{"gene":"MAGI2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"MAGI-2 was identified as a binding partner of PTEN via an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 localizes to tight junctions in epithelial cell membranes and enhances PTEN's ability to suppress Akt activation, stabilizing PTEN protein.","method":"Yeast two-hybrid screen, co-immunoprecipitation, functional Akt suppression assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid discovery confirmed by pull-down, co-IP, and functional Akt suppression assay; independently replicated in multiple subsequent studies","pmids":["10760291"],"is_preprint":false},{"year":2001,"finding":"PTEN binding to MAGI-2 is regulated by phosphorylation at threonine residues T382 and T383 in PTEN's C-terminus: phosphorylation-incompetent PTEN mutants (T382A/T383A) show dramatically reduced expression due to proteasome-mediated degradation and display significantly greater binding affinity to MAGI-2, suggesting phosphorylation status controls PTEN recruitment to cell-cell junctions via MAGI-2.","method":"Site-directed mutagenesis, co-immunoprecipitation, proteasome inhibition assay, polyubiquitination detection","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with binding assay and proteasome pathway functional dissection in a single focused study","pmids":["11431330"],"is_preprint":false},{"year":2001,"finding":"The beta1-adrenergic receptor (beta1AR) C-terminus binds with high affinity to the first PDZ domain of MAGI-2. Co-expression of MAGI-2 with beta1AR constitutively associates the two proteins (enhanced by agonist), markedly increases agonist-induced beta1AR internalization (opposite to PSD-95 effect), and promotes association of beta1AR with beta-catenin.","method":"Overlay assay, pull-down, co-immunoprecipitation, immunofluorescence co-localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus pull-down plus functional internalization assay in same study; PDZ domain specificity mapped","pmids":["11526121"],"is_preprint":false},{"year":2002,"finding":"High-risk HPV E6 proteins target MAGI-2 for proteasome-mediated degradation via a specific interaction with one PDZ domain of MAGI-2; co-expression of that PDZ domain alone can protect full-length MAGI-2 from E6-mediated degradation.","method":"Co-expression degradation assay, PDZ domain competition experiment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional degradation assay with domain competition; single lab, two orthogonal approaches","pmids":["12140759"],"is_preprint":false},{"year":2003,"finding":"The delta2 glutamate receptor interacts with MAGI-2 (S-SCAM) at a PDZ domain; PKC-mediated phosphorylation of the receptor regulates this interaction. Co-expression of both proteins in COS7 cells caused drastic changes in delta2 receptor localization, indicating MAGI-2 controls intracellular trafficking of delta2 receptor.","method":"Co-immunoprecipitation, co-expression localization in COS7 cells, PKC phosphorylation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — co-IP and localization change shown in single lab; PKC regulation of binding demonstrated but limited mechanistic detail in abstract","pmids":["12589829"],"is_preprint":false},{"year":2004,"finding":"PTEN protein levels depend on the maintenance of the beta-catenin–MAGI-2 interaction at the cell membrane, with vinculin playing a critical role by preserving adherens junction integrity. In vinculin-null cells, MAGI-2 overexpression restored PTEN protein levels, and vinculin mutants that reinstated beta-catenin–MAGI-2 interaction also restored PTEN.","method":"Vinculin-null cell transfection, MAGI-2 overexpression rescue, E-cadherin blocking antibody, co-immunoprecipitation-linked PTEN stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic and biochemical approaches in same study; null cell rescue establishes causality","pmids":["15579911"],"is_preprint":false},{"year":2005,"finding":"MAGI-2 (S-SCAM) is a component of the nephrin multiprotein complex in podocytes: GST-nephrin cytoplasmic domain pull-down from glomerular lysates specifically retrieved MAGI-2, IQGAP1, CASK, alpha-actinin, alphaII spectrin, and betaII spectrin. MAGI-2 co-localizes with nephrin in podocyte foot processes and appears at