical fractionation of rat brain tissue revealed that MAGI-1 is enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from MAGI-2 and MAGI-3, which are enriched in the postsynaptic density fraction). Immunohistochemistry showed MAGI-1 expression in Purkinje cells, hippocampal CA1 neurons, the glomerulus region of the olfactory bulb, and the dorsal root entry zone in embryonic spinal cord, with diffuse distribution in cell bodies and processes of primary cultured hippocampal neurons (unlike the synaptic enrichment of MAGI-2/3).","method":"Subcellular fractionation with Western blotting, immunofluorescence in primary neurons, immunohistochemistry in rat brain sections","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — direct fractionation and localization experiments distinguishing MAGI-1 from paralogs; single lab study","pmids":["22605569"],"is_preprint":false},{"year":2017,"finding":"MAGI1 knockdown in gastric cancer cells significantly promotes cell migration and invasion. Mechanistically, MAGI1 inhibits migration and invasion by altering expression of matrix metalloproteinases (MMPs) and EMT-related molecules through inhibition of the MAPK/ERK signaling pathway.","method":"shRNA knockdown in GC cell lines, MTT/colony formation assays, scratch wound and transwell migration/invasion assays, Western blotting for MAPK/ERK pathway components and EMT markers","journal":"Chinese journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, loss-of-function with defined pathway readout but no direct rescue or upstream mechanism","pmids":["28373751"],"is_preprint":false},{"year":2019,"finding":"MAGI1 mediates fluid shear stress-induced eNOS activation and NO production in endothelial cells. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbs KLF4 expression, endothelial cell alignment, eNOS phosphorylation, and NO production, while MAGI1 overexpression induces PKA, AMPK, and CaMKII phosphorylation. Pharmacological inhibition of PKA and AMPK prevents MAGI1-mediated eNOS phosphorylation. Endothelial-specific transgenic MAGI1 mice show increased PKA and eNOS phosphorylation in vivo and increased NO production ex vivo.","method":"siRNA silencing, MAGI1 overexpression, pharmacological kinase inhibition, flow chamber experiments, transgenic mouse model with ex vivo NO measurement, Western blotting for phospho-kinases","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — orthogonal in vitro and in vivo approaches (cell silencing, overexpression, transgenic mouse), pharmacological pathway dissection","pmids":["31035633"],"is_preprint":false},{"year":2019,"finding":"In endothelial cells exposed to disturbed flow (d-flow), p90RSK binds MAGI1 and phosphorylates MAGI1 at S741, activating Rap1 to upregulate EC activation. Separately, MAGI1-K931 deSUMOylation (mediated by SENP2-T368 phosphorylation) drives nuclear translocation of p90RSK-MAGI1 and ATF6-MAGI1 complexes, accelerating EC activation and apoptosis respectively. MAGI1 associates with ATF-6, linking it to the ER stress response. Magi1+/- heterozygous mice show inhibited d-flow-induced atherogenesis.","method":"Co-immunoprecipitation, phosphorylation/SUMOylation site mutagenesis, microarray screening, immunofluorescence, in vivo atherogenesis in Magi1+/- mice, nuclear fractionation","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods defining two distinct PTM-based mechanisms, confirmed in vivo with heterozygous mouse model","pmids":["30944250"],"is_preprint":false},{"year":2019,"finding":"MAGI1 suppresses tumor metastasis in renal cell carcinoma (RCC) by stabilizing the PTEN/MAGI1/β-catenin complex, thereby inhibiting β-catenin signaling. MAGI1 is transcriptionally suppressed by miR-520h, which is itself activated by c-Myb, defining a c-Myb/miR-520h/MAGI1 regulatory axis in RCC metastasis.","method":"Overexpression and knockdown in RCC cell lines, invasion/migration assays, co-immunoprecipitation of MAGI1/PTEN/β-catenin complex, luciferase reporter assay for miR-520h/MAGI1 3'UTR interaction","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 3 — complex formation shown by Co-IP, miRNA target validated by reporter assay; single lab study","pmids":["31352641"],"is_preprint":false},{"year":2020,"finding":"miR-486-5p directly targets the 3'UTR of MAGI1 and RASSF5, as confirmed by dual-luciferase reporter assay and FREMSA. MAGI1 knockdown in K562 cells reverses HQ-induced inhibition of erythroid differentiation via downregulation of RAPGEF2 and RAP1A, placing MAGI1 upstream of the Rap1 signaling pathway. MAGI1 and downstream Rap1 pathway genes are dose-dependently upregulated by hydroquinone.","method":"Dual-luciferase reporter assay, fluorescence-based RNA EMSA (FREMSA), miR-486-5p overexpression/knockdown, MAGI1 siRNA knockdown, Western blotting for Rap1 pathway","journal":"Toxicology in vitro","confidence":"Medium","confidence_rationale":"Tier 3 — miRNA-target interaction validated by two methods; epistasis to Rap1 pathway established by knockdown, single lab","pmids":["32198055"],"is_preprint":false},{"year":2020,"finding":"MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+)/HER2- breast cancer. MAGI1 downregulation in MCF7 cells impairs ER expression and signaling, promotes cell proliferation, reduces apoptosis, and reduces epithelial differentiation. In murine 67NR ER+ BC cells, MAGI1 downregulation accelerates primary tumor growth and enhances experimental lung metastasis formation. MAGI1 expression is upregulated by estrogen/ER signaling and downregulated by the prostaglandin E2/COX-2 axis.","method":"siRNA/shRNA knockdown, cell proliferation and apoptosis assays, in vivo tumor xenograft and lung metastasis models in mice, Western blotting for ER signaling, pharmacological stimulation/inhibition","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with mechanistic pathway links (ER signaling, COX-2 regulation), multiple functional readouts","pmids":["31963297"],"is_preprint":false},{"year":2021,"finding":"MAGI1 is a comprehensive scaffold/tumor suppressor protein: it stabilizes cadherin-mediated cell-cell adhesion in epithelial and endothelial cells, localizes at mature focal adhesions, and regulates integrin-mediated adhesion and signaling in endothelial cells. MAGI1 modulates PI3K/AKT and Wnt/β-catenin oncogenic pathways. NSAIDs upregulate MAGI1 expression in breast and colorectal cancers, suggesting MAGI1 mediates part of NSAID tumor suppressive activity.","method":"Review compiling experimental evidence from multiple studies; original data includes localization at focal adhesions","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 4 — primarily a review; focal adhesion localization claim references original experimental data","pmids":["34198584"],"is_preprint":false},{"year":2022,"finding":"HPV-16 E6 intragenic variants (E-G350, E-C188/G350, E-A176/G350, AAa, AAc) show increased binding affinity to MAGI-1 PDZ1 domain compared to the E6 reference sequence, as modeled by molecular dynamics simulation and protein-protein docking with two MAGI-1 PDZ1 structural models.","method":"Molecular dynamics simulation, protein-protein docking (in silico)","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no experimental validation of enhanced binding","pmids":["35115618"],"is_preprint":false},{"year":2019,"finding":"MAGI1 silencing in glioma cell lines and glioma stem cells (GSCs) enhances proliferation and inhibits apoptosis. MAGI1 knockdown increases N-cadherin, vimentin, β-catenin, cyclin D1, and phospho-Akt, and reduces E-cadherin and PTEN, indicating MAGI1 suppresses glioma progression via the Wnt/β-catenin and PTEN/AKT signaling pathways.","method":"shRNA knockdown, CCK8 and colony-formation assays, flow cytometry apoptosis, Western blotting for EMT/pathway markers","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with pathway marker readout; single lab study, mechanistic assignment by protein level changes without direct epistasis","pmids":["32009799"],"is_preprint":false},{"year":2011,"finding":"MAGI1 inhibits migration and invasion of hepatocellular carcinoma (HepG2) cells; stable overexpression of MAGI1 significantly slows wound healing and reduces Matrigel invasion. MAGI1 overexpression substantially elevates PTEN protein levels, and MAGI1 and PTEN expression levels are positively correlated in HCC tissues (r=0.913), suggesting MAGI1 suppresses HCC cell motility by upregulating PTEN.","method":"Stable transfection of MAGI1 plasmid in HepG2, wound healing assay, Matrigel invasion assay, Western blot for PTEN","journal":"Journal of Central South University. Medical sciences","confidence":"Medium","confidence_rationale":"Tier 3 — gain-of-function with functional readout and PTEN protein correlation; single lab, no direct epistasis proof","pmids":["21685691"],"is_preprint":false},{"year":2024,"finding":"SRC kinase phosphorylates MAGI1 in IDH-mutant intrahepatic cholangiocarcinoma (IDHm ICC), inhibiting a latent tumor-suppressing MAGI1-PP2A complex. SRC inhibition by dasatinib enables MAGI1 to recruit and activate PP2A, which dephosphorylates S6K, reducing ribosomal S6 phosphorylation and protein synthesis, leading to cell death. This MAGI1-PP2A-S6K axis operates independently of mTOR.","method":"Unbiased phosphoproteomic screen identifying MAGI1 as SRC substrate, biochemical co-IP of MAGI1-PP2A complex, functional PP2A phosphatase activity assays, patient tissue validation, patient-derived organoids, xenograft mouse models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 — phosphoproteomic identification confirmed by biochemical complex formation, functional phosphatase assays, multiple model systems including PDX","pmids":["38748774"],"is_preprint":false},{"year":2012,"finding":"Copy number variations (CNVs) >100 kb in MAGI1 are enriched in patients with bipolar affective disorder (BPAD) and schizophrenia compared to controls (pooled analysis: 7 large CNVs in cases vs. 2 in controls, p=0.023). A ~200 kb deletion in the first intron of MAGI1 segregated with BPAD in a pedigree (6/6 affected individuals carried it), suggesting MAGI1 has a role in psychiatric disease etiology.","method":"Genome-wide CNV assessment in 48 BPAD families, follow-up in 4084 psychiatric samples, pooled analysis of 10,925 cases and 16,747 controls","journal":"Biological psychiatry","confidence":"Low","confidence_rationale":"Tier 4 — genetic association only, no mechanistic experiment","pmids":["22381734"],"is_preprint":false}],"current_model":"MAGI1 is a multi-PDZ domain MAGUK scaffolding protein (with inverted GK-WW-PDZ architecture) that localizes at tight junctions and adherens junctions in epithelial and endothelial cells, where it assembles signaling complexes via its five PDZ and two WW domains: PDZ5 binds beta-catenin and anchors MAGI1 to the membrane, PDZ4 binds cadherin-23 in stereocilia, and PDZ1 is targeted by viral oncoproteins (HPV E6, adenovirus E4-ORF1); MAGI1 stabilizes Dll1 at adherens junctions to promote Notch signaling, suppresses invasiveness and migration (in part by upregulating PTEN, inhibiting MAPK/ERK and PI3K/AKT), mediates eNOS activation downstream of fluid shear stress through PKA and AMPK, and forms a latent tumor-suppressive complex with PP2A that is inhibited by SRC-mediated phosphorylation of MAGI1 and can be activated by SRC inhibition to dephosphorylate S6K independently of mTOR; in neurons, MAGI1 controls glutamate receptor clustering and regulates GLT-1 surface expression, while post-translational modifications including SUMO and phosphorylation by p90RSK regulate MAGI1's nuclear translocation and its role in endothelial activation and ER-stress-driven atherogenesis."