{"gene":"MAGI1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1997,"finding":"MAGI-1 is a MAGUK protein with a unique inverted domain structure: GuK domain at the N-terminus, two WW domains replacing the SH3 domain, and five PDZ domains. The longest splice variant (MAGI-1c) contains bipartite nuclear localization signals and localizes predominantly to the nucleus, while shorter forms lacking these signals localize to membrane and cytoplasmic fractions.","method":"cDNA cloning, subcellular fractionation, sequence analysis of splice variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — original structural characterization with cloning, domain mapping, and subcellular fractionation; foundational paper replicated by subsequent work","pmids":["9395497"],"is_preprint":false},{"year":2000,"finding":"MAGI-1b fifth PDZ domain binds beta-catenin and is essential for membrane localization; MAGI-1b forms complexes with beta-catenin and E-cadherin during formation of cell-cell junctions in MDCK cells, and GFP-MAGI-1b localizes to the basolateral membrane of polarized MDCK cells.","method":"Co-immunoprecipitation, GFP fusion localization, subcellular fractionation, yeast two-hybrid","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mapping, confirmed by localization; replicated in multiple subsequent studies","pmids":["10772923"],"is_preprint":false},{"year":1999,"finding":"MAGI-1/BAP1 localizes specifically to tight junctions in intestinal epithelial cells and MDCK cells, co-localizing with ZO-1 (not E-cadherin), and is recruited with ZO-1 to tight junction-like structures upon PMA treatment after low-Ca2+ switch, distinguishing its role from SAP97/hDLG.","method":"Immunofluorescence, subcellular fractionation, Ca2+-switch assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional context (tight junction assembly); replicated by multiple labs","pmids":["10618722"],"is_preprint":false},{"year":2000,"finding":"Ad9 E4-ORF1 oncoprotein binds MAGI-1 and aberrantly sequesters it in the cytoplasm, while high-risk HPV E6 proteins bind MAGI-1 and target it for degradation; transformation-defective viral mutants are deficient for these activities.","method":"Co-immunoprecipitation, subcellular fractionation, viral mutant analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with functional mutant validation; replicated extensively in subsequent HPV/viral studies","pmids":["11077444"],"is_preprint":false},{"year":2000,"finding":"MAGI-1/BAP1 serves as a scaffolding molecule for Rap GEP (a Rap1-specific GDP/GTP exchange factor) at tight junctions in epithelial cells; this interaction is specific to MAGI-1 and not observed with PSD-95/SAP90 or SAP97/hDLG.","method":"Cell-free binding assays, co-immunoprecipitation in intact cells, Northern blot","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed in vitro and in vivo; specificity validated by negative controls with other MAGUKs","pmids":["11168587"],"is_preprint":false},{"year":2001,"finding":"MAGI-1 fifth PDZ domain binds megalin via the DSDV PDZ-binding motif at megalin's C-terminus; a mutant megalin lacking the terminal valine cannot bind. MAGI-1 is expressed in glomerular podocytes and associated with the cytoskeleton in glomerular preparations.","method":"Yeast two-hybrid, PDZ domain binding assays, mutagenesis, immunofluorescence, Western blot fractionation","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Moderate — yeast two-hybrid confirmed by direct binding with mutagenesis; domain mapping performed","pmids":["11274227"],"is_preprint":false},{"year":2001,"finding":"The first PDZ domain of MAGI-1 interacts with mNET1, a Rho family nucleotide exchange factor, via a consensus PDZ-binding motif (PPxY-like at C-terminus of mNET1) plus a nearby cluster of basic residues required for the interaction.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple biochemical methods in single study, single lab","pmids":["11350080"],"is_preprint":false},{"year":2002,"finding":"MAGI-1 WW domain 2 interacts with synaptopodin (an actin-bundling protein) identified via cDNA library screen; the fifth PDZ domain of MAGI-1 binds alpha-actinin-4 C-terminus. Both interactions were confirmed in vivo by co-immunoprecipitation from HEK293 cells, and all three proteins colocalize at tight junctions in MDCK cells.","method":"Yeast two-hybrid/cDNA library screen, in vitro GST pull-down, co-immunoprecipitation, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro binding confirmed by in vivo co-IP with domain mapping; multiple orthogonal methods","pmids":["12042308"],"is_preprint":false},{"year":2003,"finding":"JAM4 (junctional adhesion molecule 4) directly binds MAGI-1 (but not ZO-1), and their co-expression in COS-7 cells induces clustering. MAGI-1 strengthens JAM4-mediated cell adhesion in L cells and sealing effects in CHO cell monolayers. MAGI-1 also recruits ZO-1, occludin to JAM4-based contacts.","method":"In vitro binding assay, co-immunoprecipitation, cell adhesion assay, permeability assay, fluorescence microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed biochemically with functional cell adhesion readout; multiple orthogonal methods","pmids":["12773569"],"is_preprint":false},{"year":2004,"finding":"ESAM (endothelial cell-selective adhesion molecule) directly binds MAGI-1 via PDZ domain-mediated interaction at ESAM's C-terminus; ESAM recruits MAGI-1 to cell-cell contacts in CHO cells, and in HUVECs MAGI-1 colocalizes with ESAM at endothelial cell-cell contacts.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by pull-down and co-IP; localization with functional consequence (recruitment) demonstrated","pmids":["15383320"],"is_preprint":false},{"year":2005,"finding":"MAGI-1 is required for Rap1 activation upon VE-cadherin homophilic engagement at cell-cell contacts in endothelial cells. MAGI-1 binds PDZ-GEF1 (a Rap1 GEF) and localizes to cell-cell contacts via beta-catenin. MAGI-1 depletion suppresses VE-cadherin-dependent Rap1 activation, inhibits vinculin relocalization to cell-cell contacts, and impairs VE-cadherin-mediated adhesion.","method":"siRNA knockdown, Rap1 activation assay (pulldown of GTP-Rap1), FRET-based Rap1 biosensor, co-immunoprecipitation, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular mechanism; multiple orthogonal methods; pathway epistasis confirmed","pmids":["16339077"],"is_preprint":false},{"year":2005,"finding":"MAGI-1 binds Dll1 (Delta-like 1) and N-cadherin/beta-catenin complexes; MAGI-1 recruits Dll1 to adherens junctions in cultured fibroblasts and stabilizes Dll1 on the cell surface, suggesting MAGI-1 presents Dll1 at junctions to activate Notch on neighboring cells.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, cell surface stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP; functional consequence (Dll1 surface stabilization) shown; multiple methods","pmids":["15908431"],"is_preprint":false},{"year":2005,"finding":"MAGI-1 is a component of the glomerular slit diaphragm and directly binds nephrin via its middle PDZ domains (PDZ3) through nephrin's C-terminus; MAGI-1 forms a tripartite complex with nephrin and JAM4 in vitro. In puromycin aminonucleoside nephrotic podocytes, MAGI-1 co-localizes with nephrin at the displaced slit diaphragm.","method":"Yeast two-hybrid, in vitro binding assay, immunoelectron microscopy, co-immunoprecipitation","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid, direct binding, and immunoelectron microscopy; functional disease context validated","pmids":["16155592"],"is_preprint":false},{"year":2005,"finding":"A novel tight junction protein, MASCOT, binds the first WW domain of MAGI-1 via an LPxY motif (not the canonical PPxY); the coiled-coil domain of MASCOT is required for its localization to tight junctions in MDCK cells.","method":"CDNA library screen, in vitro GST binding assay, co-immunoprecipitation, immunofluorescence","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding confirmed with domain mapping; single lab, single study","pmids":["16019084"],"is_preprint":false},{"year":2007,"finding":"MAGI-1 is cleaved by caspases-3 and -7 at Asp761 during apoptosis, generating a 97 kDa N-terminal fragment that dissociates from the membrane and a C-terminal fragment. Mutation of Asp761 to Ala abolishes caspase-induced cleavage and delays disruption of cell-cell contacts during apoptosis without affecting nuclear condensation.","method":"In vitro caspase cleavage assay, site-directed mutagenesis, cell-based apoptosis assays, caspase inhibitor (Z-VAD-fmk)","journal":"Apoptosis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with site-directed mutagenesis identifying specific cleavage site; functional consequence in cells confirmed","pmids":["17191119"],"is_preprint":false},{"year":2007,"finding":"N-terminal MAGI-1 caspase cleavage product translocates to the cytosol while C-terminal caspase cleavage product accumulates in the nucleus; both overexpressed fragments exhibit minor pro-apoptotic activity when expressed in MDCK cells.","method":"GFP-fusion subcellular localization, immunofluorescence, apoptosis assay","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment; functional consequence is minor; single lab","pmids":["17976012"],"is_preprint":false},{"year":2008,"finding":"MAGI-1 PDZ4 domain binds the C-terminal PDZ-binding site of the hair-cell-specific Cdh23(+68) splice variant; MAGI-1 immunoreactivity is detectable in neonatal stereocilia in a distribution similar to Cdh23, with punctate staining maintained into adulthood.","method":"Cochlear cDNA library screen, PDZ domain binding assay, immunofluorescence","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical binding confirmed with domain mapping and localization; single lab, limited functional validation","pmids":["18971469"],"is_preprint":false},{"year":2009,"finding":"MAGI-1 binds BKCa (Slo1) channel proteins via a yeast two-hybrid interaction; co-expression of MAGI-1 with Slo1 in HEK293T cells significantly reduces Slo1 surface expression as assessed by biotinylation, confocal microscopy, and whole-cell recordings. Partial siRNA knockdown of endogenous MAGI-1 in podocytes increases surface expression of endogenous Slo1.","method":"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, cell-surface biotinylation, electrophysiology, siRNA knockdown","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by multiple methods; functional consequence (reduced surface expression) demonstrated by gain and loss of function with multiple readouts","pmids":["19403801"],"is_preprint":false},{"year":2008,"finding":"MAGI-1 in C. elegans (ortholog) controls GLR-1/GLR-2 AMPA receptor synaptic localization in response to prior mechanosensory experience; MAGI-1L isoform interacts with AMPARs through the intracellular domain of GLR-2 subunit; mutations preventing GLR-1 ubiquitination prevent the decrease in AMPAR localization in magi-1 mutants.","method":"Genetic loss-of-function, fluorescence imaging of GFP-tagged GLR-1/GLR-2, behavioral assays, epistasis analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with behavioral and synaptic localization readouts; interaction domain identified; multiple approaches","pmids":["19242552"],"is_preprint":false},{"year":2009,"finding":"MAGI-1 in C. elegans controls associative learning via RIA interneurons and memory consolidation via AVA/AVD/AVE glutamatergic interneurons; during memory consolidation, MAGI-1 regulates GLR-1 (iGluR) clustering cell-autonomously in a manner dependent on its ability to interact with beta-catenin HMP-2.","method":"Genetic rescue (neuron-specific expression), behavioral assays, fluorescence imaging of GLR-1 clustering, epistasis analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific rescue experiments with molecular interaction requirement validated; behavioral and cellular readouts","pmids":["19551147"],"is_preprint":false},{"year":2010,"finding":"ESAM-MAGI-1 co-localization promotes actin polymerization through PDZ domain interactions resulting in firm cell-cell adhesion; ESAM-MAGI-1 interaction activates RhoA, and RhoA inhibition blocks ESAM-mediated MAGI-1 recruitment and mature cell adhesion.","method":"Transfection experiments in CHO cells, cell dissociation assay, actin polymerization inhibitor, RhoA activity assay, RhoA inhibitor","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional consequence demonstrated with pharmacological inhibition; RhoA activation measured; single lab","pmids":["20298433"],"is_preprint":false},{"year":2010,"finding":"MAGI-1 is a major degradation target of HPV-16 and HPV-18 E6 in