junctional complexes after podocyte migration.","method":"GST pull-down with mass spectrometry identification, immunofluorescence co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — affinity pull-down plus MS identification plus immunofluorescence co-localization; developmental expression timing characterized","pmids":["15994232"],"is_preprint":false},{"year":2006,"finding":"MAGI-2 (S-SCAM) localizes to inhibitory synapses in rat hippocampal neurons where its WW domains bind beta-dystroglycan (beta-DG) and its WW and second PDZ domain bind neuroligin 2. MAGI-2, beta-DG, and neuroligin 2 form a tripartite complex in vitro, and MAGI-2 functions as a linker between the dystrophin glycoprotein complex and the neurexin-neuroligin complex at inhibitory synapses.","method":"Co-immunoprecipitation from rat brain, in vitro complex reconstitution, immunofluorescence in primary hippocampal neurons, domain-binding mapping","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP from brain plus in vitro reconstitution of tripartite complex plus immunofluorescence localization","pmids":["17059560"],"is_preprint":false},{"year":2006,"finding":"MAGI-2 interacts with stargazin and other TARPs (transmembrane AMPA receptor regulating proteins) via the C-terminal -TTPV motif of stargazin and the PDZ1, PDZ3, and PDZ5 domains of MAGI-2. Co-immunoprecipitation confirmed the MAGI-2/stargazin interaction in vivo from mouse cerebral cortex. Stargazin expression recruits MAGI-2 to cell membranes and cell-cell contact sites in a -TTPV motif-dependent manner.","method":"Yeast two-hybrid screening, co-immunoprecipitation from mouse brain, in vitro binding assay, transfection-based localization in HEK-293T cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo co-IP from mouse cortex, PDZ domain specificity mapped in vitro, functional localization demonstrated in cell-based assay","pmids":["16870733"],"is_preprint":false},{"year":2007,"finding":"MAGI-2 overexpression in hepatocellular carcinoma cells inhibits migration and proliferation through PTEN upregulation: MAGI-2 increases PTEN protein stability (not mRNA), leading to downregulation of p-FAK and p-Akt. The effect was lost when PTEN was silenced or in PTEN-null cells, and restored by PTEN transfection.","method":"Transfection of myc-MAGI-2, PTEN siRNA knockdown, co-immunoprecipitation, western blot for p-FAK and p-Akt, PTEN-null cell rescue","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis established via siRNA knockdown and null cell rescue, molecular interaction confirmed by co-IP, multiple orthogonal readouts","pmids":["17880912"],"is_preprint":false},{"year":2012,"finding":"S-SCAM/MAGI-2 is an essential scaffolding molecule for maintaining GluA2-containing AMPA receptors at synapses. Increasing S-SCAM levels in rat hippocampal neurons increased surface GluA2-containing AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlarged dendritic spines without affecting NMDAR EPSCs. Knockdown by RNAi caused loss of synaptic AMPARs and severe reduction of dendritic spine density. S-SCAM regulated AMPARs in a GluA2-dependent manner, independently of activity and PSD-95.","method":"RNA interference knockdown, overexpression in rat hippocampal neurons, electrophysiology (AMPAR and NMDAR EPSCs), surface AMPAR measurement","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional (OE and KD) manipulation with electrophysiology, spine imaging, and receptor biochemistry; multiple orthogonal readouts in single study","pmids":["22593065"],"is_preprint":false},{"year":2013,"finding":"MAGI2 overexpression enhances sensitivity of BEL-7404 hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN protein stability and decreasing its degradation, leading to reduced AKT phosphorylation. The pro-apoptotic effect of MAGI-2 was reversed by PTEN siRNA, confirming PTEN dependency.","method":"Myc-MAGI2 transfection, Annexin V apoptosis assay, PTEN siRNA knockdown, western blot for PTEN protein levels and p-AKT","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue by PTEN siRNA plus MAGI-2/PTEN interaction confirmed, single lab","pmids":["23754155"],"is_preprint":false},{"year":2014,"finding":"Magi-2 knockout mice develop progressive proteinuria, podocyte foot process