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of MAGI1 as a novel MAGUK with inverted domain architecture (GK-WW-PDZ) established it as a distinct scaffolding protein with isoform-dependent nuclear versus membrane localization.","evidence":"cDNA cloning, subcellular fractionation, and immunolocalization in MDCK cells; parallel WW domain ligand screens","pmids":["9395497","9169421"],"confidence":"High","gaps":["Functional significance of nuclear isoform unclear","WW domain ligand specificity not mapped in vivo","No loss-of-function data"]},{"year":2000,"claim":"Discovery that PDZ5 anchors MAGI1 to junctional membranes via β-catenin binding, and that viral oncoproteins (HPV E6, adenovirus E4-ORF1) hijack PDZ1, established MAGI1 as a junctional scaffold targeted in oncogenesis.","evidence":"PDZ domain deletion mapping, co-IP of β-catenin/E-cadherin complexes in MDCK cells; co-IP and mutational analysis of viral oncoprotein interactions","pmids":["10772923","11077444"],"confidence":"High","gaps":["Mechanism by which E6-mediated MAGI1 degradation drives transformation not established","Relative contributions of individual PDZ domains to junctional assembly unknown"]},{"year":2002,"claim":"Mapping MAGI1 to tight junctions across epithelial tissues in vivo and demonstrating colocalization with ZO-1/ZO-2 in pre-assembled complexes showed that MAGI1 is a general tight junction component rather than a cell-type-specific adaptor.","evidence":"Immunofluorescence in multiple epithelial cell types and tissues, isoform-specific domain deletions","pmids":["11969287"],"confidence":"High","gaps":["Causal role in tight junction assembly vs. maintenance not distinguished","Redundancy with MAGI-2/MAGI-3 at tight junctions not tested"]},{"year":2003,"claim":"Identification of JAM4 as a MAGI1 partner that strengthens cell-cell adhesion and barrier sealing when scaffolded by MAGI1 provided the first functional evidence that MAGI1 actively reinforces tight junction integrity.","evidence":"GST pulldown, co-IP, functional adhesion and permeability assays in L and CHO cells","pmids":["12773569"],"confidence":"High","gaps":["In vivo barrier function of MAGI1–JAM4 interaction not tested","Stoichiometry and competition among PDZ ligands at the junction unknown"]},{"year":2005,"claim":"Demonstration that MAGI1 recruits Dll1 to adherens junctions and stabilizes it on the cell surface linked MAGI1 scaffolding to Notch ligand presentation during neural development.","evidence":"Y2H, co-IP, in situ hybridization in developing neural tube, cell-surface biotinylation in fibroblasts","pmids":["15908431"],"confidence":"High","gaps":["Downstream effect on Notch signaling output not directly measured","Whether MAGI1 is required for Dll1 function in vivo not shown by loss-of-function"]},{"year":2008,"claim":"Identification of cadherin-23 as a PDZ4 ligand in stereocilia and TRIP6 as a PDZ5 ligand that promotes invasiveness expanded the repertoire of MAGI1 PDZ interactions and revealed context-dependent roles in sensory cells and cancer.","evidence":"Cochlear library screen and immunolocalization for Cdh23; Y2H, invasion and aggregation assays with domain-specific mutants for TRIP6","pmids":["18971469","19017743"],"confidence":"High","gaps":["MAGI1–Cdh23 functional significance for hearing not tested by genetic loss-of-function","How TRIP6–MAGI1 interaction is regulated remains unknown"]},{"year":2009,"claim":"C. elegans genetic studies showed MAGI-1 controls glutamate receptor (GLR-1) clustering in specific neurons during associative learning in a β-catenin-dependent manner, establishing a conserved neuronal scaffolding function.","evidence":"magi-1 mutant behavioral analysis, neuron-specific rescue, GLR-1::GFP imaging, epistasis with hmp-2/β-catenin","pmids":["19551147"],"confidence":"High","gaps":["Mammalian counterpart of this learning/memory circuit function not established","Direct physical interaction between MAGI-1 and GLR-1 not shown"]},{"year":2010,"claim":"Quantitative biophysical characterization of PDZ1–HPV E6 binding and demonstration that HPV E6-driven MAGI1 degradation causally disrupts tight junctions defined the structural basis and functional consequence of viral targeting.","evidence":"SPR binding measurements with mutagenesis; siRNA of E6 in HPV+ cervical cancer cells with MAGI1 rescue of ZO-1 localization","pmids":["20842623","21123374"],"confidence":"High","gaps":["Crystal structure of full PDZ1–E6 complex not available at this point","Whether MAGI1 degradation is sufficient for HPV-driven malignancy not determined"]},{"year":2011,"claim":"Discovery that MAGI1 binds GLT-1 and negatively regulates its surface expression in astrocytes extended MAGI1's scaffolding function to control of glutamate transporter trafficking in glial cells, complementing its neuronal role.","evidence":"GST pulldown, co-IP, cell-surface biotinylation, siRNA knockdown with glutamate uptake assay in differentiated astrocytes","pmids":["21426345"],"confidence":"High","gaps":["Which PDZ domain mediates GLT-1 binding not mapped","In vivo relevance for glutamate homeostasis not tested"]},{"year":2011,"claim":"NMR structure of MAGI1 PDZ1 alone and in complex with E6 peptide revealed a global conformational response to ligand binding including quenching of backbone dynamics in the C-terminal extension, providing the first atomic-resolution model of MAGI1 ligand recognition.","evidence":"NMR spectroscopy, backbone dynamics analysis, mutagenesis with binding affinity measurements","pmids":["21238461"],"confidence":"High","gaps":["Structures of other PDZ domains not solved","How conformational changes propagate to multi-domain function unknown"]},{"year":2017,"claim":"Loss-of-function studies in gastric and hepatocellular carcinoma cells demonstrated that MAGI1 suppresses migration and invasion through inhibition of MAPK/ERK signaling and stabilization of PTEN, solidifying its role as a broadly acting tumor suppressor.","evidence":"shRNA knockdown in gastric cancer cells with MAPK/ERK and EMT marker readouts; MAGI1 overexpression in HepG2 with PTEN correlation in HCC tissues","pmids":["28373751","21685691"],"confidence":"Medium","gaps":["Direct mechanism linking MAGI1 scaffolding to PTEN stabilization not defined","No epistasis experiments placing MAGI1 upstream of MAPK directly"]},{"year":2019,"claim":"Two studies revealed MAGI1 as a mechanosensitive endothelial signaling hub: shear stress induces MAGI1 expression to activate eNOS via PKA/AMPK, while disturbed flow triggers p90RSK-mediated MAGI1 phosphorylation and SENP2-mediated deSUMOylation that drive nuclear translocation and pro-atherogenic endothelial activation.","evidence":"siRNA/overexpression with pharmacological kinase inhibition and flow chambers; transgenic MAGI1 mice with ex vivo NO measurement; phosphorylation/SUMOylation site mutagenesis and Magi1+/- atherogenesis model","pmids":["31035633","30944250"],"confidence":"High","gaps":["How MAGI1 senses or transduces mechanical force is unknown","Relative contribution of phosphorylation vs. SUMOylation to atherogenesis not separated in vivo"]},{"year":2020,"claim":"MAGI1 was established as a tumor suppressor in ER+ breast cancer where it sustains ER expression, and its loss accelerates primary tumor growth and metastasis; MAGI1 is itself regulated by estrogen/ER and suppressed by COX-2/PGE2, forming a feed-forward regulatory loop.","evidence":"shRNA knockdown in MCF7 and 67NR cells, in vivo xenograft and lung metastasis models, pharmacological stimulation/inhibition of ER and COX-2 pathways","pmids":["31963297"],"confidence":"High","gaps":["Mechanism by which MAGI1 maintains ER expression is unknown","Whether NSAID-mediated MAGI1 upregulation is clinically actionable not tested"]},{"year":2024,"claim":"Phosphoproteomic identification of MAGI1 as a SRC substrate revealed a latent MAGI1–PP2A tumor-suppressive complex: SRC phosphorylation inhibits this complex, while SRC inhibition enables MAGI1–PP2A to dephosphorylate S6K independently of mTOR, defining a druggable axis in IDH-mutant cholangiocarcinoma.","evidence":"Unbiased phosphoproteomics, co-IP of MAGI1–PP2A, PP2A activity assays, patient tissue validation, patient-derived organoids and xenograft models","pmids":["38748774"],"confidence":"High","gaps":["Structural basis of SRC phosphorylation-dependent PP2A dissociation unknown","Whether MAGI1–PP2A complex operates in other SRC-driven cancers not tested","Which MAGI1 phosphosite(s) regulate PP2A binding not fully mapped"]},{"year":null,"claim":"How MAGI1's multiple PDZ and WW domain interactions are coordinated in space and time to balance its junctional scaffolding, tumor-suppressive, and endothelial signaling functions remains unresolved, as does the in vivo phenotype of complete MAGI1 loss in mammals.