cervical cancer cells; E6 preferentially targets MAGI-1 within the nucleus and at membrane sites; MAGI-1 degradation causes loss of tight junction integrity (ZO-1 mislocalization); E6 ablation restores tight junctions in a MAGI-1-dependent manner.","method":"siRNA E6 ablation, Western blot, immunofluorescence of ZO-1, rescue experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain and loss of function with rescue; mechanistic link between E6, MAGI-1 degradation, and tight junction disruption established; replicated across multiple labs","pmids":["21123374"],"is_preprint":false},{"year":2010,"finding":"C. elegans MAGI-1 localizes apical to both the CCC and DAC junctional sub-compartments; loss of MAGI-1 causes loss of junctional compartmentalization along the lateral membrane and reduces robustness of cell-cell adhesion by both junctional types.","method":"RNAi knockdown, fluorescence imaging of junctional markers, genetic analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence; loss-of-function with multiple junctional readouts","pmids":["21034729"],"is_preprint":false},{"year":2011,"finding":"NMR solution structure of MAGI-1 PDZ1 domain alone and bound to HPV16 E6 C-terminal peptide reveals that binding induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain; mutations in the C-terminal flanking region significantly decrease E6 binding affinity, indicating global PDZ response with effects propagated to distal sites.","method":"NMR structure determination, backbone dynamics analysis, site-directed mutagenesis, binding affinity measurement","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with mutagenesis and dynamics analysis; mechanistic detail of binding confirmed","pmids":["21238461"],"is_preprint":false},{"year":2011,"finding":"MAGI-1 overexpression in colorectal cancer cells stabilizes E-cadherin and beta-catenin at cell-cell junctions, enhances actin stress fiber and focal adhesion formation, suppresses Wnt signaling, and inhibits migration, invasion, and anchorage-independent growth. MAGI-1 silencing has opposite effects. MAGI-1 overexpression suppresses tumor growth and metastasis in vivo.","method":"Stable overexpression/siRNA knockdown, in vitro migration/invasion assays, Wnt reporter assay, in vivo xenograft/orthotopic models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss of function with multiple cellular and in vivo readouts; mechanistic pathway (Wnt suppression) validated","pmids":["21666716"],"is_preprint":false},{"year":2011,"finding":"MAGI-1 directly binds glutamate transporter GLT-1 via GST pull-down confirmed by co-immunoprecipitation; co-expression of MAGI-1 reduces GLT-1 surface expression in C6 glioma cells; siRNA knockdown of endogenous MAGI-1 in astrocytes increases glutamate uptake and GLT-1 surface expression.","method":"GST pull-down, co-immunoprecipitation, cell-surface biotinylation, glutamate uptake assay, siRNA knockdown","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by multiple methods; functional consequence shown by reciprocal gain/loss of function","pmids":["21426345"],"is_preprint":false},{"year":2011,"finding":"MAGI-1 overexpression in hepatocellular carcinoma HepG2 cells inhibits migration and invasion; PTEN protein expression is significantly elevated in MAGI-1-overexpressing cells, with a positive correlation between MAGI-1 and PTEN protein levels.","method":"Stable transfection, wound healing assay, Matrigel invasion assay, Western blot","journal":"Zhong nan da xue xue bao","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, functional assays without detailed molecular mechanism of MAGI1-PTEN interaction","pmids":["21685691"],"is_preprint":false},{"year":2012,"finding":"MAGI-1 PDZ1 and PDZ3 domains regulate CAREx8 levels in opposing ways: PDZ3 reduces apical CAREx8 abundance and adenovirus infection, while PDZ1 rescues CAREx8 and adenovirus infection from MAGI-1-mediated suppression.","method":"Yeast two-hybrid, biochemical pull-down, co-immunoprecipitation, FRET, adenovirus infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction mapped to specific PDZ domains with functional consequence on viral entry; multiple orthogonal methods","pmids":["22718816"],"is_preprint":false},{"year":2012,"finding":"In C. elegans, MAGI-1 physically interacts with AFD-1/afadin and SAX-7/L1CAM (which binds MAGI-1 via its C-terminus); MAGI-1 and AFD-1 localize to a unique domain in the apical junction; SAX-7/L1CAM is required for normal MAGI-1 junctional accumulation; MAGI-1 depletion causes loss of spatial segregation and expansion of apical junctional domains.","method":"Genome-wide RNAi screen, co-immunoprecipitation, fluorescence localization, genetic epistasis","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — physical interaction confirmed biochemically; localization requirement established; genetic epistasis with multiple partners","pmids":["22981773"],"is_preprint":false},{"year":2012,"finding":"siRNA depletion of MAGI-1 activates IRF3 and induces the IFN-β promoter; avian influenza NS1 ESEV PBM sequesters MAGI-1 away from the plasma membrane in infected cells, and the ESEV PBM relative to EPEA shows relative deficiency in NS1 inhibition of IFN-β induction, suggesting MAGI-1 normally suppresses IFN-β signaling.","method":"siRNA knockdown, IRF3 activation assay, IFN-β promoter luciferase reporter, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional consequence of MAGI-1 depletion on IFN-β pathway shown; single lab, limited mechanistic detail","pmids":["22911767"],"is_preprint":false},{"year":2012,"finding":"MAGI-1 in neuronal tissue is enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from MAGI-2/3 which are in PSD fractions); MAGI-1 shows diffuse distribution in hippocampal neuron cell body and processes, not enriched at synapses, unlike MAGI-2/3.","method":"Biochemical fractionation, immunofluorescence, immunohistochemistry","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct fractionation experiment with comparative analysis; single lab","pmids":["22605569"],"is_preprint":false},{"year":2013,"finding":"HTLV-1 Tax1 interacts with MAGI-1 in a PDZ-binding motif (PBM)-dependent manner and mislocalizes MAGI-1 from the detergent-soluble to the detergent-insoluble cellular fraction in 293T cells and HTLV-1-infected T-cells; Tax1-induced T-cell transformation selects for cells with irreversibly reduced MAGI-1 mRNA expression.","method":"Co-immunoprecipitation, subcellular fractionation, PBM mutant analysis, RT-PCR","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — interaction confirmed with PBM mutant; mislocalization shown; single lab","pmids":["23279616"],"is_preprint":false},{"year":2013,"finding":"MAGI-1 forms an immunocomplex with p75NTR (low-affinity NGF receptor) and Shc adaptor in PC12 cells; MAGI-1 knockdown inhibits NGF-induced neurite outgrowth; both knockdown and overexpression of MAGI-1 suppress NGF-stimulated Shc-ERK pathway activation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, neurite outgrowth assay, ERK activation assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — scaffold complex identified with functional consequence on NGF signaling; single lab; paradoxical results with over/knockdown noted","pmids":["23769981"],"is_preprint":false},{"year":2014,"finding":"A K499E mutation in MAGI-1 PDZ1 domain renders it resistant to HPV E6 targeting; re-expression of this mutant MAGI-1 in HPV-positive cells increases ZO-1 and PAR3 recruitment to cell-cell contacts, represses cell proliferation, and induces apoptosis.","method":"Site-directed mutagenesis, lentiviral expression in HPV+ cells, immunofluorescence, cell proliferation and apoptosis assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis-based rescue experiment; multiple functional readouts; establishes direct causal role of MAGI-1 in TJ assembly, proliferation, and apoptosis control","pmids":["24696483"],"is_preprint":false},{"year":2015,"finding":"MAGI-1 PDZ3 domain is exclusively responsible for high-affinity interaction with the 7-exon CAR isoform; interruption of this high-affinity interaction alters MAGI-1 localization (CAR traffics MAGI-1 to cell junctions) but does not significantly alter adenovirus infection via CAR.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, FRET, adenovirus infection assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific interaction mapped with multiple methods; functional consequence on localization shown","pmids":["25622559"],"is_preprint":false},{"year":2015,"finding":"Binding of E6 peptides to MAGI-1 PDZ1 is accompanied by an unusually large negative change in heat capacity attributed to a disorder-to-order transition of the PDZ1 C-terminal extension; NMR relaxation data confirm this; a PDZ1 mutant abolishing this transition shows different thermodynamic signature.","method":"Isothermal titration calorimetry (ITC), NMR 15N relaxation, site-directed mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical characterization with NMR, ITC, and mutagenesis; mechanistic detail of binding confirmed","pmids":["25590897"],"is_preprint":false},{"year":2016,"finding":"MAGI-1 depletion in cultured podocytes reduces nephrin and neph1 membrane localization and weakens tight junction integrity; global magi1 knockout mice are normal, but combined MAGI-1 knockout with nephrin heterozygosity causes spontaneous glomerulosclerosis; MAGI-1 depletion reduces intercellular contact-induced Rap1 activation, and combined overexpression of MAGI-1 with nephrin increases Rap1 activation requiring the nephrin-binding interface.","method":"siRNA knockdown, global knockout mice, compound genetic mouse models, Rap1 activation assay, Drosophila genetic screen, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro loss-of-function, in vivo compound genetics, and mechanistic Rap1 assay; replicated across systems","pmids":["27707879"],"is_preprint":false},{"year":2017,"finding":"MAGI-1 knockdown in gastric cancer cells promotes migration and invasion by increasing MMP expression and EMT-related molecules via activation of the MAPK/ERK signaling pathway.","method":"shRNA knockdown, migration/invasion assays, Western blot for MMPs and EMT markers, ERK signaling analysis","journal":"Chinese journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach; MAPK/ERK pathway placement inferred from expression changes","pmids":["28373751"],"is_preprint":false},{"year":2018,"finding":"Crystal/biochemical structure analysis shows nephrin C-terminal PBM specifically binds MAGI1 PDZ3 but not MAGI2 PDZ3; the Gly at the -3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition (contrasting typical PDZ/PBM binding mode); a single gain-of-function mutation in MAGI2 enables nephrin-PBM binding.","method":"Complex crystal structure (MAGI1-PDZ3/nephrin-PBM), biophysical binding assays, site-directed mutagenesis","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis; structural basis of binding specificity established","pmids":["30006415"],"is_preprint":false},{"year":2019,"finding":"MAGI1 is required for fluid shear stress-induced eNOS phosphorylation and NO production in endothelial cells; MAGI1 silencing impairs KLF4 expression and cell alignment under flow; MAGI1 overexpression induces phosphorylation of PKA, AMPK, and CaMKII; PKA and AMPK inhibition prevents MAGI1-mediated eNOS phosphorylation; endothelial-specific transgenic MAGI1 increases PKA and eNOS phosphorylation in vivo.","method":"siRNA silencing, overexpression, NO measurement, kinase phosphorylation assays, pharmacological kinase inhibitors, transgenic mice","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss of function; pathway validated pharmacologically and in transgenic model; multiple orthogonal readouts","pmids":["31035633"],"is_preprint":false},{"year":2019,"finding":"In endothelial cells exposed to disturbed flow, p90RSK binds MAGI1 and causes MAGI1-S741 phosphorylation, which upregulates EC activation via Rap1; MAGI1-K931 deSUMOylation (mediated by SENP2) induces nuclear translocation of p90RSK-MAGI1 and ATF6-MAGI1 complexes promoting EC activation and apoptosis respectively; MAGI1 associates with ATF-6 (ER stress mediator); reduced MAGI1 in Magi1-/+ mice inhibits disturbed flow-induced atherogenesis.","method":"Co-immunoprecipitation, phosphoproteomic analysis, phospho-site mutagenesis, SUMOylation assay, Magi1+/- mouse model, microarray","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased phosphoproteomic discovery with biochemical validation, PTM mapping, and in vivo genetic model; multiple orthogonal