effacement, loss of nephrin expression, podocyte hypertrophy, and die of renal failure by 3 months. MAGI-2 is required for kidney filter integrity and podocyte survival; parietal epithelial cells (PECs) are activated to form glomerular lesions following rapid podocyte loss.","method":"Homologous recombination knockout mouse, immunohistochemistry, electron microscopy, proteinuria assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive KO mouse with defined molecular and cellular phenotype, multiple histological and functional readouts","pmids":["25271328"],"is_preprint":false},{"year":2014,"finding":"Homozygous deletion of Magi2 in mice causes neonatal lethality due to podocyte morphological abnormalities and anuria. Loss of MAGI-2 function leads to significant decreases in nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, and enhanced expression of cathepsin L, which is critical for actin cytoskeleton rearrangement in podocytes.","method":"Constitutive knockout mouse, immunohistological analysis, expression analysis of slit diaphragm components","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with specific molecular downstream effects (dendrin nuclear translocation, cathepsin L upregulation) identified; independently replicates MAGI-2 kidney function","pmids":["25108225"],"is_preprint":false},{"year":2014,"finding":"MAGI-2 interacts with the USH1G protein SANS through SANS's sterile alpha motif (SAM) domain via an internal PDZ-binding motif, and this interaction is regulated by CK2 phosphorylation of SANS. MAGI-2 participates in clathrin-dependent endocytosis; phosphorylated SANS tightly regulates MAGI-2-mediated endocytosis. SANS-MAGI-2-mediated endocytosis also regulates ciliogenesis. The SANS-MAGI-2 complex localizes to the periciliary membrane complex in retinal photoreceptors. USH1G patient mutations in SANS that eliminate MAGI-2 binding deregulate endocytosis and disrupt photoreceptor cell function.","method":"Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, endocytosis assay, immunolocalization in retina, patient mutation functional analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, co-IP, RNAi with functional endocytosis readout, patient mutation validation, immunolocalization) in single study","pmids":["24608321"],"is_preprint":false},{"year":2015,"finding":"WT1 (Wilms' tumor suppressor) directly transcriptionally regulates Magi2 expression in podocytes, as identified by chromatin immunoprecipitation sequencing (ChIP-seq) of glomeruli combined with transcriptomic analysis of WT1 knockout mice. Functional assays in zebrafish confirmed Magi2 is required for normal embryonic kidney development.","method":"ChIP-seq from glomeruli, cDNA microarray of WT1 knockout mice, zebrafish morpholino knockdown","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq identifies WT1 binding at Magi2 locus; zebrafish functional knockdown validates requirement, single lab","pmids":["25556170"],"is_preprint":false},{"year":2019,"finding":"MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor RapGEF2, and this complex activates the small GTPase Rap1 in podocytes. MAGI2 congenital nephrotic syndrome (CNS) variants fail to form this complex and do not enhance Rap1 activation. Podocyte-specific RapGEF2 deletion in mice produces spontaneous glomerulosclerosis similar to MAGI2 KO. MAGI2 CNS variant-expressing human podocytes show severe actin cytoskeletal disorganization that is rescued by pharmacological Rap1 activation.","method":"Co-immunoprecipitation, Rap1 activation assay, podocyte-specific RapGEF2 conditional KO mouse, RNAi knockdown, pharmacological Rap1 activation rescue, immunostaining of patient kidney sections","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including KO mouse, patient mutation co-IP, Rap1 activity assay, and pharmacological rescue; mechanistic pathway placement established","pmids":["31171376"],"is_preprint":false},{"year":2020,"finding":"Podocyte-specific deficiency of MAGI-2 in mice abrogates localization of Nephrin and Neph1 at the slit diaphragm independently of other scaffold proteins. The PDZ domains of MAGI-2 are required for its interaction with slit diaphragm backbone proteins Nephrin and Neph1, as shown by co-immunoprecipitation and pull-down