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full mammalian knockout phenotype published","No structural model of multi-domain MAGI1 or full-length complex assembly","Interplay among PTMs (phosphorylation, SUMOylation) in different tissue contexts not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,6,7,10,14,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,6,7,10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,19]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,17,18,19,20,25,27]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,5,6,7,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,12,22,27]}],"complexes":["MAGI1-PP2A complex","MAGI1-beta-catenin-E-cadherin junctional complex"],"partners":["CTNNB1","PTEN","CDH23","DLL1","AMICA1","TRIP6","SLC1A2","PPP2CA"],"other_free_text":[]},"mechanistic_narrative":"MAGI1 is a multi-domain MAGUK scaffolding protein that organizes signaling complexes at epithelial tight junctions, adherens junctions, and endothelial cell contacts, thereby regulating cell-cell adhesion, barrier integrity, and signal transduction. Its five PDZ domains mediate binding to β-catenin (PDZ5), cadherin-23 (PDZ4), and viral oncoproteins such as HPV E6 and adenovirus E4-ORF1 (PDZ1), while its WW domains engage PY-motif-containing partners; through these interactions MAGI1 stabilizes Dll1 at adherens junctions to promote Notch signaling, recruits JAM4 to strengthen tight junctions, negatively regulates GLT-1 surface expression in astrocytes, and suppresses tumor cell migration and invasion by stabilizing a PTEN/β-catenin complex and inhibiting MAPK/ERK and PI3K/AKT pathways [PMID:10772923, PMID:15908431, PMID:12773569, PMID:21426345, PMID:28373751, PMID:31352641]. In endothelial cells, MAGI1 transduces fluid shear stress into eNOS activation via PKA and AMPK, and its phosphorylation by p90RSK and deSUMOylation drive nuclear translocation linked to endothelial activation and atherogenesis [PMID:31035633, PMID:30944250]. SRC-mediated phosphorylation of MAGI1 inhibits a latent MAGI1–PP2A tumor-suppressive complex; upon SRC inhibition, this complex dephosphorylates S6K independently of mTOR, suppressing protein synthesis and promoting cell death in cholangiocarcinoma [PMID:38748774]."},"prefetch_data":{"uniprot":{"accession":"Q96QZ7","full_name":"Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1","aliases":["Atrophin-1-interacting protein 3","AIP-3","BAI1-associated protein 1","BAP-1","Membrane-associated guanylate kinase inverted 1","MAGI-1","Trinucleotide repeat-containing gene 19 protein","WW domain-containing protein 3","WWP3"],"length_aa":1491,"mass_kda":164.6,"function":"Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5 (By similarity). May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface (By similarity)","subcellular_location":"Cell junction, tight junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96QZ7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAGI1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TJP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAGI1","total_profiled":1310},"omim":[{"mim_id":"610638","title":"IMMUNOGLOBULIN SUPERFAMILY, MEMBER 5; IGSF5","url":"https://www.omim.org/entry/610638"},{"mim_id":"609590","title":"QKI, KH DOMAIN-CONTAINING RNA-BINDING PROTEIN; QKI","url":"https://www.omim.org/entry/609590"},{"mim_id":"608155","title":"SYNAPTOPODIN; SYNPO","url":"https://www.omim.org/entry/608155"},{"mim_id":"606382","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 2; MAGI2","url":"https://www.omim.org/entry/606382"},{"mim_id":"604638","title":"ACTININ, ALPHA-4; ACTN4","url":"https://www.omim.org/entry/604638"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":62238,"output_tokens":8717,"usd":0.158735},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":12286,"output_tokens":3826,"usd":0.23562}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"MAGI1 localizes to tight junctions of all epithelial cell types examined, co-localizes with ZO-1 and ZO-2 in nonpolarized epithelial cells, and this localization occurs in the absence of the guanylate kinase, WW domains, and extended carboxy terminus; human MAGI1 transcripts are alternatively spliced at three sites producing isoforms with differential tissue expression.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, expression analysis in cultured cells and tissues\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional domain dissection, replicated across multiple cell types\",\n      \"pmids\": [\"11969287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI1 recruits Delta-like 1 (Dll1) to cadherin-based adherens junctions (AJs) in developing neural tube; MAGI1 binds both Dll1 and N-cadherin–β-catenin complexes, stabilizes Dll1 on the cell surface, and thus presents Dll1 at apical AJ termini to activate Notch signaling on neighboring cells.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, immunofluorescence in developing spinal cord and cultured AJ-forming fibroblasts, cell-surface protein stabilization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus localization with functional consequence, in vivo and in vitro\",\n      \"pmids\": [\"15908431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAGI1 binds via its PDZ4 domain to a C-terminal PDZ-binding site on the hair-cell-specific Cdh23(+68) splice variant of cadherin 23 in cochlear stereocilia, positioning MAGI1 as a candidate intracellular scaffolding partner within the tip-link complex that connects to the cytoskeleton.\",\n      \"method\": \"Yeast two-hybrid screen, pulldown, immunofluorescence in neonatal and adult cochlea\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus localization, single lab\",\n      \"pmids\": [\"18971469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIP6 interacts directly with MAGI-1b via the fifth PDZ domain of MAGI-1b, and this interaction promotes cell invasiveness in a PI3-kinase- and NF-κB-dependent manner; a TRIP6 mutant lacking the PDZ-binding motif cannot promote invasiveness or impair cell-cell aggregation, demonstrating the requirement for PDZ scaffolding in junctional complex activity.\",\n      \"method\": \"Yeast two-hybrid screening, direct binding assays, MDCK invasion and aggregation assays, intracellular delivery of competing peptides\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed plus domain-mutant rescue experiments with defined cellular phenotype\",\n      \"pmids\": [\"19017743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans MAGI-1 (ortholog of mammalian MAGI) is required cell-autonomously in AVA/AVD interneurons for GLR-1 (ionotropic glutamate receptor) clustering at synapses during memory consolidation, and this function depends on its ability to interact with β-catenin HMP-2; in RIA interneurons MAGI-1 controls synaptic remodeling of AVA/AVD in a cell non-autonomous manner during associative learning.\",\n      \"method\": \"Genetic loss-of-function, cell-specific rescue experiments, GFP-tagged GLR-1 imaging in live C. elegans\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with cell-specific rescue and live imaging of synaptic phenotype\",\n      \"pmids\": [\"19551147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAGI-1 is a major degradation target of high-risk HPV-16 and HPV-18 E6 oncoproteins; E6 preferentially targets MAGI-1 at nuclear and membrane sites, and one direct consequence of MAGI-1 degradation is loss of tight-junction integrity (ZO-1 mislocalization); restoration of E6 ablation restores tight junctions in a MAGI-1-dependent manner.\",\n      \"method\": \"siRNA ablation of E6 in CaSKi (HPV-16+) and HeLa (HPV-18+) cells, immunofluorescence of ZO-1, rescue by MAGI-1 re-expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype and rescue, two HPV types tested\",\n      \"pmids\": [\"21123374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The NMR solution structure of the MAGI-1 PDZ1 domain (with noncanonical extended boundaries) bound to an HPV-16 E6 C-terminal peptide reveals that binding quenches high-frequency backbone motions in the C-terminal tail of the PDZ domain and that this flanking region contacts the peptide upstream of the canonical binding motif; mutations in the C-terminal flanking region significantly decrease binding affinity for E6 peptides.\",\n      \"method\": \"NMR structure determination, backbone dynamics analysis, site-directed mutagenesis, binding affinity measurement\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with mutagenesis and functional validation\",\n      \"pmids\": [\"21238461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI-1 binds directly to the glutamate transporter GLT-1; co-expression of MAGI-1 with GLT-1 reduces GLT-1 surface expression, while partial knockdown of endogenous MAGI-1 in astrocytes increases GLT-1 surface expression and GLT-1-mediated glutamate uptake.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, immunofluorescence, cell-surface biotinylation, siRNA knockdown, glutamate uptake assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown/Co-IP plus functional surface expression and uptake assays\",\n      \"pmids\": [\"21426345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel tight-junction protein, MASCOT, interacts with MAGI-1 through the first WW domain of MAGI-1 via an LPxY variant WW-binding motif (not the conventional PPxY), and this interaction is required for MASCOT localization to tight junctions in MDCK cells; the coiled-coil domain of MASCOT is necessary for its junctional targeting.\",\n      \"method\": \"GST fusion binding assay with endogenous and ectopic MAGI-1, domain mapping, confocal colocalization in MDCK cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pulldown plus localization\",\n      \"pmids\": [\"16019084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Surface plasmon resonance quantification of MAGI-1 PDZ1 binding to HPV E6 C-terminal peptides shows dissociation constants in the micromolar range comparable to cellular partners; binding selectivity is determined by a valine at position 0, a negative charge at position -3, and the K499 residue of MAGI-1 PDZ1; LPP and Tax protein C-termini also bind MAGI-1 PDZ1.\",\n      \"method\": \"Surface plasmon resonance (SPR), site-directed mutagenesis of HPV16 E6 peptide and PDZ1\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro binding assay with systematic mutagenesis\",\n      \"pmids\": [\"20842623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAGI-1 is biochemically enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from the postsynaptic density localization of MAGI-2/3) in rat neuronal tissues, and shows diffuse distribution in hippocampal neuron cell bodies and processes rather than synaptic puncta, indicating a distinct neuronal role from MAGI-2/3.\",\n      \"method\": \"Subcellular biochemical fractionation, Western blotting with isoform-specific antibody, immunofluorescence in primary cultured neurons and immunohistochemistry in rat brain sections\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation plus localization, single lab\",\n      \"pmids\": [\"22605569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAGI1 knockdown in gastric cancer cells significantly promotes cell migration and invasion; mechanistically, MAGI1 loss increases MMP expression and induces EMT-related molecular changes via activation of the MAPK/ERK signaling pathway.\",\n      \"method\": \"shRNA knockdown, scratch wound migration assay, Transwell invasion assay, Western blotting for MAPK/ERK and EMT markers\",\n      \"journal\": \"Chinese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"28373751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 constitutively localizes with VE-cadherin at endothelial cell junctions; fluid shear stress increases MAGI1 expression; MAGI1 silencing impairs KLF4 expression, endothelial alignment, eNOS phosphorylation, and NO production; MAGI1 overexpression induces PKA, AMPK, and CaMKII phosphorylation; pharmacological inhibition of PKA and AMPK prevents MAGI1-mediated eNOS phosphorylation; endothelial-specific transgenic MAGI1 induces PKA and eNOS phosphorylation in vivo and increases NO production ex vivo.