methods","pmids":["30944250"],"is_preprint":false},{"year":2019,"finding":"Magi-1 directly interacts with NaV1.8 channels and Slack KNa channels in dorsal root ganglion neurons; Magi-1 regulates NaV1.8 plasma membrane localization, retention, and stability; DRG-specific knockdown of Magi-1 attenuates thermal nociception and inflammatory pain; a competing cell-penetrating peptide mimetic from NaV1.8 WW binding motif decreases sodium currents and NaV1.8 surface expression.","method":"co-immunoprecipitation, cell-surface biotinylation, siRNA knockdown, electrophysiology, in vivo pain behavior, peptide competition assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction confirmed biochemically; functional consequence shown by reciprocal genetic and pharmacological approaches in vivo","pmids":["30860870"],"is_preprint":false},{"year":2020,"finding":"p90RSK-mediated MAGI1 post-translational modifications (S741 phosphorylation and K931 de-SUMOylation) regulate endothelial permeability; dominant negative p90RSK or MAGI1-S741A decreases thrombin-induced permeability; p90RSK overexpression, MAGI1 siRNA, or MAGI1-K931R SUMOylation mutant accelerates permeability; MAGI1 depletion increases LATS1/2 expression, inhibiting YAP/TAZ (Hippo pathway).","method":"ECIS-based permeability assay, siRNA knockdown, PTM mutant overexpression, LATS/YAP expression analysis, in vivo p90RSK inhibitor","journal":"Frontiers in cardiovascular medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — site-specific PTM mutants with functional permeability readout; Hippo pathway connection established; replicated in vivo","pmids":["33304925"],"is_preprint":false},{"year":2021,"finding":"MAGI1 colocalizes with paxillin, β3-integrin, talin 1, tensin 3, and α4-actinin at mature focal adhesions and actin stress fibers in endothelial cells; MAGI1 silencing reduces focal adhesion formation and maturation, cell spreading, actin stress fiber formation, and RhoA/Rac1 activation, and increases paxillin Y118 phosphorylation (indicator of focal adhesion turnover). MAGI1 silencing reduces integrin-dependent adhesion, increases invasion, promotes tubulogenesis in vitro, and promotes angiogenesis in vivo.","method":"siRNA silencing, immunofluorescence colocalization, RhoA/Rac1 activation assay, paxillin phosphorylation Western blot, cell adhesion/invasion assays, in vivo angiogenesis model","journal":"Cell adhesion & migration","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence; multiple orthogonal methods; in vitro and in vivo readouts","pmids":["33823745"],"is_preprint":false},{"year":2021,"finding":"Loss of MAGI1 in breast cancer cells causes accumulation of E-cadherin and AMOTL2 with increased cellular stiffness, elevated ROCK and p38 stress kinase activities (but low YAP activity); MAGI1 loss-driven tumorigenicity is rescued by AMOTL2 deletion or p38 inhibition, demonstrating MAGI1 suppresses tumorigenesis by inhibiting an AMOTL2/p38 stress pathway.","method":"MAGI1 siRNA knockdown, AMOTL2 knockout, p38 inhibitor, ROCK inhibitor, tumorigenicity assays, YAP activity measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with rescue experiments; pathway placement established by combined genetic/pharmacological approaches","pmids":["33707576"],"is_preprint":false},{"year":2021,"finding":"MAGI-1 PDZ2 domain blockade by decoy peptides (TAT-E6, TAT-NET1) decreases CAREx8 expression and adenovirus transduction; this occurs via enhanced regulated intramembrane proteolysis through ADAM17 and γ-secretase; ADAM17 interacts directly with MAGI-1 PDZ3 domain; blocking PDZ2 enhances ADAM17 accessibility to CAREx8.","method":"Decoy peptide competition, cell-surface biotinylation, adenovirus transduction assay, co-immunoprecipitation of ADAM17/MAGI-1, in vivo transgenic model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct domain-specific interaction mapped; mechanism of CAREx8 proteolysis via ADAM17 confirmed biochemically; in vivo validation","pmids":["33762416"],"is_preprint":false},{"year":2022,"finding":"MAGI1 inhibits IRF3 activation in endothelial cells by maintaining IRF3 SUMOylation; MAGI1 depletion leads to IRF3 nuclear translocation without phosphorylation, upregulates STAT1, IFNβ1, MX1, OAS2, and activates STAT5 upon IAV infection; MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression.","method":"siRNA knockdown, overexpression, microarray, RT-PCR, Western blot for STAT1/MX1/OAS2, IRF3 nuclear translocation assay, IRF3 SUMOylation assay","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic connection to IRF3 SUMOylation established; single lab; pathway placement supported by multiple markers","pmids":["36082118"],"is_preprint":false},{"year":2024,"finding":"SRC phosphorylates MAGI1 in IDH-mutant cholangiocarcinoma; SRC inhibition (dasatinib) enables formation of a MAGI1-PP2A complex that dephosphorylates and inhibits S6K, reducing protein synthesis and causing cell death; SRC normally inhibits this latent tumor-suppressing MAGI1-PP2A function.","method":"Unbiased phosphoproteomic screen, co-immunoprecipitation, PP2A activity assay, S6K phosphorylation Western blot, cell viability assays, patient-derived xenografts","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased phosphoproteomics with biochemical validation; MAGI1-PP2A complex functionally characterized; in vivo xenograft validation; multiple orthogonal methods","pmids":["38748774"],"is_preprint":false},{"year":2024,"finding":"Tissue factor (TF) associates predominantly with MAGI1 (less with MAGI2/3); TF interacts with the PDZ1 domain of MAGI1; phosphorylation of Ser253 in TF prevents its association with MAGI1; PAR2 activation disrupts TF-MAGI1 association; blocking PDZ1 with competing peptide augments TF procoagulant and signaling activity, suggesting MAGI1 stabilizes and 'encrypts' TF.","method":"Proximity ligation assay, co-immunoprecipitation (reciprocal), pull-down with TF cytoplasmic domain peptides, PDZ domain overexpression, thrombin generation assay","journal":"Thrombosis journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and phospho-site mutant; functional consequence on TF activity validated","pmids":["38233821"],"is_preprint":false},{"year":2025,"finding":"MAGI1 suppresses osteoclast fusion and differentiation through the RhoA/ROCK1 signaling pathway; MAGI1 overexpression decreases RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts; knockdown of MAGI1 in subchondral bone increases osteoclast numbers and worsens subchondral bone microarchitecture; RhoA activator narciclasine rescues MAGI1 overexpression effects.","method":"AAV-mediated shMagi1 knockdown in vivo, overexpression experiments, RANKL-induced osteoclastogenesis in vitro, LC-MS/MS, Western blot, micro-CT, histological staining","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockdown with in vitro mechanistic follow-up; RhoA pathway placement supported by pharmacological rescue; single study","pmids":["40322041"],"is_preprint":false},{"year":2026,"finding":"The MAGI-1 WW tandem architecture substantially enhances affinity towards bidentate ligands compared to individual WW domains; binding proceeds through a conformational selection mechanism sampling alternative conformational states; affinity is modulated by environmental pH with cooperative dissociation linked to electrostatic contacts; swapping linker length between PY motifs alters complex stability (longer linkers weaken binding).","method":"Time-resolved kinetic analyses, isothermal titration calorimetry, biochemical binding assays","journal":"International journal of biological macromolecules","confidence":"High","confidence_rationale":"Tier 1 / Weak — reconstitution-level biophysical analysis with kinetics and calorimetry; linker swap experiments; mechanistic detail; single study","pmids":["41786191"],"is_preprint":false},{"year":2019,"finding":"miR-486-5p directly binds the 3'-UTR of MAGI1 mRNA (confirmed by dual-luciferase and FREMSA); MAGI1 knockdown reverses hydroquinone-induced inhibition of erythroid differentiation in K562 cells via downregulation of RAPGEF2 and RAP1A (downstream of MAGI1 in Rap1 signaling).","method":"Dual-luciferase reporter assay, FREMSA, siRNA knockdown, overexpression, erythroid differentiation assay","journal":"Toxicology in vitro","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — miRNA-target confirmed by luciferase; functional consequence on Rap1 pathway shown; single lab","pmids":["32198055"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, the SAX-7/L1CAM PDZ-binding motif binds MAGI-1 in pull-down assays; MAGI-1 bridges SAX-7 to HMP-2/β-catenin; MAGI-1 acts in glia (non-cell-autonomously) to promote dendrite extension; MAGI-1 also binds AFD-1/afadin via SAX-7 PB motif, and loss of AFD-1 enhances sax-7 dendrite defects.","method":"Pull-down assay, cell-specific rescue, genetic depletion, double mutant analysis","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pull-down with cell-specific rescue; preprint; genetic epistasis confirmed","pmids":["38260503"],"is_preprint":true},{"year":2026,"finding":"OGT mediates O-GlcNAcylation of MAGI1, stabilizing its expression; OGT knockdown reduces MAGI1 levels and inhibits PI3K/AKT pathway activation in high-glucose-treated VSMCs; MAGI1 overexpression activates PI3K/AKT signaling and promotes VSMC proliferation, migration, and inflammation.","method":"OGT knockdown, MAGI1 overexpression/knockdown, O-GlcNAcylation assay, Western blot for PI3K/AKT, cell function assays, diabetic mouse model","journal":"Hereditas","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — O-GlcNAcylation modification shown with functional consequence; PI3K/AKT pathway placement supported; single study","pmids":["41546072"],"is_preprint":false}],"current_model":"MAGI1 is a multi-domain cytoplasmic scaffolding protein (MAGUK family, inverted domain structure: N-terminal GuK, two WW domains, six PDZ domains) that localizes to tight junctions, adherens junctions, and focal adhesions in epithelial and endothelial cells, where it assembles signaling complexes by recruiting partners including beta-catenin/E-cadherin, PDZ-GEF1/Rap1 GEF (activating Rap1 to promote adherens junction maturation), PTEN, nephrin, JAM4, ESAM, Dll1, actin-binding proteins (synaptopodin, alpha-actinin-4), and ion channels (BKCa/Slo1, NaV1.8, GLT-1) to regulate surface expression; it is subject to PTMs including p90RSK-mediated S741 phosphorylation, K931 deSUMOylation (controlling nuclear translocation and EC activation/ER stress), caspase-3/7 cleavage at Asp761 (releasing junctional contacts during apoptosis), SRC-mediated phosphorylation (inhibiting a latent MAGI1-PP2A tumor-suppressive complex), and OGT-mediated O-GlcNAcylation (stabilizing expression); its disruption by viral oncoproteins (HPV E6 causing proteasomal degradation, Ad9 E4-ORF1 causing cytoplasmic sequestration, HTLV-1 Tax1 causing fraction mislocalization) results in loss of tight junction integrity and deregulation of cell growth, establishing MAGI1 as a central junction organizer and tumor suppressor that modulates Wnt/β-catenin, PI3K/AKT, MAPK/ERK, RhoA/ROCK, and Hippo signaling pathways."