assays.","method":"Podocyte-specific MAGI-2 knockout mouse, co-immunoprecipitation, pull-down, immunofluorescence, super-resolution microscopy","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with specific molecular phenotype, PDZ domain requirement confirmed by biochemical assays; multiple orthogonal approaches","pmids":["33144214"],"is_preprint":false},{"year":2021,"finding":"MAGI2 can autonomously undergo liquid-liquid phase separation. Multivalent interactions among the MAGI2-Dendrin-CD2AP complex drive formation of highly dense slit diaphragm condensates that recruit Nephrin. A nephrotic syndrome-associated mutation of MAGI2 interferes with condensate formation and impairs Nephrin enrichment.","method":"In vitro phase separation assay, biochemical reconstitution of MAGI2-Dendrin-CD2AP complex, biophysical assays, cell biology condensate visualization, disease mutant analysis","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of phase separation, complex reconstitution, and disease mutant functional validation; multiple orthogonal biochemical and biophysical methods","pmids":["34330769"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the MAGI2 PDZ4 domain in complex with the PDZ-binding motif (PBM) of ARMS (ankyrin repeat-rich membrane spanning protein) was solved, revealing a canonical PDZ/PBM interaction at the αB/βB groove. Serial mutagenesis validated key contact residues. The conserved 'GLGF' motif in PSD-95-PDZ3 changes to 'GFGF' in the MAGI2-PDZ4/ARMS-PBM complex.","method":"X-ray crystallography, in vitro binding assays, site-directed mutagenesis","journal":"Neurochemistry international","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis validation; rigorous structural and biochemical characterization in one study","pmids":["34371146"],"is_preprint":false},{"year":2023,"finding":"MAGI2 deficiency induced by high-glucose activates TGF-β signaling, which decreases expression of anti-apoptotic proteins in podocytes. AAV-mediated enforced expression of MAGI2 in db/db mice protected podocytes from apoptosis and improved renal function, placing MAGI2 upstream of TGF-β-Smad3/nephrin pathway in podocyte survival.","method":"AAV transduction in db/db mice, high-glucose in vitro model, western blot for TGF-β signaling components and apoptotic proteins, renal function measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV rescue combined with in vitro mechanistic dissection; TGF-β pathway epistasis established but single lab","pmids":["37950637"],"is_preprint":false}],"current_model":"MAGI2 is a multi-PDZ/WW domain scaffold protein that stabilizes PTEN at the cell membrane (through PDZ2–PTEN C-terminal PDZ-binding motif interaction, regulated by PTEN phosphorylation at T382/T383) to suppress PI3K/Akt signaling; in podocytes it assembles a slit diaphragm condensate via liquid-liquid phase separation with Dendrin and CD2AP to anchor Nephrin and Neph1, activates Rap1 through a complex with RapGEF2, and functions downstream of the WT1 transcription factor, while in neurons it scaffolds AMPA receptor (GluA2-containing) maintenance, TARP/stargazin trafficking via PDZ1/3/5, beta1-adrenergic receptor internalization via PDZ1, and inhibitory synapse organization by linking beta-dystroglycan and neuroligin 2."},"narrative":{"mechanistic_narrative":"MAGI2 is a multi-PDZ/WW domain scaffold protein that organizes membrane-associated signaling complexes at cell-cell junctions, the podocyte slit diaphragm, and neuronal synapses [PMID:10760291, PMID:15994232, PMID:22593065]. A core function is stabilization of the tumor suppressor PTEN: the second PDZ domain of MAGI2 engages the PTEN C-terminal PDZ-binding motif, an interaction tuned by PTEN phosphorylation at T382/T383, which enhances PTEN protein stability and suppresses Akt activation [PMID:10760291, PMID:11431330]. This stabilization depends on an intact beta-catenin–MAGI2 interface at adherens junctions maintained by vinculin [PMID:15579911], and in hepatocellular carcinoma cells MAGI2 overexpression curbs migration and proliferation and sensitizes cells to apoptosis through PTEN-dependent downregulation of p-FAK and p-Akt [PMID:17880912, PMID:23754155]. In podocytes, MAGI2 is a transcriptional target of WT1 and is essential