\",\n      \"method\": \"siRNA silencing, overexpression, pharmacological inhibition, immunofluorescence, in vivo transgenic mouse model, ex vivo NO measurement\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo transgenic model and pharmacological dissection\",\n      \"pmids\": [\"31035633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In endothelial cells exposed to disturbed flow, p90RSK binds MAGI1 and phosphorylates MAGI1-S741, activating Rap1 and EC activation; MAGI1-K931 deSUMOylation induces nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, driving EC activation and apoptosis respectively; MAGI1 associates with ATF-6 and links to ER stress response; reduced MAGI1 in Magi1-/+ mice inhibits disturbed flow-induced atherogenesis.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation/SUMOylation site mutagenesis, microarray, Magi1+/- mouse atherosclerosis model, endothelial cell fractionation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple PTMs identified with functional consequences in vitro and in vivo haploinsufficient model\",\n      \"pmids\": [\"30944250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-486-5p directly targets the 3'-UTR of MAGI1 mRNA (confirmed by dual-luciferase and FREMSA assays), suppressing MAGI1 expression; MAGI1 knockdown reverses hydroquinone-induced inhibition of erythroid differentiation in K562 cells via downregulation of downstream Rap1 pathway genes RAPGEF2 and RAP1A.\",\n      \"method\": \"Dual-luciferase reporter assay, FREMSA, miR-486-5p overexpression/knockdown, MAGI1 siRNA knockdown, erythroid differentiation assay\",\n      \"journal\": \"Toxicology in vitro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miRNA-target interaction validated plus pathway epistasis, single lab\",\n      \"pmids\": [\"32198055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 suppresses invasion and migration of renal cell carcinoma cells; mechanistically, MAGI1 stabilizes a PTEN/MAGI1/β-catenin complex that inhibits β-catenin signaling; miR-520h (transcriptionally activated by c-Myb) targets MAGI1 to suppress its expression.\",\n      \"method\": \"Invasion/migration assays, Co-IP, Western blotting, luciferase reporter, chromatin immunoprecipitation\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic data from single lab with several complementary assays\",\n      \"pmids\": [\"31352641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAGI1 downregulation in ER+/HER2- breast cancer cells (MCF7) impairs estrogen receptor expression and signaling, promotes proliferation, and reduces apoptosis and epithelial differentiation; MAGI1 expression is upregulated by estrogen/ER signaling and downregulated by the prostaglandin E2/COX-2 axis.\",\n      \"method\": \"siRNA knockdown, overexpression, proliferation/apoptosis assays, signaling pathway analysis in MCF7 cells and 67NR murine BC cells, in vivo xenograft and metastasis models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype, in vivo tumor model, and upstream regulation identified\",\n      \"pmids\": [\"31963297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRC phosphorylates MAGI1 in IDH-mutant cholangiocarcinoma, identified by unbiased phosphoproteomic screen; SRC inhibition enables formation of a MAGI1-PP2A complex that dephosphorylates and inactivates S6K, suppressing mTOR-independent S6 signaling and inducing cell death; dasatinib combined with S6K/AKT inhibitor M2698 shows potent anti-tumor effect in patient-derived xenografts.\",\n      \"method\": \"Phosphoproteomic screen, Co-IP, biochemical/functional PP2A activity assays, patient tissue analysis, ICC cell lines, patient-derived organoids, patient-derived xenografts\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — unbiased phosphoproteomics plus biochemical reconstitution, patient tissue, organoids, and in vivo xenograft validation\",\n      \"pmids\": [\"38748774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI1 overexpression in HepG2 hepatocellular carcinoma cells inhibits cell migration and invasion and significantly elevates PTEN protein levels; MAGI1 and PTEN protein expression are positively correlated in ccRCC tissues.\",\n      \"method\": \"Stable overexpression in HepG2, wound-healing assay, Transwell invasion assay, Western blotting\",\n      \"journal\": \"Journal of Central South University Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method per assay, no direct mechanistic link shown\",\n      \"pmids\": [\"21685691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 silencing in glioma cells enhances proliferation and inhibits apoptosis; knockdown increases β-catenin, cyclin D1, phospho-AKT and N-cadherin/vimentin, while reducing E-cadherin and PTEN, implicating the Wnt/β-catenin and PTEN/AKT signaling pathways.\",\n      \"method\": \"MAGI1 siRNA knockdown in glioma cell lines and GSCs, CCK8, colony formation, flow cytometry, Western blotting\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined phenotype and pathway markers, strong preponderance with multiple readouts\",\n      \"pmids\": [\"32009799\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGI1 is a cytoplasmic scaffolding protein that localizes to tight junctions and adherens junctions in epithelial and endothelial cells, where it organizes multiprotein complexes through its PDZ, WW, and other domains: it recruits PTEN, β-catenin, Dll1, cadherin 23, TRIP6, and PP2A to junctional and synaptic sites, suppresses oncogenic PI3K/AKT, MAPK/ERK, and Wnt/β-catenin signaling, is degraded by HPV E6 oncoprotein causing tight-junction disruption, mediates fluid shear stress-induced eNOS activation via PKA/AMPK in endothelial cells, and forms a tumor-suppressive complex with PP2A that is released upon SRC inhibition to dephosphorylate S6K independently of mTOR.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers 1-20, 22, 25, 27-30, 33, 36, 41, 45, 47-48, 50, 52, 58, 60-62, 65-66, 76-77, 81, 83, 85, 88, 91-92, 94, 96, 98-100 → EXCLUDE (about BAP1/BRCA1-associated protein 1, not MAGI1)\n- Paper 64, 89 → EXCLUDE (Case B: alt-locus products MAGI1-IT1, a lncRNA)\n- Papers about MAGI1 (canonical protein): 21, 26, 31, 32, 34, 38, 40, 43, 44, 46, 49, 53, 54, 57, 63, 71, 74, 79, 82, 84, 87, 93, 95, 97 → KEEP\n- Additional curated papers about MAGI1: 18, 23, 27, 28, 29, 30 → KEEP (directly about MAGI1 protein)\n- Papers 1-17 in additional list (large proteomics screens, GWAS, etc.) → EXCLUDE or treat as low-value background; paper 22 (GWAS for neuroticism with MAGI1 SNP) → EXCLUDE (GWAS, no mechanism)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"MAGI-1 was identified as a novel MAGUK scaffolding protein with an inverted domain structure: guanylate kinase (GK) domain at the N-terminus, two WW domains replacing the SH3 domain, and five PDZ domains at the C-terminus. Subcellular fractionation and immunolocalization in MDCK cells showed that the longest splice variant (MAGI-1c), which contains bipartite nuclear localization signals in its unique C-terminal sequence, localizes predominantly to the nucleus, while shorter forms lacking these signals are found in membrane and cytoplasmic fractions.\",\n      \"method\": \"cDNA cloning, subcellular fractionation, immunolocalization in MDCK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original cloning and characterization with direct localization experiments; foundational study replicated by subsequent work\",\n      \"pmids\": [\"9395497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MAGI-1 WW domains were identified as binding partners for PY-motif (PPxY)-containing proteins; cloning of ligand targets (COLT) screen identified MAGI-1 among novel WW domain proteins capable of binding PY-motif ligands from signaling and regulatory proteins.\",\n      \"method\": \"COLT screen (cDNA expression library screening with peptide ligands), in vitro WW domain binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single in vitro binding screen identifying WW domain ligand interaction\",\n      \"pmids\": [\"9169421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MAGI-1 (as AIP1/AIP3) was identified as an atrophin-1 interacting protein through its WW domains; yeast two-hybrid and in vitro binding assays confirmed that atrophin-1 binds to MAGI-1 in the vicinity of its polyglutamine tract.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assays (GST pulldown)\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid confirmed by in vitro binding, single study\",\n      \"pmids\": [\"9647693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI-1 was identified as a binding partner of adenovirus type 9 E4-ORF1 and high-risk HPV E6 oncoproteins via PDZ domain interaction. E4-ORF1 aberrantly sequesters MAGI-1 in the cytoplasm, while high-risk HPV E6 targets MAGI-1 for degradation. Transformation-defective viral mutants are deficient for these activities, implicating MAGI-1 interaction in viral oncogenesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, mutational analysis of viral oncoproteins\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, localization, functional mutant analysis in multiple viral systems\",\n      \"pmids\": [\"11077444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI-1b fifth PDZ domain (PDZ5) is essential for membrane localization of MAGI-1b, and this PDZ domain binds beta-catenin. MAGI-1b forms complexes with beta-catenin and E-cadherin during formation of cell-cell junctions in MDCK cells; GFP-MAGI-1b localizes to the basolateral membrane of polarized MDCK cells.\",\n      \"method\": \"PDZ domain deletion analysis, co-immunoprecipitation, GFP-fusion localization in MDCK cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with deletion mutants plus co-IP and live-cell localization with functional context\",\n      \"pmids\": [\"10772923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MAGI-1 and MAGI-3 are components of tight junctions in cultured epithelial cells and in all epithelial cell types examined in vivo. Human MAGI-1 is alternatively spliced at three sites producing isoforms with different C-termini; two brain-specific forms lack nuclear targeting signals. MAGI-1 colocalizes with ZO-1 and ZO-2 in non-polarized epithelial cells, suggesting a pre-assembled complex incorporated into tight junctions upon polarization. All alternatively spliced forms show tight junction localization independently of the GK and WW domains or extended C-terminus.