},"narrative":{"mechanistic_narrative":"MAGI1 is a multi-domain MAGUK scaffolding protein with an inverted domain architecture (N-terminal GuK, two WW domains, and multiple PDZ domains) that organizes epithelial and endothelial cell-cell junctions and assembles signaling complexes through its modular interaction surfaces [PMID:9395497]. At junctions it engages the cadherin/catenin machinery—binding beta-catenin through its fifth PDZ domain to drive membrane localization and complex with E-cadherin during junction formation [PMID:10772923]—and localizes specifically to tight junctions alongside ZO-1 [PMID:10618722]. Its PDZ and WW domains recruit a diverse repertoire of transmembrane and adhesion partners, including JAM4, ESAM, Dll1, nephrin, and the actin-associated proteins synaptopodin and alpha-actinin-4, linking junctional receptors to the cortical cytoskeleton [PMID:12042308, PMID:12773569, PMID:15383320, PMID:15908431, PMID:16155592]. A central output of this scaffolding is activation of the small GTPase Rap1: MAGI1 binds the Rap1 GEF (PDZ-GEF1/Rap GEP) at junctions and is required for cadherin-engagement-induced Rap1 activation and junction maturation [PMID:11168587, PMID:16339077, PMID:27707879]. MAGI1 also controls the surface abundance and stability of multiple membrane proteins, including ion channels and transporters (Slo1/BKCa, GLT-1, NaV1.8) and the coxsackie-adenovirus receptor, in a PDZ-domain-specific manner [PMID:19403801, PMID:21426345, PMID:30860870, PMID:22718816]. Through these activities MAGI1 functions as a tumor suppressor, stabilizing E-cadherin/beta-catenin junctions, suppressing Wnt signaling, and restraining migration and invasion in colorectal, gastric, and breast cancers [PMID:21666716, PMID:28373751, PMID:33707576]; a latent MAGI1-PP2A complex dephosphorylates S6K to limit protein synthesis, an activity held off by SRC phosphorylation [PMID:38748774]. In endothelium MAGI1 is heavily regulated by post-translational modification, with p90RSK-mediated S741 phosphorylation and SENP2-controlled K931 deSUMOylation governing Rap1-dependent EC activation, nuclear translocation, ATF6/ER-stress responses, permeability, and Hippo (LATS/YAP) signaling under disturbed flow [PMID:30944250, PMID:33304925]. MAGI1 is a prominent target of viral oncoproteins—HPV E6 (proteasomal degradation), Ad9 E4-ORF1 (cytoplasmic sequestration), and HTLV-1 Tax1 (mislocalization)—whose disruption of MAGI1 produces loss of tight junction integrity and deregulated growth [PMID:11077444, PMID:21123374, PMID:23279616, PMID:24696483], and it is cleaved by caspases-3/7 at Asp761 to release junctional contacts during apoptosis [PMID:17191119].","teleology":[{"year":1997,"claim":"Established MAGI1 as a structurally unusual MAGUK, defining the inverted domain layout (GuK, WW, PDZ) and splice-variant-dependent nuclear versus membrane partitioning that frames all later mechanistic work.","evidence":"cDNA cloning, domain mapping, and subcellular fractionation of splice variants","pmids":["9395497"],"confidence":"High","gaps":["No functional role assigned to individual domains at this stage","Nuclear function of the long isoform not mechanistically defined"]},{"year":1999,"claim":"Localized MAGI1 specifically to tight junctions with ZO-1 rather than to adherens junctions, placing it as a candidate junction organizer distinct from other MAGUKs.","evidence":"Immunofluorescence, fractionation, and Ca2+-switch assay in epithelial cells","pmids":["10618722"],"confidence":"High","gaps":["Binding partners at tight junctions not yet identified","Mechanism of recruitment unresolved"]},{"year":2000,"claim":"Identified beta-catenin/E-cadherin binding via the fifth PDZ domain as the determinant of MAGI1 membrane localization, linking it directly to the cadherin junctional machinery.","evidence":"Co-IP, GFP localization, and yeast two-hybrid in MDCK cells","pmids":["10772923"],"confidence":"High","gaps":["Did not establish a downstream signaling output","Relationship between PDZ5-catenin binding and tight junction localization unclear"]},{"year":2001,"claim":"Defined MAGI1 as a scaffold for a Rap1-specific GEF at junctions, establishing the first link between MAGI1 scaffolding and small-GTPase signaling.","evidence":"Cell-free binding, co-IP, with MAGUK specificity controls","pmids":["11168587"],"confidence":"High","gaps":["Functional consequence of Rap1 GEF recruitment not yet tested","No loss-of-function data"]},{"year":2005,"claim":"Demonstrated that MAGI1 is functionally required for cadherin-engagement-induced Rap1 activation and adhesion maturation, converting the earlier binding observation into a causal pathway.","evidence":"siRNA knockdown, GTP-Rap1 pulldown, FRET biosensor in endothelial cells","pmids":["16339077"],"confidence":"High","gaps":["Whether Rap1 output applies across all junction types not addressed","Upstream regulators of the MAGI1-GEF complex unknown"]},{"year":2005,"claim":"Expanded the partner repertoire to adhesion and slit-diaphragm proteins (nephrin, JAM4, Dll1) with domain-resolved binding, showing MAGI1 organizes multiple junctional/adhesion modules.","evidence":"Yeast two-hybrid, in vitro binding, immunoelectron microscopy, co-IP across systems","pmids":["16155592","12773569","15908431"],"confidence":"High","gaps":["In vivo requirement for each interaction not yet established","Combinatorial assembly of tripartite complexes not fully resolved"]},{"year":2007,"claim":"Identified caspase-3/7 cleavage at Asp761 as the mechanism by which MAGI1 junctional anchoring is dismantled during apoptosis, linking the scaffold to programmed cell death.","evidence":"In vitro caspase cleavage, Asp761Ala mutagenesis, apoptosis assays","pmids":["17191119"],"confidence":"High","gaps":["Physiological trigger of cleavage in tissue not defined","Fate and function of the resulting fragments only partially characterized [#15]"]},{"year":2011,"claim":"Established MAGI1 as a tumor suppressor that stabilizes E-cadherin/beta-catenin junctions and suppresses Wnt signaling and invasion in vivo.","evidence":"Reciprocal overexpression/knockdown, Wnt reporter, xenograft/orthotopic models in colorectal cancer","pmids":["21666716"],"confidence":"High","gaps":["Direct biochemical mechanism of Wnt suppression not fully resolved","Generality across cancer types tested only later"]},{"year":2011,"claim":"Generalized MAGI1's role in membrane-protein surface regulation, showing PDZ-mediated control of ion channel and transporter surface abundance (Slo1, GLT-1).","evidence":"Yeast two-hybrid/GST pulldown, biotinylation, electrophysiology, glutamate uptake, siRNA","pmids":["19403801","21426345"],"confidence":"High","gaps":["Trafficking machinery downstream of MAGI1 binding not defined","Whether retention vs internalization is the mechanism unclear"]},{"year":2011,"claim":"Resolved the structural and thermodynamic basis of MAGI1 PDZ1 binding to HPV16 E6, revealing a disorder-to-order transition and allosteric tail dynamics governing affinity.","evidence":"NMR structure, backbone dynamics, ITC, and mutagenesis","pmids":["21238461","25590897"],"confidence":"High","gaps":["Whether the same dynamics govern endogenous ligand binding not tested","Functional impact of the C-terminal extension in cells unaddressed"]},{"year":2016,"claim":"Provided in vivo genetic evidence that MAGI1 supports slit-diaphragm integrity via nephrin membrane localization and contact-induced Rap1 activation, with disease relevance in compound mutants.","evidence":"Podocyte knockdown, global and compound knockout mice, Rap1 assays, Drosophila screen","pmids":["27707879"],"confidence":"High","gaps":["Single-gene knockout is phenotypically normal, indicating redundancy not yet mapped","Tissue-specific requirements beyond glomerulus unaddressed"]},{"year":2018,"claim":"Defined the structural determinant of MAGI1-versus-MAGI2 specificity for nephrin, explaining paralog-selective scaffolding through an atypical PDZ recognition mode.","evidence":"MAGI1-PDZ3/nephrin-PBM crystal structure with gain-of-function mutagenesis","pmids":["30006415"],"confidence":"High","gaps":["Whether other partners use similar atypical recognition not tested","In vivo consequence of disrupting the Gly(-3) contact unknown"]},{"year":2020,"claim":"Mapped MAGI1 as a hub for flow- and stress-responsive endothelial signaling controlled by p90RSK phosphorylation (S741) and SENP2-dependent deSUMOylation (K931), connecting it to EC activation, permeability, ER stress, and Hippo signaling.","evidence":"Phosphoproteomics, PTM-site mutants, SUMOylation/permeability assays, Magi1+/- mice","pmids":["30944250","33304925","31035633"],"confidence":"High","gaps":["How nuclear MAGI1 complexes execute transcriptional effects not fully defined","Integration of Rap1, Hippo, and ER-stress outputs into a single circuit unresolved"]},{"year":2021,"claim":"Extended MAGI1 function to focal adhesions and RhoA/Rac1 signaling and dissected its tumor-suppressive mechanism via an AMOTL2/p38 stress pathway.","evidence":"siRNA, colocalization, GTPase activation assays, AMOTL2 knockout and p38 inhibitor rescue, in vivo angiogenesis","pmids":["33823745","33707576"],"confidence":"High","gaps":["Direct biochemical link from MAGI1 to AMOTL2 sequestration not fully mapped","Reconciliation of RhoA-activating and RhoA-suppressing contexts unresolved"]},{"year":2024,"claim":"Identified a latent MAGI1-PP2A tumor-suppressive complex that dephosphorylates S6K, held inactive by SRC phosphorylation, providing a druggable mechanism in IDH-mutant cholangiocarcinoma.","evidence":"Unbiased phosphoproteomics, co-IP, PP2A activity and S6K assays, patient-derived xenografts","pmids":["38748774"],"confidence":"High","gaps":["SRC phospho-site(s) on MAGI1 not pinpointed in the timeline","Whether the PP2A complex operates outside cholangiocarcinoma untested"]},{"year":2026,"claim":"Characterized the biophysical logic of the MAGI1 WW tandem, showing avidity-driven bidentate binding via conformational selection tuned by pH and inter-motif linker length.","evidence":"Time-resolved kinetics, ITC, and linker-swap binding assays","pmids":["41786191"],"confidence":"High","gaps":["Physiological bidentate ligands engaging both WW domains not identified","In-cell relevance of pH-tuning not demonstrated"]},{"year":null,"claim":"How MAGI1's many domain-specific interactions, PTM states, and pathway outputs (Rap1, Wnt, Hippo, RhoA, PI3K/AKT, MAPK/ERK) are coordinated into context-specific programs in distinct tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking junctional, cytosolic, and nuclear MAGI1 pools","Stoichiometry and competition among partners for shared PDZ/WW domains undefined","Tissue-specific PTM regulation not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4,7,10,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,43]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,25,41,27,48]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,9,17,41]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,40]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,7,43]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[43]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,10,36,39,40,42]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,2,8,9,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,21,24,47]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[29,46]}],"complexes":["MAGI1-PP2A complex","glomerular slit diaphragm","tight junction"],"partners":["CTNNB1","PDZ-GEF1","NPHS1","JAM4","ESAM","PTEN","ATF6","ADAM17"],"other_free_text":[]}},"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 many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAGI1"},"hgnc":{"alias_symbol":["BAP1","MAGI-1","TNRC19","AIP3","WWP3"],"prev_symbol":["BAIAP1"]},"alphafold":{"accession":"Q96QZ7","domains":[{"cath_id":"2.30.42.10","chopping":"12-53_60-142_192-213","consensus_level":"high","plddt":82.7526,"start":12,"end":213},{"cath_id":"2.20.70","chopping":"364-401","consensus_level":"medium","plddt":79.8232,"start":364,"end":401},{"cath_id":"2.30.42.10","chopping":"464-565","consensus_level":"high","plddt":87.1854,"start":464,"end":565},{"cath_id":"2.30.42.10","chopping":"641-722","consensus_level":"high","plddt":84.7895,"start":641,"end":722},{"cath_id":"2.30.42.10","chopping":"838-925","consensus_level":"medium","plddt":89.7289,"start":838,"end":925},{"cath_id":"2.30.42.10","chopping":"998-1017_1034-1092","consensus_level":"medium","plddt":84.7994,"start":998,"end":1092},{"cath_id":"2.30.42.10","chopping":"1152-1232","consensus_level":"high","plddt":91.4384,"start":1152,"end":1232}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ7-F1-predicted_aligned_error_v6.png","plddt_mean":59.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAGI1","jax_strain_url":"https://www.jax.org/strain/search?query=MAGI1"},"sequence":{"accession":"Q96QZ7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QZ7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QZ7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ7"}},"corpus_meta":[{"pmid":"11077444","id":"PMC_11077444","title":"Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11077444","citation_count":244,"is_preprint":false},{"pmid":"9395497","id":"PMC_9395497","title":"MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of protein-protein interaction domains.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9395497","citation_count":171,"is_preprint":false},{"pmid":"10772923","id":"PMC_10772923","title":"MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10772923","citation_count":146,"is_preprint":false},{"pmid":"12773569","id":"PMC_12773569","title":"JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12773569","citation_count":142,"is_preprint":false},{"pmid":"16339077","id":"PMC_16339077","title":"MAGI-1 is required for Rap1 activation upon cell-cell contact and for enhancement of vascular endothelial cadherin-mediated cell adhesion.","date":"2005","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16339077","citation_count":128,"is_preprint":false},{"pmid":"12042308","id":"PMC_12042308","title":"Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12042308","citation_count":116,"is_preprint":false},{"pmid":"10618722","id":"PMC_10618722","title":"Localization of membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10618722","citation_count":106,"is_preprint":false},{"pmid":"11969287","id":"PMC_11969287","title":"MAGI-1: a widely expressed, alternatively spliced tight junction protein.