for kidney filter integrity: its loss in mice causes proteinuria, foot process effacement, loss of nephrin, and renal failure [PMID:25271328, PMID:25108225, PMID:25556170]. There it scaffolds the slit diaphragm by binding Nephrin and Neph1 through its PDZ domains [PMID:33144214], drives formation of slit diaphragm condensates via liquid-liquid phase separation with Dendrin and CD2AP that recruit Nephrin [PMID:34330769], and activates the small GTPase Rap1 through a complex with RapGEF2 to maintain podocyte actin organization [PMID:31171376]; congenital nephrotic syndrome variants disrupt these assemblies [PMID:31171376, PMID:34330769]. In neurons, MAGI2 maintains GluA2-containing AMPA receptors at synapses and controls dendritic spine density [PMID:22593065], traffics TARPs/stargazin via PDZ1/3/5 [PMID:16870733], links beta-dystroglycan and neuroligin 2 to organize inhibitory synapses [PMID:17059560], and mediates beta1-adrenergic receptor internalization via PDZ1 [PMID:11526121]. MAGI2 also participates in CK2-regulated, SANS-dependent clathrin endocytosis required for photoreceptor ciliogenesis, where USH1G patient mutations abolish MAGI2 binding [PMID:24608321].","teleology":[{"year":2000,"claim":"Established MAGI2's founding molecular role by showing it binds and stabilizes PTEN, linking a junctional scaffold to PI3K/Akt suppression.","evidence":"Yeast two-hybrid, co-IP, and Akt suppression assay in epithelial cells","pmids":["10760291"],"confidence":"High","gaps":["Did not define how PTEN recruitment is dynamically regulated","Physiological context beyond epithelial tight junctions unaddressed"]},{"year":2001,"claim":"Defined the regulatory switch for the MAGI2-PTEN interaction, showing PTEN C-terminal phosphorylation at T382/T383 controls binding affinity and protects PTEN from proteasomal degradation.","evidence":"Site-directed mutagenesis, co-IP, proteasome inhibition, polyubiquitination detection","pmids":["11431330"],"confidence":"High","gaps":["Kinase responsible for T382/T383 phosphorylation not identified","In vivo relevance of the phospho-switch untested"]},{"year":2001,"claim":"Extended MAGI2 beyond PTEN by mapping a high-affinity beta1AR–PDZ1 interaction that promotes receptor internalization, establishing MAGI2 as a GPCR trafficking scaffold.","evidence":"Overlay assay, pull-down, reciprocal co-IP, internalization assay","pmids":["11526121"],"confidence":"High","gaps":["Endogenous neuronal/cardiac context not examined","Mechanism coupling MAGI2 to the internalization machinery unresolved"]},{"year":2002,"claim":"Revealed MAGI2 as a viral oncoprotein target, with high-risk HPV E6 driving its proteasomal degradation through a single PDZ domain.","evidence":"Co-expression degradation assay with PDZ domain competition","pmids":["12140759"],"confidence":"Medium","gaps":["Functional consequence of MAGI2 loss for HPV transformation not established","Single-lab, two-approach study"]},{"year":2003,"claim":"Showed MAGI2 controls neurotransmitter receptor trafficking, binding delta2 glutamate receptor in a PKC-phosphorylation-dependent manner.","evidence":"Co-IP and co-expression localization in COS7 cells with PKC phosphorylation assay","pmids":["12589829"],"confidence":"Medium","gaps":["Limited mechanistic detail beyond localization change","Not validated in neurons"]},{"year":2004,"claim":"Connected junctional architecture to PTEN stability, demonstrating that vinculin-maintained beta-catenin–MAGI2 interaction at adherens junctions is required to sustain PTEN protein.","evidence":"Vinculin-null cell rescue, E-cadherin blocking antibody, co-IP-linked PTEN stability assay","pmids":["15579911"],"confidence":"High","gaps":["Direct structural basis of the beta-catenin–MAGI2 contact undefined","Did not address tissue-specific dependence"]},{"year":2005,"claim":"Placed MAGI2 within the podocyte slit diaphragm by identifying it as a component of the nephrin multiprotein complex, opening its renal biology.","evidence":"GST-nephrin pull-down with mass spectrometry and immunofluorescence in glomeruli","pmids":["15994232"],"confidence":"High","gaps":["Functional requirement in podocytes not yet tested","Direct vs indirect nephrin association unresolved at this stage"]},{"year":2006,"claim":"Defined