\",\n      \"method\": \"Immunofluorescence colocalization, isoform-specific domain deletion analysis in cultured epithelial cells, in vivo tissue expression analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization across multiple cell types and tissues, domain deletion functional analysis, replicated with multiple isoforms\",\n      \"pmids\": [\"11969287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAM4 (junctional adhesion molecule 4) was identified as a novel MAGI-1 binding protein at tight junctions. JAM4 binds MAGI-1 (but not ZO-1) in vitro, co-clusters with MAGI-1 in COS-7 cells, and MAGI-1 strengthens JAM4-mediated cell-cell adhesion and epithelial barrier sealing effects. MAGI-1 also recruits ZO-1, occludin, and other tight junction proteins to JAM4-based cell contacts.\",\n      \"method\": \"In vitro GST pulldown, co-immunoprecipitation, colocalization in COS-7 cells, functional adhesion and permeability assays in L cells and CHO cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed in vitro and in cells, functional consequence (adhesion, barrier permeability) demonstrated\",\n      \"pmids\": [\"12773569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI-1 recruits Delta-like 1 (Dll1) to cadherin-based adherens junctions (AJs) and stabilizes Dll1 on the cell surface. In developing neural tube, MAGI-1 accumulates at AJs at apical termini of radial processes. MAGI-1 binds both Dll1 and N-cadherin-beta-catenin complexes. In cultured fibroblasts, MAGI-1 localizes to AJs and recruits Dll1 to these sites through direct binding, stabilizing Dll1 on the cell surface.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in situ hybridization, immunofluorescence colocalization in vivo and in cultured fibroblasts, cell surface biotinylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, Co-IP, in vivo localization, cell-surface assay) with clear functional outcome\",\n      \"pmids\": [\"15908431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel MAGI-1-associated protein (MASCOT) was identified that binds to the first WW domain of MAGI-1 via a variant LPxY motif (not the canonical PPxY). MASCOT colocalizes with MAGI-1 at tight junctions in MDCK cells and its coiled-coil domain is necessary for this junctional localization.\",\n      \"method\": \"Glomerular cDNA library screen, GST pulldown assays, co-immunoprecipitation with endogenous MAGI-1, immunofluorescence in MDCK cells, domain deletion analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study with GST pulldown, Co-IP, and colocalization; LPxY motif as novel WW domain ligand is mechanistically informative\",\n      \"pmids\": [\"16019084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAGI-1 was identified as a candidate stereociliary scaffolding protein that binds the hair-cell-specific Cdh23(+68) splice variant of cadherin 23 via its PDZ4 domain interacting with the C-terminal PDZ-binding site of Cdh23. MAGI-1 immunoreactivity is present throughout neonatal stereocilia in a distribution similar to Cdh23, becoming punctate in adult, and is proposed to replace harmonin's PDZ2 binding at the Cdh23 C-terminus in the tip-link complex.\",\n      \"method\": \"Cochlear cDNA library screen using Cdh23 intracellular domain as bait, PDZ domain binding assays, immunofluorescence in cochlear hair cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — library screen and binding domain mapping confirmed by immunolocalization; functional replacement of harmonin is proposed but not directly tested\",\n      \"pmids\": [\"18971469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRIP6, a zyxin-family protein, was identified as a direct MAGI-1b interactor binding to its fifth PDZ domain (PDZ5). Ectopic TRIP6 expression induced invasiveness in MDCK cells in a PI3-kinase- and NF-κB-dependent manner and impaired cell-cell aggregation by uncoupling adherens junctional complexes from the cytoskeleton. A TRIP6 mutant lacking the PDZ-binding motif could not promote invasiveness or interfere with cell-cell aggregation, despite retaining NF-κB and Akt activation, demonstrating that PDZ scaffold interactions are required for these functions.\",\n      \"method\": \"Yeast two-hybrid screening, direct binding assays, ectopic expression in MDCK/MDCKts-src cells, invasion assays, cell aggregation assays, intracellular peptide delivery competition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Y2H confirmed by direct binding, functional rescue with competing peptides, clear mechanistic pathway placement with domain-specific mutants\",\n      \"pmids\": [\"19017743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans MAGI-1 (ortholog of mammalian MAGI/S-SCAM) is required in specific neurons for different aspects of associative learning and memory. MAGI-1 in RIA interneurons controls, in a cell non-autonomous manner, the dynamic remodeling of AVA/AVD/AVE synapses containing ionotropic glutamate receptor (iGluR) GLR-1 during learning. During memory consolidation, MAGI-1 controls GLR-1 clustering in AVA and AVD interneurons cell-autonomously, dependent on interaction with beta-catenin HMP-2.\",\n      \"method\": \"Genetic analysis of magi-1 mutants, neuron-specific rescue experiments, fluorescence imaging of GLR-1::GFP synaptic clusters, epistasis analysis with hmp-2 (beta-catenin)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function with cell-type-specific rescue and mechanistic pathway placement via epistasis; ortholog in C. elegans with conserved domain function\",\n      \"pmids\": [\"19551147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAGI-1 is a major degradation target of both HPV-16 and HPV-18 E6 oncoproteins in cervical cancer cells. E6 preferentially targets MAGI-1 within the nucleus and at membrane sites. MAGI-1 degradation directly causes loss of tight junction integrity (mislocalization of ZO-1), and restoration of tight junctions after E6 ablation is dependent on the presence of MAGI-1.\",\n      \"method\": \"siRNA knockdown of E6 in CaSKi (HPV-16+) and HeLa (HPV-18+) cells, Western blot quantification of PDZ substrates, immunofluorescence of ZO-1, MAGI-1 rescue experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic comparison of multiple PDZ substrates in two HPV+ cell lines, direct rescue demonstrating MAGI-1's causal role in tight junction integrity\",\n      \"pmids\": [\"21123374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Surface plasmon resonance (SPR) quantification established that high-risk HPV E6 C-terminal peptides bind the PDZ1 domain of MAGI-1 with dissociation constants in the micromolar range, comparable to cellular PDZ1 ligands (LPP, Tax). MAGI-1 PDZ1 shows preference for C-termini with valine at position 0 and a negative charge at position -3. Mutagenesis identified K499 of MAGI-1 PDZ1 as a novel determinant of binding specificity; charged residues upstream of the PDZ-binding motif strongly contribute to binding selectivity.\",\n      \"method\": \"Surface plasmon resonance (SPR) with GST-fusion peptides, site-directed mutagenesis of HPV16 E6 C-terminal peptide and MAGI-1 PDZ1\",\n      \"journal\": \"Journal of molecular recognition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative biophysical binding measurements with mutagenesis defining binding determinants\",\n      \"pmids\": [\"20842623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI-1 binds glutamate transporter GLT-1 (EAAT2) as shown by GST pulldown and co-immunoprecipitation; the two proteins co-distribute in astrocytes. Co-expression of MAGI-1 with GLT-1 in C6 glioma cells significantly reduces GLT-1 surface expression as measured by cell-surface biotinylation. Conversely, partial knockdown of endogenous MAGI-1 in differentiated astrocytes increases glutamate uptake and surface expression of GLT-1, demonstrating that MAGI-1 negatively regulates GLT-1 surface expression and GLT-1-mediated glutamate uptake.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, immunofluorescence, cell-surface biotinylation, siRNA knockdown, glutamate uptake assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pulldown, Co-IP, biotinylation, functional uptake assay) with both gain- and loss-of-function in relevant cell types\",\n      \"pmids\": [\"21426345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR solution structure of MAGI-1 PDZ1 domain (with noncanonical extended boundaries) was solved alone and in complex with HPV16 E6 C-terminal peptide. E6 peptide binding induces quenching of high-frequency backbone motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical binding motif. Mutations in the C-terminal flanking region of PDZ1 significantly decrease binding affinity for E6 peptides, revealing a global conformational response to binding with effects propagated to distal sites.\",\n      \"method\": \"NMR spectroscopy (3D structure determination), backbone dynamics analysis, site-directed mutagenesis with binding affinity measurements\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic resolution NMR structure with dynamics analysis and mutagenesis validation\",\n      \"pmids\": [\"21238461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Biochemical fractionation of rat brain tissue revealed that MAGI-1 is enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from MAGI-2 and MAGI-3, which are enriched in the postsynaptic density fraction). Immunohistochemistry showed MAGI-1 expression in Purkinje cells, hippocampal CA1 neurons, the glomerulus region of the olfactory bulb, and the dorsal root entry zone in embryonic spinal cord, with diffuse distribution in cell bodies and processes of primary cultured hippocampal neurons (unlike the synaptic enrichment of MAGI-2/3).\",\n      \"method\": \"Subcellular fractionation with Western blotting, immunofluorescence in primary neurons, immunohistochemistry in rat brain sections\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct fractionation and localization experiments distinguishing MAGI-1 from paralogs; single lab study\",\n      \"pmids\": [\"22605569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAGI1 knockdown in gastric cancer cells significantly promotes cell migration and invasion. Mechanistically, MAGI1 inhibits migration and invasion by altering expression of matrix metalloproteinases (MMPs) and EMT-related molecules through inhibition of the MAPK/ERK signaling pathway.