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11969287","citation_count":82,"is_preprint":false},{"pmid":"21123374","id":"PMC_21123374","title":"A systematic analysis of human papillomavirus (HPV) E6 PDZ substrates identifies MAGI-1 as a major target of HPV type 16 (HPV-16) and HPV-18 whose loss accompanies disruption of tight junctions.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21123374","citation_count":74,"is_preprint":false},{"pmid":"15383320","id":"PMC_15383320","title":"Endothelial adhesion molecule ESAM binds directly to the multidomain adaptor MAGI-1 and recruits it to cell contacts.","date":"2004","source":"Experimental cell 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MAGUK protein with a unique inverted domain structure: GuK domain at the N-terminus, two WW domains replacing the SH3 domain, and five PDZ domains. The longest splice variant (MAGI-1c) contains bipartite nuclear localization signals and localizes predominantly to the nucleus, while shorter forms lacking these signals localize to membrane and cytoplasmic fractions.\",\n      \"method\": \"cDNA cloning, subcellular fractionation, sequence analysis of splice variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original structural characterization with cloning, domain mapping, and subcellular fractionation; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"9395497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI-1b fifth PDZ domain binds beta-catenin and is essential for membrane localization; MAGI-1b forms complexes with beta-catenin and E-cadherin during formation of cell-cell junctions in MDCK cells, and GFP-MAGI-1b localizes to the basolateral membrane of polarized MDCK cells.\",\n      \"method\": \"Co-immunoprecipitation, GFP fusion localization, subcellular fractionation, yeast two-hybrid\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mapping, confirmed by localization; replicated in multiple subsequent studies\",\n      \"pmids\": [\"10772923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MAGI-1/BAP1 localizes specifically to tight junctions in intestinal epithelial cells and MDCK cells, co-localizing with ZO-1 (not E-cadherin), and is recruited with ZO-1 to tight junction-like structures upon PMA treatment after low-Ca2+ switch, distinguishing its role from SAP97/hDLG.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, Ca2+-switch assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional context (tight junction assembly); replicated by multiple labs\",\n      \"pmids\": [\"10618722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ad9 E4-ORF1 oncoprotein binds MAGI-1 and aberrantly sequesters it in the cytoplasm, while high-risk HPV E6 proteins bind MAGI-1 and target it for degradation; transformation-defective viral mutants are deficient for these activities.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, viral mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with functional mutant validation; replicated extensively in subsequent HPV/viral studies\",\n      \"pmids\": [\"11077444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI-1/BAP1 serves as a scaffolding molecule for Rap GEP (a Rap1-specific GDP/GTP exchange factor) at tight junctions in epithelial cells; this interaction is specific to MAGI-1 and not observed with PSD-95/SAP90 or SAP97/hDLG.\",\n      \"method\": \"Cell-free binding assays, co-immunoprecipitation in intact cells, Northern blot\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed in vitro and in vivo; specificity validated by negative controls with other MAGUKs\",\n      \"pmids\": [\"11168587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MAGI-1 fifth PDZ domain binds megalin via the DSDV PDZ-binding motif at megalin's C-terminus; a mutant megalin lacking the terminal valine cannot bind. MAGI-1 is expressed in glomerular podocytes and associated with the cytoskeleton in glomerular preparations.\",\n      \"method\": \"Yeast two-hybrid, PDZ domain binding assays, mutagenesis, immunofluorescence, Western blot fractionation\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — yeast two-hybrid confirmed by direct binding with mutagenesis; domain mapping performed\",\n      \"pmids\": [\"11274227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The first PDZ domain of MAGI-1 interacts with mNET1, a Rho family nucleotide exchange factor, via a consensus PDZ-binding motif (PPxY-like at C-terminus of mNET1) plus a nearby cluster of basic residues required for the interaction.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple biochemical methods in single study, single lab\",\n      \"pmids\": [\"11350080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MAGI-1 WW domain 2 interacts with synaptopodin (an actin-bundling protein) identified via cDNA library screen; the fifth PDZ domain of MAGI-1 binds alpha-actinin-4 C-terminus. Both interactions were confirmed in vivo by co-immunoprecipitation from HEK293 cells, and all three proteins colocalize at tight junctions in MDCK cells.\",\n      \"method\": \"Yeast two-hybrid/cDNA library screen, in vitro GST pull-down, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding confirmed by in vivo co-IP with domain mapping; multiple orthogonal methods\",\n      \"pmids\": [\"12042308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"JAM4 (junctional adhesion molecule 4) directly binds MAGI-1 (but not ZO-1), and their co-expression in COS-7 cells induces clustering. MAGI-1 strengthens JAM4-mediated cell adhesion in L cells and sealing effects in CHO cell monolayers. MAGI-1 also recruits ZO-1, occludin to JAM4-based contacts.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, cell adhesion assay, permeability assay, fluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed biochemically with functional cell adhesion readout; multiple orthogonal methods\",\n      \"pmids\": [\"12773569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ESAM (endothelial cell-selective adhesion molecule) directly binds MAGI-1 via PDZ domain-mediated interaction at ESAM's C-terminus; ESAM recruits MAGI-1 to cell-cell contacts in CHO cells, and in HUVECs MAGI-1 colocalizes with ESAM at endothelial cell-cell contacts.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by pull-down and co-IP; localization with functional consequence (recruitment) demonstrated\",\n      \"pmids\": [\"15383320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI-1 is required for Rap1 activation upon VE-cadherin homophilic engagement at cell-cell contacts in endothelial cells. MAGI-1 binds PDZ-GEF1 (a Rap1 GEF) and localizes to cell-cell contacts via beta-catenin. MAGI-1 depletion suppresses VE-cadherin-dependent Rap1 activation, inhibits vinculin relocalization to cell-cell contacts, and impairs VE-cadherin-mediated adhesion.\",\n      \"method\": \"siRNA knockdown, Rap1 activation assay (pulldown of GTP-Rap1), FRET-based Rap1 biosensor, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular mechanism; multiple orthogonal methods; pathway epistasis confirmed\",\n      \"pmids\": [\"16339077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI-1 binds Dll1 (Delta-like 1) and N-cadherin/beta-catenin complexes; MAGI-1 recruits Dll1 to adherens junctions in cultured fibroblasts and stabilizes Dll1 on the cell surface, suggesting MAGI-1 presents Dll1 at junctions to activate Notch on neighboring cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, cell surface stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP; functional consequence (Dll1 surface stabilization) shown; multiple methods\",\n      \"pmids\": [\"15908431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI-1 is a component of the glomerular slit diaphragm and directly binds nephrin via its middle PDZ domains (PDZ3) through nephrin's C-terminus; MAGI-1 forms a tripartite complex with nephrin and JAM4 in vitro. In puromycin aminonucleoside nephrotic podocytes, MAGI-1 co-localizes with nephrin at the displaced slit diaphragm.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, immunoelectron microscopy, co-immunoprecipitation\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid, direct binding, and immunoelectron microscopy; functional disease context validated\",\n      \"pmids\": [\"16155592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel tight junction protein, MASCOT, binds the first WW domain of MAGI-1 via an LPxY motif (not the canonical PPxY); the coiled-coil domain of MASCOT is required for its localization to tight junctions in MDCK cells.\",\n      \"method\": \"CDNA library screen, in vitro GST binding assay, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding confirmed with domain mapping; single lab, single study\",\n      \"pmids\": [\"16019084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MAGI-1 is cleaved by caspases-3 and -7 at Asp761 during apoptosis, generating a 97 kDa N-terminal fragment that dissociates from the membrane and a C-terminal fragment. Mutation of Asp761 to Ala abolishes caspase-induced cleavage and delays disruption of cell-cell contacts during apoptosis without affecting nuclear condensation.\",\n      \"method\": \"In vitro caspase cleavage assay, site-directed mutagenesis, cell-based apoptosis assays, caspase inhibitor (Z-VAD-fmk)\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with site-directed mutagenesis identifying specific cleavage site; functional consequence in cells confirmed\",\n      \"pmids\": [\"17191119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"N-terminal MAGI-1 caspase cleavage product translocates to the cytosol while C-terminal caspase cleavage product accumulates in the nucleus; both overexpressed fragments exhibit minor pro-apoptotic activity when expressed in MDCK cells.\",\n      \"method\": \"GFP-fusion subcellular localization, immunofluorescence, apoptosis assay\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment; functional consequence is minor; single lab\",\n      \"pmids\": [\"17976012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAGI-1 PDZ4 domain binds the C-terminal PDZ-binding site of the hair-cell-specific Cdh23(+68) splice variant; MAGI-1 immunoreactivity is detectable in neonatal stereocilia in a distribution similar to Cdh23, with punctate staining maintained into adulthood.\",\n      \"method\": \"Cochlear cDNA library screen, PDZ domain binding assay, immunofluorescence\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical binding confirmed with domain mapping and localization; single lab, limited functional validation\",\n      \"pmids\": [\"18971469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAGI-1 binds BKCa (Slo1) channel proteins via a yeast two-hybrid interaction; co-expression of MAGI-1 with Slo1 in HEK293T cells significantly reduces Slo1 surface expression as assessed by biotinylation, confocal microscopy, and whole-cell recordings. Partial siRNA knockdown of endogenous MAGI-1 in podocytes increases surface expression of endogenous Slo1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, GST pull-down, cell-surface biotinylation, electrophysiology, siRNA knockdown\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by multiple methods; functional consequence (reduced surface expression) demonstrated by gain and loss of function with multiple readouts\",\n      \"pmids\": [\"19403801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAGI-1 in C. elegans (ortholog) controls GLR-1/GLR-2 AMPA receptor synaptic localization in response to prior mechanosensory experience; MAGI-1L isoform interacts with AMPARs through the intracellular domain of GLR-2 subunit; mutations preventing GLR-1 ubiquitination prevent the decrease in AMPAR localization in magi-1 mutants.\",\n      \"method\": \"Genetic loss-of-function, fluorescence imaging of GFP-tagged GLR-1/GLR-2, behavioral assays, epistasis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with behavioral and synaptic localization readouts; interaction domain identified; multiple approaches\",\n      \"pmids\": [\"19242552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAGI-1 in C. elegans controls associative learning via RIA interneurons and memory consolidation via AVA/AVD/AVE glutamatergic interneurons; during memory consolidation, MAGI-1 regulates GLR-1 (iGluR) clustering cell-autonomously in a manner dependent on its ability to interact with beta-catenin HMP-2.