MAGI2's role at inhibitory synapses, showing it bridges beta-dystroglycan and neuroligin 2 via its WW and PDZ domains into a tripartite complex.","evidence":"Co-IP from rat brain, in vitro reconstitution, domain mapping, neuronal immunofluorescence","pmids":["17059560"],"confidence":"High","gaps":["Functional consequence for inhibitory transmission not measured","Stoichiometry of the tripartite complex unknown"]},{"year":2006,"claim":"Identified the PDZ determinants for AMPA receptor regulation by mapping MAGI2 binding to the stargazin/TARP -TTPV motif through PDZ1/3/5.","evidence":"Yeast two-hybrid, co-IP from mouse cortex, in vitro binding, cell-based localization","pmids":["16870733"],"confidence":"High","gaps":["Physiological effect on synaptic AMPAR currents not yet shown","Selectivity among multiple PDZ domains not fully resolved"]},{"year":2007,"claim":"Established MAGI2 as a tumor-suppressive scaffold in cancer cells, with anti-migratory and anti-proliferative effects strictly dependent on PTEN stabilization.","evidence":"MAGI2 transfection, PTEN siRNA and PTEN-null rescue, p-FAK/p-Akt western blot in HCC cells","pmids":["17880912"],"confidence":"High","gaps":["In vivo tumor relevance not addressed","Whether MAGI2 is downregulated in primary tumors untested here"]},{"year":2012,"claim":"Demonstrated a functional, activity- and PSD-95-independent requirement for MAGI2 in maintaining GluA2-containing AMPA receptors and dendritic spines.","evidence":"Bidirectional RNAi/overexpression with electrophysiology, spine imaging, surface AMPAR measurement in hippocampal neurons","pmids":["22593065"],"confidence":"High","gaps":["Molecular link from MAGI2 to GluA2 surface retention not fully defined","In vivo behavioral consequence not examined"]},{"year":2014,"claim":"Provided definitive genetic proof that MAGI2 is essential for kidney filter integrity and podocyte survival through constitutive knockout phenotypes, identifying downstream dendrin nuclear translocation and cathepsin L upregulation.","evidence":"Two independent constitutive Magi2 KO mice with histology, EM, proteinuria, and slit diaphragm component analysis","pmids":["25271328","25108225"],"confidence":"High","gaps":["Cell-autonomous vs systemic contribution not separated by constitutive KO","Mechanism triggering dendrin translocation unresolved"]},{"year":2014,"claim":"Linked MAGI2 to a ciliopathy pathway, showing CK2-regulated SANS binding directs MAGI2-mediated clathrin endocytosis required for ciliogenesis and photoreceptor function.","evidence":"Y2H, co-IP, RNAi endocytosis assay, retinal immunolocalization, USH1G patient mutation analysis","pmids":["24608321"],"confidence":"High","gaps":["Endocytic cargo regulated by SANS-MAGI2 not defined","Direct role of MAGI2 in the endocytic machinery mechanistically incomplete"]},{"year":2015,"claim":"Placed Magi2 downstream of the master podocyte transcription factor WT1, providing a transcriptional basis for its glomerular expression and a developmental requirement.","evidence":"Glomerular ChIP-seq, WT1 KO microarray, zebrafish morpholino knockdown","pmids":["25556170"],"confidence":"Medium","gaps":["Direct WT1 binding element not functionally dissected","Single-lab transcriptional regulation evidence"]},{"year":2020,"claim":"Resolved how MAGI2 anchors the slit diaphragm, showing podocyte-specific loss abrogates Nephrin and Neph1 localization and that its PDZ domains directly engage these backbone proteins.","evidence":"Podocyte-specific KO mouse, co-IP, pull-down, super-resolution microscopy","pmids":["33144214"],"confidence":"High","gaps":["Whether scaffolding is sufficient or requires partner cooperativity untested in this study"]},{"year":2019,"claim":"Identified the signaling output of MAGI2 in podocytes, showing it forms a RapGEF2 complex to activate Rap1 and maintain actin organization, with disease variants failing to activate Rap1.","evidence":"Co-IP, Rap1 activity assay, podocyte-specific RapGEF2 KO mouse, CNS variant analysis, pharmacological Rap1 rescue","pmids":["31171376"],"confidence":"High","gaps":["How the MAGI2-RapGEF2 complex is spatially coupled to the slit diaphragm unclear","Rap1 effectors driving actin remodeling not delineated"]},{"year":2021,"claim":"Defined the