\",\n      \"method\": \"shRNA knockdown in GC cell lines, MTT/colony formation assays, scratch wound and transwell migration/invasion assays, Western blotting for MAPK/ERK pathway components and EMT markers\",\n      \"journal\": \"Chinese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, loss-of-function with defined pathway readout but no direct rescue or upstream mechanism\",\n      \"pmids\": [\"28373751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 mediates fluid shear stress-induced eNOS activation and NO production in endothelial cells. Fluid shear stress increases MAGI1 expression. MAGI1 silencing perturbs KLF4 expression, endothelial cell alignment, eNOS phosphorylation, and NO production, while MAGI1 overexpression induces PKA, AMPK, and CaMKII phosphorylation. Pharmacological inhibition of PKA and AMPK prevents MAGI1-mediated eNOS phosphorylation. Endothelial-specific transgenic MAGI1 mice show increased PKA and eNOS phosphorylation in vivo and increased NO production ex vivo.\",\n      \"method\": \"siRNA silencing, MAGI1 overexpression, pharmacological kinase inhibition, flow chamber experiments, transgenic mouse model with ex vivo NO measurement, Western blotting for phospho-kinases\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal in vitro and in vivo approaches (cell silencing, overexpression, transgenic mouse), pharmacological pathway dissection\",\n      \"pmids\": [\"31035633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In endothelial cells exposed to disturbed flow (d-flow), p90RSK binds MAGI1 and phosphorylates MAGI1 at S741, activating Rap1 to upregulate EC activation. Separately, MAGI1-K931 deSUMOylation (mediated by SENP2-T368 phosphorylation) drives nuclear translocation of p90RSK-MAGI1 and ATF6-MAGI1 complexes, accelerating EC activation and apoptosis respectively. MAGI1 associates with ATF-6, linking it to the ER stress response. Magi1+/- heterozygous mice show inhibited d-flow-induced atherogenesis.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation/SUMOylation site mutagenesis, microarray screening, immunofluorescence, in vivo atherogenesis in Magi1+/- mice, nuclear fractionation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods defining two distinct PTM-based mechanisms, confirmed in vivo with heterozygous mouse model\",\n      \"pmids\": [\"30944250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 suppresses tumor metastasis in renal cell carcinoma (RCC) by stabilizing the PTEN/MAGI1/β-catenin complex, thereby inhibiting β-catenin signaling. MAGI1 is transcriptionally suppressed by miR-520h, which is itself activated by c-Myb, defining a c-Myb/miR-520h/MAGI1 regulatory axis in RCC metastasis.\",\n      \"method\": \"Overexpression and knockdown in RCC cell lines, invasion/migration assays, co-immunoprecipitation of MAGI1/PTEN/β-catenin complex, luciferase reporter assay for miR-520h/MAGI1 3'UTR interaction\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — complex formation shown by Co-IP, miRNA target validated by reporter assay; single lab study\",\n      \"pmids\": [\"31352641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-486-5p directly targets the 3'UTR of MAGI1 and RASSF5, as confirmed by dual-luciferase reporter assay and FREMSA. MAGI1 knockdown in K562 cells reverses HQ-induced inhibition of erythroid differentiation via downregulation of RAPGEF2 and RAP1A, placing MAGI1 upstream of the Rap1 signaling pathway. MAGI1 and downstream Rap1 pathway genes are dose-dependently upregulated by hydroquinone.\",\n      \"method\": \"Dual-luciferase reporter assay, fluorescence-based RNA EMSA (FREMSA), miR-486-5p overexpression/knockdown, MAGI1 siRNA knockdown, Western blotting for Rap1 pathway\",\n      \"journal\": \"Toxicology in vitro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — miRNA-target interaction validated by two methods; epistasis to Rap1 pathway established by knockdown, single lab\",\n      \"pmids\": [\"32198055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAGI1 acts as a tumor suppressor in estrogen receptor-positive (ER+)/HER2- breast cancer. MAGI1 downregulation in MCF7 cells impairs ER expression and signaling, promotes cell proliferation, reduces apoptosis, and reduces epithelial differentiation. In murine 67NR ER+ BC cells, MAGI1 downregulation accelerates primary tumor growth and enhances experimental lung metastasis formation. MAGI1 expression is upregulated by estrogen/ER signaling and downregulated by the prostaglandin E2/COX-2 axis.\",\n      \"method\": \"siRNA/shRNA knockdown, cell proliferation and apoptosis assays, in vivo tumor xenograft and lung metastasis models in mice, Western blotting for ER signaling, pharmacological stimulation/inhibition\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with mechanistic pathway links (ER signaling, COX-2 regulation), multiple functional readouts\",\n      \"pmids\": [\"31963297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAGI1 is a comprehensive scaffold/tumor suppressor protein: it stabilizes cadherin-mediated cell-cell adhesion in epithelial and endothelial cells, localizes at mature focal adhesions, and regulates integrin-mediated adhesion and signaling in endothelial cells. MAGI1 modulates PI3K/AKT and Wnt/β-catenin oncogenic pathways. NSAIDs upregulate MAGI1 expression in breast and colorectal cancers, suggesting MAGI1 mediates part of NSAID tumor suppressive activity.\",\n      \"method\": \"Review compiling experimental evidence from multiple studies; original data includes localization at focal adhesions\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — primarily a review; focal adhesion localization claim references original experimental data\",\n      \"pmids\": [\"34198584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HPV-16 E6 intragenic variants (E-G350, E-C188/G350, E-A176/G350, AAa, AAc) show increased binding affinity to MAGI-1 PDZ1 domain compared to the E6 reference sequence, as modeled by molecular dynamics simulation and protein-protein docking with two MAGI-1 PDZ1 structural models.\",\n      \"method\": \"Molecular dynamics simulation, protein-protein docking (in silico)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no experimental validation of enhanced binding\",\n      \"pmids\": [\"35115618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 silencing in glioma cell lines and glioma stem cells (GSCs) enhances proliferation and inhibits apoptosis. MAGI1 knockdown increases N-cadherin, vimentin, β-catenin, cyclin D1, and phospho-Akt, and reduces E-cadherin and PTEN, indicating MAGI1 suppresses glioma progression via the Wnt/β-catenin and PTEN/AKT signaling pathways.\",\n      \"method\": \"shRNA knockdown, CCK8 and colony-formation assays, flow cytometry apoptosis, Western blotting for EMT/pathway markers\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with pathway marker readout; single lab study, mechanistic assignment by protein level changes without direct epistasis\",\n      \"pmids\": [\"32009799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI1 inhibits migration and invasion of hepatocellular carcinoma (HepG2) cells; stable overexpression of MAGI1 significantly slows wound healing and reduces Matrigel invasion. MAGI1 overexpression substantially elevates PTEN protein levels, and MAGI1 and PTEN expression levels are positively correlated in HCC tissues (r=0.913), suggesting MAGI1 suppresses HCC cell motility by upregulating PTEN.\",\n      \"method\": \"Stable transfection of MAGI1 plasmid in HepG2, wound healing assay, Matrigel invasion assay, Western blot for PTEN\",\n      \"journal\": \"Journal of Central South University. Medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — gain-of-function with functional readout and PTEN protein correlation; single lab, no direct epistasis proof\",\n      \"pmids\": [\"21685691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRC kinase phosphorylates MAGI1 in IDH-mutant intrahepatic cholangiocarcinoma (IDHm ICC), inhibiting a latent tumor-suppressing MAGI1-PP2A complex. SRC inhibition by dasatinib enables MAGI1 to recruit and activate PP2A, which dephosphorylates S6K, reducing ribosomal S6 phosphorylation and protein synthesis, leading to cell death. This MAGI1-PP2A-S6K axis operates independently of mTOR.\",\n      \"method\": \"Unbiased phosphoproteomic screen identifying MAGI1 as SRC substrate, biochemical co-IP of MAGI1-PP2A complex, functional PP2A phosphatase activity assays, patient tissue validation, patient-derived organoids, xenograft mouse models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphoproteomic identification confirmed by biochemical complex formation, functional phosphatase assays, multiple model systems including PDX\",\n      \"pmids\": [\"38748774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Copy number variations (CNVs) >100 kb in MAGI1 are enriched in patients with bipolar affective disorder (BPAD) and schizophrenia compared to controls (pooled analysis: 7 large CNVs in cases vs. 2 in controls, p=0.023). A ~200 kb deletion in the first intron of MAGI1 segregated with BPAD in a pedigree (6/6 affected individuals carried it), suggesting MAGI1 has a role in psychiatric disease etiology.\",\n      \"method\": \"Genome-wide CNV assessment in 48 BPAD families, follow-up in 4084 psychiatric samples, pooled analysis of 10,925 cases and 16,747 controls\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genetic association only, no mechanistic experiment\",\n      \"pmids\": [\"22381734\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGI1 is a multi-PDZ domain MAGUK scaffolding protein (with inverted GK-WW-PDZ architecture) that localizes at tight junctions and adherens junctions in epithelial and endothelial cells, where it assembles signaling complexes via its five PDZ and two WW domains: PDZ5 binds beta-catenin and anchors MAGI1 to the membrane, PDZ4 binds cadherin-23 in stereocilia, and PDZ1 is targeted by viral oncoproteins (HPV E6, adenovirus E4-ORF1); MAGI1 stabilizes Dll1 at adherens junctions to promote Notch signaling, suppresses invasiveness and migration (in part by upregulating PTEN, inhibiting MAPK/ERK and PI3K/AKT), mediates eNOS activation downstream of fluid shear stress through PKA and AMPK, and forms a latent tumor-suppressive complex with PP2A that is inhibited by SRC-mediated phosphorylation of MAGI1 and can be activated by SRC inhibition to dephosphorylate S6K independently of mTOR; in neurons, MAGI1 controls glutamate receptor clustering and regulates GLT-1 surface expression, while post-translational modifications including SUMO and phosphorylation by p90RSK regulate MAGI1's nuclear translocation and its role in endothelial activation and ER-stress-driven atherogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAGI1 is a multi-domain scaffolding protein that organizes signaling complexes at epithelial tight junctions, endothelial adherens junctions, and neuronal synapses through its PDZ and WW domains. At cell–cell junctions it recruits PTEN, β-catenin, Dll1, and TRIP6, stabilizing junctional integrity and suppressing oncogenic PI3K/AKT, MAPK/ERK, and Wnt/β-catenin signaling; its degradation by HPV E6 oncoproteins directly disrupts tight-junction organization [PMID:21123374, PMID:31352641, PMID:15908431, PMID:19017743]. In endothelial cells MAGI1 transduces fluid shear stress signals by scaffolding PKA/AMPK-dependent eNOS activation under laminar flow, while under disturbed flow p90RSK-mediated phosphorylation of MAGI1-S741 and deSUMOylation at K931 drive endothelial activation and atherogenesis [PMID:31035633, PMID:30944250]. MAGI1 also forms a tumor-suppressive complex with PP2A that, when released from SRC-mediated phosphorylation, dephosphorylates S6K independently of mTOR to suppress cholangiocarcinoma cell survival [PMID:38748774].