\",\n      \"method\": \"Genetic rescue (neuron-specific expression), behavioral assays, fluorescence imaging of GLR-1 clustering, epistasis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific rescue experiments with molecular interaction requirement validated; behavioral and cellular readouts\",\n      \"pmids\": [\"19551147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ESAM-MAGI-1 co-localization promotes actin polymerization through PDZ domain interactions resulting in firm cell-cell adhesion; ESAM-MAGI-1 interaction activates RhoA, and RhoA inhibition blocks ESAM-mediated MAGI-1 recruitment and mature cell adhesion.\",\n      \"method\": \"Transfection experiments in CHO cells, cell dissociation assay, actin polymerization inhibitor, RhoA activity assay, RhoA inhibitor\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional consequence demonstrated with pharmacological inhibition; RhoA activation measured; single lab\",\n      \"pmids\": [\"20298433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAGI-1 is a major degradation target of HPV-16 and HPV-18 E6 in cervical cancer cells; E6 preferentially targets MAGI-1 within the nucleus and at membrane sites; MAGI-1 degradation causes loss of tight junction integrity (ZO-1 mislocalization); E6 ablation restores tight junctions in a MAGI-1-dependent manner.\",\n      \"method\": \"siRNA E6 ablation, Western blot, immunofluorescence of ZO-1, rescue experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain and loss of function with rescue; mechanistic link between E6, MAGI-1 degradation, and tight junction disruption established; replicated across multiple labs\",\n      \"pmids\": [\"21123374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans MAGI-1 localizes apical to both the CCC and DAC junctional sub-compartments; loss of MAGI-1 causes loss of junctional compartmentalization along the lateral membrane and reduces robustness of cell-cell adhesion by both junctional types.\",\n      \"method\": \"RNAi knockdown, fluorescence imaging of junctional markers, genetic analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence; loss-of-function with multiple junctional readouts\",\n      \"pmids\": [\"21034729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR solution structure of MAGI-1 PDZ1 domain alone and bound to HPV16 E6 C-terminal peptide reveals that binding induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain; mutations in the C-terminal flanking region significantly decrease E6 binding affinity, indicating global PDZ response with effects propagated to distal sites.\",\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 / Moderate — NMR structure with mutagenesis and dynamics analysis; mechanistic detail of binding confirmed\",\n      \"pmids\": [\"21238461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI-1 overexpression in colorectal cancer cells stabilizes E-cadherin and beta-catenin at cell-cell junctions, enhances actin stress fiber and focal adhesion formation, suppresses Wnt signaling, and inhibits migration, invasion, and anchorage-independent growth. MAGI-1 silencing has opposite effects. MAGI-1 overexpression suppresses tumor growth and metastasis in vivo.\",\n      \"method\": \"Stable overexpression/siRNA knockdown, in vitro migration/invasion assays, Wnt reporter assay, in vivo xenograft/orthotopic models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss of function with multiple cellular and in vivo readouts; mechanistic pathway (Wnt suppression) validated\",\n      \"pmids\": [\"21666716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI-1 directly binds glutamate transporter GLT-1 via GST pull-down confirmed by co-immunoprecipitation; co-expression of MAGI-1 reduces GLT-1 surface expression in C6 glioma cells; siRNA knockdown of endogenous MAGI-1 in astrocytes increases glutamate uptake and GLT-1 surface expression.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, cell-surface biotinylation, glutamate uptake assay, siRNA knockdown\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by multiple methods; functional consequence shown by reciprocal gain/loss of function\",\n      \"pmids\": [\"21426345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGI-1 overexpression in hepatocellular carcinoma HepG2 cells inhibits migration and invasion; PTEN protein expression is significantly elevated in MAGI-1-overexpressing cells, with a positive correlation between MAGI-1 and PTEN protein levels.\",\n      \"method\": \"Stable transfection, wound healing assay, Matrigel invasion assay, Western blot\",\n      \"journal\": \"Zhong nan da xue xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assays without detailed molecular mechanism of MAGI1-PTEN interaction\",\n      \"pmids\": [\"21685691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAGI-1 PDZ1 and PDZ3 domains regulate CAREx8 levels in opposing ways: PDZ3 reduces apical CAREx8 abundance and adenovirus infection, while PDZ1 rescues CAREx8 and adenovirus infection from MAGI-1-mediated suppression.\",\n      \"method\": \"Yeast two-hybrid, biochemical pull-down, co-immunoprecipitation, FRET, adenovirus infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped to specific PDZ domains with functional consequence on viral entry; multiple orthogonal methods\",\n      \"pmids\": [\"22718816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C. elegans, MAGI-1 physically interacts with AFD-1/afadin and SAX-7/L1CAM (which binds MAGI-1 via its C-terminus); MAGI-1 and AFD-1 localize to a unique domain in the apical junction; SAX-7/L1CAM is required for normal MAGI-1 junctional accumulation; MAGI-1 depletion causes loss of spatial segregation and expansion of apical junctional domains.\",\n      \"method\": \"Genome-wide RNAi screen, co-immunoprecipitation, fluorescence localization, genetic epistasis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction confirmed biochemically; localization requirement established; genetic epistasis with multiple partners\",\n      \"pmids\": [\"22981773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"siRNA depletion of MAGI-1 activates IRF3 and induces the IFN-β promoter; avian influenza NS1 ESEV PBM sequesters MAGI-1 away from the plasma membrane in infected cells, and the ESEV PBM relative to EPEA shows relative deficiency in NS1 inhibition of IFN-β induction, suggesting MAGI-1 normally suppresses IFN-β signaling.\",\n      \"method\": \"siRNA knockdown, IRF3 activation assay, IFN-β promoter luciferase reporter, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional consequence of MAGI-1 depletion on IFN-β pathway shown; single lab, limited mechanistic detail\",\n      \"pmids\": [\"22911767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAGI-1 in neuronal tissue is enriched in synaptosomal vesicle and synaptic plasma membrane fractions (distinct from MAGI-2/3 which are in PSD fractions); MAGI-1 shows diffuse distribution in hippocampal neuron cell body and processes, not enriched at synapses, unlike MAGI-2/3.\",\n      \"method\": \"Biochemical fractionation, immunofluorescence, immunohistochemistry\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct fractionation experiment with comparative analysis; single lab\",\n      \"pmids\": [\"22605569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HTLV-1 Tax1 interacts with MAGI-1 in a PDZ-binding motif (PBM)-dependent manner and mislocalizes MAGI-1 from the detergent-soluble to the detergent-insoluble cellular fraction in 293T cells and HTLV-1-infected T-cells; Tax1-induced T-cell transformation selects for cells with irreversibly reduced MAGI-1 mRNA expression.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, PBM mutant analysis, RT-PCR\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — interaction confirmed with PBM mutant; mislocalization shown; single lab\",\n      \"pmids\": [\"23279616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAGI-1 forms an immunocomplex with p75NTR (low-affinity NGF receptor) and Shc adaptor in PC12 cells; MAGI-1 knockdown inhibits NGF-induced neurite outgrowth; both knockdown and overexpression of MAGI-1 suppress NGF-stimulated Shc-ERK pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, neurite outgrowth assay, ERK activation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — scaffold complex identified with functional consequence on NGF signaling; single lab; paradoxical results with over/knockdown noted\",\n      \"pmids\": [\"23769981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A K499E mutation in MAGI-1 PDZ1 domain renders it resistant to HPV E6 targeting; re-expression of this mutant MAGI-1 in HPV-positive cells increases ZO-1 and PAR3 recruitment to cell-cell contacts, represses cell proliferation, and induces apoptosis.\",\n      \"method\": \"Site-directed mutagenesis, lentiviral expression in HPV+ cells, immunofluorescence, cell proliferation and apoptosis assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis-based rescue experiment; multiple functional readouts; establishes direct causal role of MAGI-1 in TJ assembly, proliferation, and apoptosis control\",\n      \"pmids\": [\"24696483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAGI-1 PDZ3 domain is exclusively responsible for high-affinity interaction with the 7-exon CAR isoform; interruption of this high-affinity interaction alters MAGI-1 localization (CAR traffics MAGI-1 to cell junctions) but does not significantly alter adenovirus infection via CAR.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, FRET, adenovirus infection assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific interaction mapped with multiple methods; functional consequence on localization shown\",\n      \"pmids\": [\"25622559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Binding of E6 peptides to MAGI-1 PDZ1 is accompanied by an unusually large negative change in heat capacity attributed to a disorder-to-order transition of the PDZ1 C-terminal extension; NMR relaxation data confirm this; a PDZ1 mutant abolishing this transition shows different thermodynamic signature.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), NMR 15N relaxation, site-directed mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical characterization with NMR, ITC, and mutagenesis; mechanistic detail of binding confirmed\",\n      \"pmids\": [\"25590897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAGI-1 depletion in cultured podocytes reduces nephrin and neph1 membrane localization and weakens tight junction integrity; global magi1 knockout mice are normal, but combined MAGI-1 knockout with nephrin heterozygosity causes spontaneous glomerulosclerosis; MAGI-1 depletion reduces intercellular contact-induced Rap1 activation, and combined overexpression of MAGI-1 with nephrin increases Rap1 activation requiring the nephrin-binding interface.\",\n      \"method\": \"siRNA knockdown, global knockout mice, compound genetic mouse models, Rap1 activation assay, Drosophila genetic screen, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro loss-of-function, in vivo compound genetics, and mechanistic Rap1 assay; replicated across systems\",\n      \"pmids\": [\"27707879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAGI-1 knockdown in gastric cancer cells promotes migration and invasion by increasing MMP expression and EMT-related molecules via activation of the MAPK/ERK signaling pathway.\",\n      \"method\": \"shRNA knockdown, migration/invasion assays, Western blot for MMPs and EMT markers, ERK signaling analysis\",\n      \"journal\": \"Chinese journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach; MAPK/ERK pathway placement inferred from expression changes\",\n      \"pmids\": [\"28373751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal/biochemical structure analysis shows nephrin C-terminal PBM specifically binds MAGI1 PDZ3 but not MAGI2 PDZ3; the Gly at the -3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition (contrasting typical PDZ/PBM binding mode); a single gain-of-function mutation in MAGI2 enables nephrin-PBM binding.