biophysical principle of slit diaphragm assembly, showing MAGI2 undergoes liquid-liquid phase separation with Dendrin and CD2AP to form condensates that enrich Nephrin, disrupted by a nephrotic syndrome mutation.","evidence":"In vitro phase separation and complex reconstitution, biophysical assays, cellular condensate imaging, disease mutant analysis","pmids":["34330769"],"confidence":"High","gaps":["In vivo demonstration of condensates in podocytes not established","Regulation of condensate dynamics unknown"]},{"year":2021,"claim":"Provided atomic-resolution insight into MAGI2 ligand recognition by solving the PDZ4–ARMS PBM crystal structure and revealing a variant binding-groove motif.","evidence":"X-ray crystallography with mutagenesis validation of contact residues","pmids":["34371146"],"confidence":"High","gaps":["Functional role of the MAGI2-ARMS interaction in cells untested","Specificity rules across the other PDZ domains not generalized"]},{"year":2023,"claim":"Placed MAGI2 upstream of TGF-beta signaling in diabetic podocyte injury, with enforced MAGI2 expression protecting podocytes and improving renal function in db/db mice.","evidence":"AAV MAGI2 transduction in db/db mice, high-glucose in vitro model, TGF-beta/apoptotic protein western blots","pmids":["37950637"],"confidence":"Medium","gaps":["Direct molecular link from MAGI2 to TGF-beta pathway not defined","Single-lab in vivo evidence"]},{"year":null,"claim":"How MAGI2's distinct multidomain assemblies are selected and coordinated across tissues — junctional PTEN stabilization, podocyte condensate/Rap1 signaling, and synaptic receptor scaffolding — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of full-length MAGI2 with multiple ligands","Regulatory logic governing tissue-specific partner choice unknown","Whether PTEN and slit-diaphragm functions intersect in podocytes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,8,17,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,6,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"complexes":["slit diaphragm (MAGI2-Dendrin-CD2AP condensate)","nephrin multiprotein complex","MAGI2-RapGEF2 complex","beta-dystroglycan-MAGI2-neuroligin 2 complex"],"partners":["PTEN","NEPHRIN","NEPH1","RAPGEF2","CD2AP","STARGAZIN","NEUROLIGIN 2","BETA-CATENIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86UL8","full_name":"Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2","aliases":["Atrophin-1-interacting protein 1","AIP-1","Atrophin-1-interacting protein A","Membrane-associated guanylate kinase inverted 2","MAGI-2"],"length_aa":1455,"mass_kda":158.8,"function":"Seems to act as a scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins (By similarity). Plays a role in nerve growth factor (NGF)-induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth (By similarity). May play a role in regulating activin-mediated signaling in neuronal cells (By similarity). Enhances the ability of PTEN to suppress AKT1 activation (PubMed:10760291). Plays a role in receptor-mediated clathrin-dependent endocytosis which is required for ciliogenesis (By similarity)","subcellular_location":"Cytoplasm; Late endosome; Synapse, synaptosome; Cell membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cell projection, cilium; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Photoreceptor inner segment; Cell projection, cilium, photoreceptor outer segment","url":"https://www.uniprot.org/uniprotkb/Q86UL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAGI2","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":[],"url":"https://opencell.sf.czbiohub.org/search/MAGI2","total_profiled":1310},"omim":[{"mim_id":"621292","title":"GLIOBLASTOMA-DOWNREGULATED RNA, NONCODING; 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MAGI2 (S-SCAM) in the gut-brain axis.