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that MAGI1 is a tight-junction scaffold answered where the protein acts: it localizes to tight junctions in all epithelial types examined and co-distributes with ZO-1/ZO-2, independent of its GUK and WW domains.\",\n      \"evidence\": \"Immunofluorescence and subcellular fractionation across multiple epithelial cell lines\",\n      \"pmids\": [\"11969287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which PDZ domain(s) mediate tight-junction targeting was not resolved\", \"Whether MAGI1 loss disrupts TJ formation was not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that MAGI1 recruits Dll1 to cadherin-based adherens junctions and stabilizes it on the cell surface extended MAGI1 function beyond tight junctions to Notch ligand presentation during neural development.\",\n      \"evidence\": \"Reciprocal Co-IP, surface stabilization assay, immunofluorescence in developing spinal cord and fibroblasts\",\n      \"pmids\": [\"15908431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI1 loss reduces Notch signaling output in vivo was not directly measured\", \"Binding stoichiometry of the Dll1–MAGI1–β-catenin ternary complex is unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of MASCOT as a WW-domain ligand that uses a non-canonical LPxY motif revealed that MAGI1 WW domains expand the interactome beyond classical PPxY partners.\",\n      \"evidence\": \"GST-pulldown with domain mapping, confocal colocalization in MDCK cells\",\n      \"pmids\": [\"16019084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MASCOT–MAGI1 interaction not confirmed by reciprocal Co-IP or in vivo\", \"Functional consequence of disrupting this interaction on TJ barrier was not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Binding of MAGI1 PDZ4 to cadherin 23 in cochlear stereocilia positioned it as a candidate scaffold within the tip-link mechanotransduction complex, while TRIP6 binding to PDZ5 linked MAGI1 to PI3K/NF-κB-dependent invasion, establishing that different PDZ domains recruit distinct partners to control different cellular outcomes.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, invasion/aggregation assays with domain mutants (TRIP6); Y2H, pulldown, cochlear immunofluorescence (Cdh23)\",\n      \"pmids\": [\"18971469\", \"19017743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No hearing phenotype in Magi1-deficient animals has been reported\", \"Whether TRIP6–MAGI1 interaction occurs at TJs versus cytoplasm is unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic studies in C. elegans showed that MAGI-1 is cell-autonomously required for glutamate receptor clustering at synapses during memory consolidation, establishing an evolutionarily conserved synaptic scaffolding function dependent on β-catenin interaction.\",\n      \"evidence\": \"Loss-of-function genetics, cell-specific rescue, live GFP::GLR-1 imaging in C. elegans\",\n      \"pmids\": [\"19551147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian MAGI1 has an analogous role in glutamate receptor clustering is untested\", \"Downstream signaling mechanism linking β-catenin interaction to receptor retention is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantitative biophysics of the MAGI1 PDZ1–HPV E6 interaction, followed by the NMR structure of the complex, revealed that a non-canonical extended C-terminal flanking region of PDZ1 contacts E6 upstream of the canonical groove, explaining how viral and cellular ligands compete for the same domain with micromolar affinity.\",\n      \"evidence\": \"Surface plasmon resonance with systematic mutagenesis; NMR solution structure with backbone dynamics\",\n      \"pmids\": [\"20842623\", \"21238461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selectivity among the six MAGI1 PDZ domains remains uncharacterized\", \"Full-length MAGI1 structure is unavailable\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"HPV E6-mediated degradation of MAGI1 was shown to be a direct cause of tight-junction disruption, as E6 ablation restored MAGI1 levels and ZO-1 junctional localization in a MAGI1-dependent manner, establishing MAGI1 as a critical HPV target in epithelial transformation.\",\n      \"evidence\": \"E6 siRNA ablation/rescue in CaSKi and HeLa cells, immunofluorescence of ZO-1\",\n      \"pmids\": [\"21123374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI1 degradation alone is sufficient to explain HPV-driven junctional loss versus combined loss of MAGI1/2/3\", \"In vivo cervical tissue confirmation is lacking\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"MAGI1 directly binds glutamate transporter GLT-1 and negatively regulates its surface expression, revealing a role in astrocytic glutamate clearance distinct from its epithelial junctional functions.\",\n      \"evidence\": \"GST-pulldown, Co-IP, surface biotinylation, siRNA knockdown with glutamate uptake assay in astrocytes\",\n      \"pmids\": [\"21426345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MAGI1 retains GLT-1 intracellularly is unknown\", \"In vivo relevance for synaptic glutamate homeostasis not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Functional studies across multiple cancer types converged on MAGI1 as a tumor suppressor that stabilizes PTEN and β-catenin complexes to restrain PI3K/AKT, Wnt/β-catenin, and MAPK/ERK signaling, with MAGI1 loss promoting EMT, invasion, and proliferation.\",\n      \"evidence\": \"shRNA/siRNA knockdown and overexpression in gastric cancer, glioma, renal cell carcinoma, and breast cancer cells; Co-IP of PTEN/β-catenin; xenograft models\",\n      \"pmids\": [\"28373751\", \"31352641\", \"32009799\", \"31963297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No Magi1-knockout mouse tumor phenotype has been reported\", \"Direct biochemical mechanism by which MAGI1 stabilizes PTEN protein remains undefined\", \"Relative contribution of individual PDZ domains to tumor suppression is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"In endothelial cells, MAGI1 was established as a flow-responsive signaling hub: laminar shear stress upregulates MAGI1 to drive PKA/AMPK-dependent eNOS activation and NO production, while disturbed flow triggers p90RSK phosphorylation (S741) and deSUMOylation (K931) of MAGI1 to promote endothelial activation and atherogenesis, with Magi1 haploinsufficiency protecting against atherosclerosis in vivo.\",\n      \"evidence\": \"siRNA, overexpression, pharmacological inhibitors, endothelial-specific transgenic mice, Magi1+/− atherosclerosis model, phospho/SUMO-site mutagenesis\",\n      \"pmids\": [\"31035633\", \"30944250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI1 PTMs switch junctional versus nuclear pools is mechanistically unresolved\", \"Identity of the SUMO E3 ligase and deSUMOylase acting on K931 is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An unbiased phosphoproteomic screen revealed that SRC phosphorylates MAGI1 to prevent formation of a MAGI1–PP2A complex; SRC inhibition releases this complex to dephosphorylate S6K independently of mTOR, identifying a druggable vulnerability in IDH-mutant cholangiocarcinoma.\",\n      \"evidence\": \"Phosphoproteomics, Co-IP, PP2A activity assays, patient-derived organoids and xenografts treated with dasatinib ± M2698\",\n      \"pmids\": [\"38748774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MAGI1 phosphosite(s) mediating PP2A release are not fully mapped\", \"Whether the MAGI1–PP2A axis operates in other cancer types is unknown\", \"Structural basis for MAGI1–PP2A association is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full-length structure of MAGI1, the mechanisms governing isoform-specific localization and function, and whether Magi1 knockout in mammals produces developmental, neurological, or tumor-suppressive phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structural model exists\", \"Complete Magi1 knockout phenotype in mammals has not been described\", \"Isoform-specific functions remain largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4, 7, 12, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5, 8, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 11, 12, 13, 15, 17, 19]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 5, 8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 9, 11, 15, 16, 17, 19]}\n    ],\n    \"complexes\": [\n      \"MAGI1–PP2A complex\",\n      \"MAGI1–PTEN–β-catenin complex\",\n      \"MAGI1–VE-cadherin junctional complex\"\n    ],\n    \"partners\": [\n      \"PTEN\",\n      \"CTNNB1\",\n      \"DLL1\",\n      \"TRIP6\",\n      \"PPP2CA\",\n      \"CDH23\",\n      \"SLC1A2\",\n      \"RPS6KB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MAGI1 is a multi-domain MAGUK scaffolding protein that organizes signaling complexes at epithelial tight junctions, adherens junctions, and endothelial cell contacts, thereby regulating cell-cell adhesion, barrier integrity, and signal transduction. Its five PDZ domains mediate binding to β-catenin (PDZ5), cadherin-23 (PDZ4), and viral oncoproteins such as HPV E6 and adenovirus E4-ORF1 (PDZ1), while its WW domains engage PY-motif-containing partners; through these interactions MAGI1 stabilizes Dll1 at adherens junctions to promote Notch signaling, recruits JAM4 to strengthen tight junctions, negatively regulates GLT-1 surface expression in astrocytes, and suppresses tumor cell migration and invasion by stabilizing a PTEN/β-catenin complex and inhibiting MAPK/ERK and PI3K/AKT pathways [PMID:10772923, PMID:15908431, PMID:12773569, PMID:21426345, PMID:28373751, PMID:31352641]. In endothelial cells, MAGI1 transduces fluid shear stress into eNOS activation via PKA and AMPK, and its phosphorylation by p90RSK and deSUMOylation drive nuclear translocation linked to endothelial activation and atherogenesis [PMID:31035633, PMID:30944250]. SRC-mediated phosphorylation of MAGI1 inhibits a latent MAGI1–PP2A tumor-suppressive complex; upon SRC inhibition, this complex dephosphorylates S6K independently of mTOR, suppressing protein synthesis and promoting cell death in cholangiocarcinoma [PMID:38748774].