\",\n      \"method\": \"Complex crystal structure (MAGI1-PDZ3/nephrin-PBM), biophysical binding assays, site-directed mutagenesis\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis; structural basis of binding specificity established\",\n      \"pmids\": [\"30006415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI1 is required for fluid shear stress-induced eNOS phosphorylation and NO production in endothelial cells; MAGI1 silencing impairs KLF4 expression and cell alignment under flow; MAGI1 overexpression induces phosphorylation of PKA, AMPK, and CaMKII; PKA and AMPK inhibition prevents MAGI1-mediated eNOS phosphorylation; endothelial-specific transgenic MAGI1 increases PKA and eNOS phosphorylation in vivo.\",\n      \"method\": \"siRNA silencing, overexpression, NO measurement, kinase phosphorylation assays, pharmacological kinase inhibitors, transgenic mice\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss of function; pathway validated pharmacologically and in transgenic model; multiple orthogonal readouts\",\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 causes MAGI1-S741 phosphorylation, which upregulates EC activation via Rap1; MAGI1-K931 deSUMOylation (mediated by SENP2) induces nuclear translocation of p90RSK-MAGI1 and ATF6-MAGI1 complexes promoting EC activation and apoptosis respectively; MAGI1 associates with ATF-6 (ER stress mediator); reduced MAGI1 in Magi1-/+ mice inhibits disturbed flow-induced atherogenesis.\",\n      \"method\": \"Co-immunoprecipitation, phosphoproteomic analysis, phospho-site mutagenesis, SUMOylation assay, Magi1+/- mouse model, microarray\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased phosphoproteomic discovery with biochemical validation, PTM mapping, and in vivo genetic model; multiple orthogonal methods\",\n      \"pmids\": [\"30944250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Magi-1 directly interacts with NaV1.8 channels and Slack KNa channels in dorsal root ganglion neurons; Magi-1 regulates NaV1.8 plasma membrane localization, retention, and stability; DRG-specific knockdown of Magi-1 attenuates thermal nociception and inflammatory pain; a competing cell-penetrating peptide mimetic from NaV1.8 WW binding motif decreases sodium currents and NaV1.8 surface expression.\",\n      \"method\": \"co-immunoprecipitation, cell-surface biotinylation, siRNA knockdown, electrophysiology, in vivo pain behavior, peptide competition assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed biochemically; functional consequence shown by reciprocal genetic and pharmacological approaches in vivo\",\n      \"pmids\": [\"30860870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p90RSK-mediated MAGI1 post-translational modifications (S741 phosphorylation and K931 de-SUMOylation) regulate endothelial permeability; dominant negative p90RSK or MAGI1-S741A decreases thrombin-induced permeability; p90RSK overexpression, MAGI1 siRNA, or MAGI1-K931R SUMOylation mutant accelerates permeability; MAGI1 depletion increases LATS1/2 expression, inhibiting YAP/TAZ (Hippo pathway).\",\n      \"method\": \"ECIS-based permeability assay, siRNA knockdown, PTM mutant overexpression, LATS/YAP expression analysis, in vivo p90RSK inhibitor\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM mutants with functional permeability readout; Hippo pathway connection established; replicated in vivo\",\n      \"pmids\": [\"33304925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAGI1 colocalizes with paxillin, β3-integrin, talin 1, tensin 3, and α4-actinin at mature focal adhesions and actin stress fibers in endothelial cells; MAGI1 silencing reduces focal adhesion formation and maturation, cell spreading, actin stress fiber formation, and RhoA/Rac1 activation, and increases paxillin Y118 phosphorylation (indicator of focal adhesion turnover). MAGI1 silencing reduces integrin-dependent adhesion, increases invasion, promotes tubulogenesis in vitro, and promotes angiogenesis in vivo.\",\n      \"method\": \"siRNA silencing, immunofluorescence colocalization, RhoA/Rac1 activation assay, paxillin phosphorylation Western blot, cell adhesion/invasion assays, in vivo angiogenesis model\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence; multiple orthogonal methods; in vitro and in vivo readouts\",\n      \"pmids\": [\"33823745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of MAGI1 in breast cancer cells causes accumulation of E-cadherin and AMOTL2 with increased cellular stiffness, elevated ROCK and p38 stress kinase activities (but low YAP activity); MAGI1 loss-driven tumorigenicity is rescued by AMOTL2 deletion or p38 inhibition, demonstrating MAGI1 suppresses tumorigenesis by inhibiting an AMOTL2/p38 stress pathway.\",\n      \"method\": \"MAGI1 siRNA knockdown, AMOTL2 knockout, p38 inhibitor, ROCK inhibitor, tumorigenicity assays, YAP activity measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with rescue experiments; pathway placement established by combined genetic/pharmacological approaches\",\n      \"pmids\": [\"33707576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAGI-1 PDZ2 domain blockade by decoy peptides (TAT-E6, TAT-NET1) decreases CAREx8 expression and adenovirus transduction; this occurs via enhanced regulated intramembrane proteolysis through ADAM17 and γ-secretase; ADAM17 interacts directly with MAGI-1 PDZ3 domain; blocking PDZ2 enhances ADAM17 accessibility to CAREx8.\",\n      \"method\": \"Decoy peptide competition, cell-surface biotinylation, adenovirus transduction assay, co-immunoprecipitation of ADAM17/MAGI-1, in vivo transgenic model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct domain-specific interaction mapped; mechanism of CAREx8 proteolysis via ADAM17 confirmed biochemically; in vivo validation\",\n      \"pmids\": [\"33762416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAGI1 inhibits IRF3 activation in endothelial cells by maintaining IRF3 SUMOylation; MAGI1 depletion leads to IRF3 nuclear translocation without phosphorylation, upregulates STAT1, IFNβ1, MX1, OAS2, and activates STAT5 upon IAV infection; MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression.\",\n      \"method\": \"siRNA knockdown, overexpression, microarray, RT-PCR, Western blot for STAT1/MX1/OAS2, IRF3 nuclear translocation assay, IRF3 SUMOylation assay\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic connection to IRF3 SUMOylation established; single lab; pathway placement supported by multiple markers\",\n      \"pmids\": [\"36082118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SRC phosphorylates MAGI1 in IDH-mutant cholangiocarcinoma; SRC inhibition (dasatinib) enables formation of a MAGI1-PP2A complex that dephosphorylates and inhibits S6K, reducing protein synthesis and causing cell death; SRC normally inhibits this latent tumor-suppressing MAGI1-PP2A function.\",\n      \"method\": \"Unbiased phosphoproteomic screen, co-immunoprecipitation, PP2A activity assay, S6K phosphorylation Western blot, cell viability assays, patient-derived xenografts\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased phosphoproteomics with biochemical validation; MAGI1-PP2A complex functionally characterized; in vivo xenograft validation; multiple orthogonal methods\",\n      \"pmids\": [\"38748774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tissue factor (TF) associates predominantly with MAGI1 (less with MAGI2/3); TF interacts with the PDZ1 domain of MAGI1; phosphorylation of Ser253 in TF prevents its association with MAGI1; PAR2 activation disrupts TF-MAGI1 association; blocking PDZ1 with competing peptide augments TF procoagulant and signaling activity, suggesting MAGI1 stabilizes and 'encrypts' TF.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation (reciprocal), pull-down with TF cytoplasmic domain peptides, PDZ domain overexpression, thrombin generation assay\",\n      \"journal\": \"Thrombosis journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and phospho-site mutant; functional consequence on TF activity validated\",\n      \"pmids\": [\"38233821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAGI1 suppresses osteoclast fusion and differentiation through the RhoA/ROCK1 signaling pathway; MAGI1 overexpression decreases RhoA, ROCK1, and p-p65 in RANKL-treated osteoclasts; knockdown of MAGI1 in subchondral bone increases osteoclast numbers and worsens subchondral bone microarchitecture; RhoA activator narciclasine rescues MAGI1 overexpression effects.\",\n      \"method\": \"AAV-mediated shMagi1 knockdown in vivo, overexpression experiments, RANKL-induced osteoclastogenesis in vitro, LC-MS/MS, Western blot, micro-CT, histological staining\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockdown with in vitro mechanistic follow-up; RhoA pathway placement supported by pharmacological rescue; single study\",\n      \"pmids\": [\"40322041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The MAGI-1 WW tandem architecture substantially enhances affinity towards bidentate ligands compared to individual WW domains; binding proceeds through a conformational selection mechanism sampling alternative conformational states; affinity is modulated by environmental pH with cooperative dissociation linked to electrostatic contacts; swapping linker length between PY motifs alters complex stability (longer linkers weaken binding).\",\n      \"method\": \"Time-resolved kinetic analyses, isothermal titration calorimetry, biochemical binding assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution-level biophysical analysis with kinetics and calorimetry; linker swap experiments; mechanistic detail; single study\",\n      \"pmids\": [\"41786191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-486-5p directly binds the 3'-UTR of MAGI1 mRNA (confirmed by dual-luciferase and FREMSA); MAGI1 knockdown reverses hydroquinone-induced inhibition of erythroid differentiation in K562 cells via downregulation of RAPGEF2 and RAP1A (downstream of MAGI1 in Rap1 signaling).\",\n      \"method\": \"Dual-luciferase reporter assay, FREMSA, siRNA knockdown, overexpression, erythroid differentiation assay\",\n      \"journal\": \"Toxicology in vitro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — miRNA-target confirmed by luciferase; functional consequence on Rap1 pathway shown; single lab\",\n      \"pmids\": [\"32198055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, the SAX-7/L1CAM PDZ-binding motif binds MAGI-1 in pull-down assays; MAGI-1 bridges SAX-7 to HMP-2/β-catenin; MAGI-1 acts in glia (non-cell-autonomously) to promote dendrite extension; MAGI-1 also binds AFD-1/afadin via SAX-7 PB motif, and loss of AFD-1 enhances sax-7 dendrite defects.\",\n      \"method\": \"Pull-down assay, cell-specific rescue, genetic depletion, double mutant analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pull-down with cell-specific rescue; preprint; genetic epistasis confirmed\",\n      \"pmids\": [\"38260503\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OGT mediates O-GlcNAcylation of MAGI1, stabilizing its expression; OGT knockdown reduces MAGI1 levels and inhibits PI3K/AKT pathway activation in high-glucose-treated VSMCs; MAGI1 overexpression activates PI3K/AKT signaling and promotes VSMC proliferation, migration, and inflammation.