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of MAGI1 as a novel MAGUK with inverted domain architecture (GK-WW-PDZ) established it as a distinct scaffolding protein with isoform-dependent nuclear versus membrane localization.\",\n      \"evidence\": \"cDNA cloning, subcellular fractionation, and immunolocalization in MDCK cells; parallel WW domain ligand screens\",\n      \"pmids\": [\"9395497\", \"9169421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of nuclear isoform unclear\", \"WW domain ligand specificity not mapped in vivo\", \"No loss-of-function data\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that PDZ5 anchors MAGI1 to junctional membranes via β-catenin binding, and that viral oncoproteins (HPV E6, adenovirus E4-ORF1) hijack PDZ1, established MAGI1 as a junctional scaffold targeted in oncogenesis.\",\n      \"evidence\": \"PDZ domain deletion mapping, co-IP of β-catenin/E-cadherin complexes in MDCK cells; co-IP and mutational analysis of viral oncoprotein interactions\",\n      \"pmids\": [\"10772923\", \"11077444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which E6-mediated MAGI1 degradation drives transformation not established\", \"Relative contributions of individual PDZ domains to junctional assembly unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping MAGI1 to tight junctions across epithelial tissues in vivo and demonstrating colocalization with ZO-1/ZO-2 in pre-assembled complexes showed that MAGI1 is a general tight junction component rather than a cell-type-specific adaptor.\",\n      \"evidence\": \"Immunofluorescence in multiple epithelial cell types and tissues, isoform-specific domain deletions\",\n      \"pmids\": [\"11969287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal role in tight junction assembly vs. maintenance not distinguished\", \"Redundancy with MAGI-2/MAGI-3 at tight junctions not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of JAM4 as a MAGI1 partner that strengthens cell-cell adhesion and barrier sealing when scaffolded by MAGI1 provided the first functional evidence that MAGI1 actively reinforces tight junction integrity.\",\n      \"evidence\": \"GST pulldown, co-IP, functional adhesion and permeability assays in L and CHO cells\",\n      \"pmids\": [\"12773569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo barrier function of MAGI1–JAM4 interaction not tested\", \"Stoichiometry and competition among PDZ ligands at the junction unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that MAGI1 recruits Dll1 to adherens junctions and stabilizes it on the cell surface linked MAGI1 scaffolding to Notch ligand presentation during neural development.\",\n      \"evidence\": \"Y2H, co-IP, in situ hybridization in developing neural tube, cell-surface biotinylation in fibroblasts\",\n      \"pmids\": [\"15908431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effect on Notch signaling output not directly measured\", \"Whether MAGI1 is required for Dll1 function in vivo not shown by loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of cadherin-23 as a PDZ4 ligand in stereocilia and TRIP6 as a PDZ5 ligand that promotes invasiveness expanded the repertoire of MAGI1 PDZ interactions and revealed context-dependent roles in sensory cells and cancer.\",\n      \"evidence\": \"Cochlear library screen and immunolocalization for Cdh23; Y2H, invasion and aggregation assays with domain-specific mutants for TRIP6\",\n      \"pmids\": [\"18971469\", \"19017743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MAGI1–Cdh23 functional significance for hearing not tested by genetic loss-of-function\", \"How TRIP6–MAGI1 interaction is regulated remains unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"C. elegans genetic studies showed MAGI-1 controls glutamate receptor (GLR-1) clustering in specific neurons during associative learning in a β-catenin-dependent manner, establishing a conserved neuronal scaffolding function.\",\n      \"evidence\": \"magi-1 mutant behavioral analysis, neuron-specific rescue, GLR-1::GFP imaging, epistasis with hmp-2/β-catenin\",\n      \"pmids\": [\"19551147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian counterpart of this learning/memory circuit function not established\", \"Direct physical interaction between MAGI-1 and GLR-1 not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantitative biophysical characterization of PDZ1–HPV E6 binding and demonstration that HPV E6-driven MAGI1 degradation causally disrupts tight junctions defined the structural basis and functional consequence of viral targeting.\",\n      \"evidence\": \"SPR binding measurements with mutagenesis; siRNA of E6 in HPV+ cervical cancer cells with MAGI1 rescue of ZO-1 localization\",\n      \"pmids\": [\"20842623\", \"21123374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of full PDZ1–E6 complex not available at this point\", \"Whether MAGI1 degradation is sufficient for HPV-driven malignancy not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that MAGI1 binds GLT-1 and negatively regulates its surface expression in astrocytes extended MAGI1's scaffolding function to control of glutamate transporter trafficking in glial cells, complementing its neuronal role.\",\n      \"evidence\": \"GST pulldown, co-IP, cell-surface biotinylation, siRNA knockdown with glutamate uptake assay in differentiated astrocytes\",\n      \"pmids\": [\"21426345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which PDZ domain mediates GLT-1 binding not mapped\", \"In vivo relevance for glutamate homeostasis not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NMR structure of MAGI1 PDZ1 alone and in complex with E6 peptide revealed a global conformational response to ligand binding including quenching of backbone dynamics in the C-terminal extension, providing the first atomic-resolution model of MAGI1 ligand recognition.\",\n      \"evidence\": \"NMR spectroscopy, backbone dynamics analysis, mutagenesis with binding affinity measurements\",\n      \"pmids\": [\"21238461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of other PDZ domains not solved\", \"How conformational changes propagate to multi-domain function unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Loss-of-function studies in gastric and hepatocellular carcinoma cells demonstrated that MAGI1 suppresses migration and invasion through inhibition of MAPK/ERK signaling and stabilization of PTEN, solidifying its role as a broadly acting tumor suppressor.\",\n      \"evidence\": \"shRNA knockdown in gastric cancer cells with MAPK/ERK and EMT marker readouts; MAGI1 overexpression in HepG2 with PTEN correlation in HCC tissues\",\n      \"pmids\": [\"28373751\", \"21685691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking MAGI1 scaffolding to PTEN stabilization not defined\", \"No epistasis experiments placing MAGI1 upstream of MAPK directly\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies revealed MAGI1 as a mechanosensitive endothelial signaling hub: shear stress induces MAGI1 expression to activate eNOS via PKA/AMPK, while disturbed flow triggers p90RSK-mediated MAGI1 phosphorylation and SENP2-mediated deSUMOylation that drive nuclear translocation and pro-atherogenic endothelial activation.\",\n      \"evidence\": \"siRNA/overexpression with pharmacological kinase inhibition and flow chambers; transgenic MAGI1 mice with ex vivo NO measurement; phosphorylation/SUMOylation site mutagenesis and Magi1+/- atherogenesis model\",\n      \"pmids\": [\"31035633\", \"30944250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MAGI1 senses or transduces mechanical force is unknown\", \"Relative contribution of phosphorylation vs. SUMOylation to atherogenesis not separated in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"MAGI1 was established as a tumor suppressor in ER+ breast cancer where it sustains ER expression, and its loss accelerates primary tumor growth and metastasis; MAGI1 is itself regulated by estrogen/ER and suppressed by COX-2/PGE2, forming a feed-forward regulatory loop.\",\n      \"evidence\": \"shRNA knockdown in MCF7 and 67NR cells, in vivo xenograft and lung metastasis models, pharmacological stimulation/inhibition of ER and COX-2 pathways\",\n      \"pmids\": [\"31963297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MAGI1 maintains ER expression is unknown\", \"Whether NSAID-mediated MAGI1 upregulation is clinically actionable not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Phosphoproteomic identification of MAGI1 as a SRC substrate revealed a latent MAGI1–PP2A tumor-suppressive complex: SRC phosphorylation inhibits this complex, while SRC inhibition enables MAGI1–PP2A to dephosphorylate S6K independently of mTOR, defining a druggable axis in IDH-mutant cholangiocarcinoma.\",\n      \"evidence\": \"Unbiased phosphoproteomics, co-IP of MAGI1–PP2A, PP2A activity assays, patient tissue validation, patient-derived organoids and xenograft models\",\n      \"pmids\": [\"38748774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SRC phosphorylation-dependent PP2A dissociation unknown\", \"Whether MAGI1–PP2A complex operates in other SRC-driven cancers not tested\", \"Which MAGI1 phosphosite(s) regulate PP2A binding not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAGI1's multiple PDZ and WW domain interactions are coordinated in space and time to balance its junctional scaffolding, tumor-suppressive, and endothelial signaling functions remains unresolved, as does the in vivo phenotype of complete MAGI1 loss in mammals.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full mammalian knockout phenotype published\", \"No structural model of multi-domain MAGI1 or full-length complex assembly\", \"Interplay among PTMs (phosphorylation, SUMOylation) in different tissue contexts not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 6, 7, 10, 14, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 6, 7, 10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 17, 18, 19, 20, 25, 27]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 5, 6, 7, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 12, 22, 27]}\n    ],\n    \"complexes\": [\n      \"MAGI1-PP2A complex\",\n      \"MAGI1-beta-catenin-E-cadherin junctional complex\"\n    ],\n    \"partners\": [\n      \"CTNNB1\",\n      \"PTEN\",\n      \"CDH23\",\n      \"DLL1\",\n      \"AMICA1\",\n      \"TRIP6\",\n      \"SLC1A2\",\n      \"PPP2CA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}