\",\n      \"method\": \"OGT knockdown, MAGI1 overexpression/knockdown, O-GlcNAcylation assay, Western blot for PI3K/AKT, cell function assays, diabetic mouse model\",\n      \"journal\": \"Hereditas\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — O-GlcNAcylation modification shown with functional consequence; PI3K/AKT pathway placement supported; single study\",\n      \"pmids\": [\"41546072\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGI1 is a multi-domain cytoplasmic scaffolding protein (MAGUK family, inverted domain structure: N-terminal GuK, two WW domains, six PDZ domains) that localizes to tight junctions, adherens junctions, and focal adhesions in epithelial and endothelial cells, where it assembles signaling complexes by recruiting partners including beta-catenin/E-cadherin, PDZ-GEF1/Rap1 GEF (activating Rap1 to promote adherens junction maturation), PTEN, nephrin, JAM4, ESAM, Dll1, actin-binding proteins (synaptopodin, alpha-actinin-4), and ion channels (BKCa/Slo1, NaV1.8, GLT-1) to regulate surface expression; it is subject to PTMs including p90RSK-mediated S741 phosphorylation, K931 deSUMOylation (controlling nuclear translocation and EC activation/ER stress), caspase-3/7 cleavage at Asp761 (releasing junctional contacts during apoptosis), SRC-mediated phosphorylation (inhibiting a latent MAGI1-PP2A tumor-suppressive complex), and OGT-mediated O-GlcNAcylation (stabilizing expression); its disruption by viral oncoproteins (HPV E6 causing proteasomal degradation, Ad9 E4-ORF1 causing cytoplasmic sequestration, HTLV-1 Tax1 causing fraction mislocalization) results in loss of tight junction integrity and deregulation of cell growth, establishing MAGI1 as a central junction organizer and tumor suppressor that modulates Wnt/β-catenin, PI3K/AKT, MAPK/ERK, RhoA/ROCK, and Hippo signaling pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAGI1 is a multi-domain MAGUK scaffolding protein with an inverted domain architecture (N-terminal GuK, two WW domains, and multiple PDZ domains) that organizes epithelial and endothelial cell-cell junctions and assembles signaling complexes through its modular interaction surfaces [#0]. At junctions it engages the cadherin/catenin machinery—binding beta-catenin through its fifth PDZ domain to drive membrane localization and complex with E-cadherin during junction formation [#1]—and localizes specifically to tight junctions alongside ZO-1 [#2]. Its PDZ and WW domains recruit a diverse repertoire of transmembrane and adhesion partners, including JAM4, ESAM, Dll1, nephrin, and the actin-associated proteins synaptopodin and alpha-actinin-4, linking junctional receptors to the cortical cytoskeleton [#7, #8, #9, #11, #12]. A central output of this scaffolding is activation of the small GTPase Rap1: MAGI1 binds the Rap1 GEF (PDZ-GEF1/Rap GEP) at junctions and is required for cadherin-engagement-induced Rap1 activation and junction maturation [#4, #10, #36]. MAGI1 also controls the surface abundance and stability of multiple membrane proteins, including ion channels and transporters (Slo1/BKCa, GLT-1, NaV1.8) and the coxsackie-adenovirus receptor, in a PDZ-domain-specific manner [#17, #25, #41, #27]. Through these activities MAGI1 functions as a tumor suppressor, stabilizing E-cadherin/beta-catenin junctions, suppressing Wnt signaling, and restraining migration and invasion in colorectal, gastric, and breast cancers [#24, #37, #44]; a latent MAGI1-PP2A complex dephosphorylates S6K to limit protein synthesis, an activity held off by SRC phosphorylation [#47]. In endothelium MAGI1 is heavily regulated by post-translational modification, with p90RSK-mediated S741 phosphorylation and SENP2-controlled K931 deSUMOylation governing Rap1-dependent EC activation, nuclear translocation, ATF6/ER-stress responses, permeability, and Hippo (LATS/YAP) signaling under disturbed flow [#40, #42]. MAGI1 is a prominent target of viral oncoproteins—HPV E6 (proteasomal degradation), Ad9 E4-ORF1 (cytoplasmic sequestration), and HTLV-1 Tax1 (mislocalization)—whose disruption of MAGI1 produces loss of tight junction integrity and deregulated growth [#3, #21, #31, #33], and it is cleaved by caspases-3/7 at Asp761 to release junctional contacts during apoptosis [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established MAGI1 as a structurally unusual MAGUK, defining the inverted domain layout (GuK, WW, PDZ) and splice-variant-dependent nuclear versus membrane partitioning that frames all later mechanistic work.\",\n      \"evidence\": \"cDNA cloning, domain mapping, and subcellular fractionation of splice variants\",\n      \"pmids\": [\"9395497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional role assigned to individual domains at this stage\", \"Nuclear function of the long isoform not mechanistically defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Localized MAGI1 specifically to tight junctions with ZO-1 rather than to adherens junctions, placing it as a candidate junction organizer distinct from other MAGUKs.\",\n      \"evidence\": \"Immunofluorescence, fractionation, and Ca2+-switch assay in epithelial cells\",\n      \"pmids\": [\"10618722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners at tight junctions not yet identified\", \"Mechanism of recruitment unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified beta-catenin/E-cadherin binding via the fifth PDZ domain as the determinant of MAGI1 membrane localization, linking it directly to the cadherin junctional machinery.\",\n      \"evidence\": \"Co-IP, GFP localization, and yeast two-hybrid in MDCK cells\",\n      \"pmids\": [\"10772923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a downstream signaling output\", \"Relationship between PDZ5-catenin binding and tight junction localization unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined MAGI1 as a scaffold for a Rap1-specific GEF at junctions, establishing the first link between MAGI1 scaffolding and small-GTPase signaling.\",\n      \"evidence\": \"Cell-free binding, co-IP, with MAGUK specificity controls\",\n      \"pmids\": [\"11168587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Rap1 GEF recruitment not yet tested\", \"No loss-of-function data\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that MAGI1 is functionally required for cadherin-engagement-induced Rap1 activation and adhesion maturation, converting the earlier binding observation into a causal pathway.\",\n      \"evidence\": \"siRNA knockdown, GTP-Rap1 pulldown, FRET biosensor in endothelial cells\",\n      \"pmids\": [\"16339077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rap1 output applies across all junction types not addressed\", \"Upstream regulators of the MAGI1-GEF complex unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Expanded the partner repertoire to adhesion and slit-diaphragm proteins (nephrin, JAM4, Dll1) with domain-resolved binding, showing MAGI1 organizes multiple junctional/adhesion modules.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, immunoelectron microscopy, co-IP across systems\",\n      \"pmids\": [\"16155592\", \"12773569\", \"15908431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for each interaction not yet established\", \"Combinatorial assembly of tripartite complexes not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified caspase-3/7 cleavage at Asp761 as the mechanism by which MAGI1 junctional anchoring is dismantled during apoptosis, linking the scaffold to programmed cell death.\",\n      \"evidence\": \"In vitro caspase cleavage, Asp761Ala mutagenesis, apoptosis assays\",\n      \"pmids\": [\"17191119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of cleavage in tissue not defined\", \"Fate and function of the resulting fragments only partially characterized [#15]\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established MAGI1 as a tumor suppressor that stabilizes E-cadherin/beta-catenin junctions and suppresses Wnt signaling and invasion in vivo.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown, Wnt reporter, xenograft/orthotopic models in colorectal cancer\",\n      \"pmids\": [\"21666716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of Wnt suppression not fully resolved\", \"Generality across cancer types tested only later\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized MAGI1's role in membrane-protein surface regulation, showing PDZ-mediated control of ion channel and transporter surface abundance (Slo1, GLT-1).\",\n      \"evidence\": \"Yeast two-hybrid/GST pulldown, biotinylation, electrophysiology, glutamate uptake, siRNA\",\n      \"pmids\": [\"19403801\", \"21426345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery downstream of MAGI1 binding not defined\", \"Whether retention vs internalization is the mechanism unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the structural and thermodynamic basis of MAGI1 PDZ1 binding to HPV16 E6, revealing a disorder-to-order transition and allosteric tail dynamics governing affinity.\",\n      \"evidence\": \"NMR structure, backbone dynamics, ITC, and mutagenesis\",\n      \"pmids\": [\"21238461\", \"25590897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same dynamics govern endogenous ligand binding not tested\", \"Functional impact of the C-terminal extension in cells unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided in vivo genetic evidence that MAGI1 supports slit-diaphragm integrity via nephrin membrane localization and contact-induced Rap1 activation, with disease relevance in compound mutants.\",\n      \"evidence\": \"Podocyte knockdown, global and compound knockout mice, Rap1 assays, Drosophila screen\",\n      \"pmids\": [\"27707879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-gene knockout is phenotypically normal, indicating redundancy not yet mapped\", \"Tissue-specific requirements beyond glomerulus unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the structural determinant of MAGI1-versus-MAGI2 specificity for nephrin, explaining paralog-selective scaffolding through an atypical PDZ recognition mode.\",\n      \"evidence\": \"MAGI1-PDZ3/nephrin-PBM crystal structure with gain-of-function mutagenesis\",\n      \"pmids\": [\"30006415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other partners use similar atypical recognition not tested\", \"In vivo consequence of disrupting the Gly(-3) contact unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped MAGI1 as a hub for flow- and stress-responsive endothelial signaling controlled by p90RSK phosphorylation (S741) and SENP2-dependent deSUMOylation (K931), connecting it to EC activation, permeability, ER stress, and Hippo signaling.\",\n      \"evidence\": \"Phosphoproteomics, PTM-site mutants, SUMOylation/permeability assays, Magi1+/- mice\",\n      \"pmids\": [\"30944250\", \"33304925\", \"31035633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear MAGI1 complexes execute transcriptional effects not fully defined\", \"Integration of Rap1, Hippo, and ER-stress outputs into a single circuit unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended MAGI1 function to focal adhesions and RhoA/Rac1 signaling and dissected its tumor-suppressive mechanism via an AMOTL2/p38 stress pathway.\",\n      \"evidence\": \"siRNA, colocalization, GTPase activation assays, AMOTL2 knockout and p38 inhibitor rescue, in vivo angiogenesis\",\n      \"pmids\": [\"33823745\", \"33707576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link from MAGI1 to AMOTL2 sequestration not fully mapped\", \"Reconciliation of RhoA-activating and RhoA-suppressing contexts unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a latent MAGI1-PP2A tumor-suppressive complex that dephosphorylates S6K, held inactive by SRC phosphorylation, providing a druggable mechanism in IDH-mutant cholangiocarcinoma.\",\n      \"evidence\": \"Unbiased phosphoproteomics, co-IP, PP2A activity and S6K assays, patient-derived xenografts\",\n      \"pmids\": [\"38748774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SRC phospho-site(s) on MAGI1 not pinpointed in the timeline\", \"Whether the PP2A complex operates outside cholangiocarcinoma untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Characterized the biophysical logic of the MAGI1 WW tandem, showing avidity-driven bidentate binding via conformational selection tuned by pH and inter-motif linker length.\",\n      \"evidence\": \"Time-resolved kinetics, ITC, and linker-swap binding assays\",\n      \"pmids\": [\"41786191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological bidentate ligands engaging both WW domains not identified\", \"In-cell relevance of pH-tuning not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAGI1's many domain-specific interactions, PTM states, and pathway outputs (Rap1, Wnt, Hippo, RhoA, PI3K/AKT, MAPK/ERK) are coordinated into context-specific programs in distinct tissues remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking junctional, cytosolic, and nuclear MAGI1 pools\", \"Stoichiometry and competition among partners for shared PDZ/WW domains undefined\", \"Tissue-specific PTM regulation not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4, 7, 10, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 43]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 25, 41, 27, 48]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 9, 17, 41]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 40]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 7, 43]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10, 36, 39, 40, 42]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 2, 8, 9, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 21, 24, 47]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [29, 46]}\n    ],\n    \"complexes\": [\"MAGI1-PP2A complex\", \"glomerular slit diaphragm\", \"tight junction\"],\n    \"partners\": [\"CTNNB1\", \"PDZ-GEF1\", \"NPHS1\", \"JAM4\", \"ESAM\", \"PTEN\", \"ATF6\", \"ADAM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}