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36685848","citation_count":9,"is_preprint":false},{"pmid":"27543977","id":"PMC_27543977","title":"MAGI-2 Is a Sensitive and Specific Marker of Prostatic Adenocarcinoma:  A Comparison With AMACR.","date":"2016","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27543977","citation_count":8,"is_preprint":false},{"pmid":"34484334","id":"PMC_34484334","title":"lncRNA MAGI2-AS3 Exerts Antioncogenic Roles in Hepatocellular Carcinoma via Regulating the miR-519c-3p/TXNIP Axis.","date":"2021","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34484334","citation_count":8,"is_preprint":false},{"pmid":"33323781","id":"PMC_33323781","title":"Polymorphism in the MAGI2 Gene Modifies the Effect of Amyloid β on Neurodegeneration.","date":"2021","source":"Alzheimer disease and associated disorders","url":"https://pubmed.ncbi.nlm.nih.gov/33323781","citation_count":8,"is_preprint":false},{"pmid":"36852700","id":"PMC_36852700","title":"Hypermethylation-Mediated lncRNA MAGI2-AS3 Downregulation Facilitates Malignant Progression of Laryngeal Squamous Cell Carcinoma via Interacting With SPT6.","date":"2023","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/36852700","citation_count":7,"is_preprint":false},{"pmid":"32167077","id":"PMC_32167077","title":"MAGI-2 downregulation: a potential predictor of tumor progression and early recurrence in Han Chinese patients with prostate cancer.","date":"2020","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/32167077","citation_count":7,"is_preprint":false},{"pmid":"34026068","id":"PMC_34026068","title":"lncRNA MAGI2-AS3 overexpression had antitumor effect on Hepatic cancer via miRNA-23a-3p/PTEN axis.","date":"2021","source":"Food science & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/34026068","citation_count":7,"is_preprint":false},{"pmid":"37102649","id":"PMC_37102649","title":"Role of lncRNA MAGI2-AS3 in lipopolysaccharide-induced nucleus pulposus cells injury by regulating miR-374b-5p/interleukin-10 axis.","date":"2023","source":"Immunity, inflammation and disease","url":"https://pubmed.ncbi.nlm.nih.gov/37102649","citation_count":6,"is_preprint":false},{"pmid":"38277283","id":"PMC_38277283","title":"Long non-coding RNAs PTENP1, GNG12-AS1, MAGI2-AS3 and MEG3 as tumor suppressors in breast cancer and their associations with clinicopathological parameters.","date":"2024","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/38277283","citation_count":6,"is_preprint":false},{"pmid":"35126958","id":"PMC_35126958","title":"LncRNA MAGI2-As3 Suppresses the Proliferation and Invasion of Cervical Cancer by Sponging MiR-15b.","date":"2022","source":"Journal of healthcare engineering","url":"https://pubmed.ncbi.nlm.nih.gov/35126958","citation_count":5,"is_preprint":false},{"pmid":"37551766","id":"PMC_37551766","title":"Targeting MAGI2-AS3-modulated Akt-dependent ATP-binding cassette transporters as a possible strategy to reverse temozolomide resistance in temozolomide-resistant glioblastoma cells.","date":"2023","source":"Drug development research","url":"https://pubmed.ncbi.nlm.nih.gov/37551766","citation_count":5,"is_preprint":false},{"pmid":"34237299","id":"PMC_34237299","title":"GLIDR promotes the progression of glioma by regulating the miR-4677-3p/MAGI2 axis.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34237299","citation_count":5,"is_preprint":false},{"pmid":"35294925","id":"PMC_35294925","title":"The TLR4/NF-κB/MAGI-2 signaling pathway mediates postoperative delirium.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/35294925","citation_count":4,"is_preprint":false},{"pmid":"33713943","id":"PMC_33713943","title":"Comparative study of immunohistochemical expression of ERG and MAGI2 in prostatic carcinoma.","date":"2021","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33713943","citation_count":4,"is_preprint":false},{"pmid":"38806109","id":"PMC_38806109","title":"BMSC derived EVs inhibit colorectal Cancer progression by transporting MAGI2-AS3 or something similar.","date":"2024","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38806109","citation_count":4,"is_preprint":false},{"pmid":"35656441","id":"PMC_35656441","title":"MAGI2-AS3 restrains proliferation, glycolysis, and triggers apoptosis in acute lymphoblastic leukemia via regulating miR-452-5p/FOXN3 pathway.","date":"2022","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35656441","citation_count":3,"is_preprint":false},{"pmid":"38084836","id":"PMC_38084836","title":"LncRNA MAGI2-AS3 inhibites tumor progression by up-regulating STAM via interacting with miR-142-3p in clear cell renal cell carcinoma.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/38084836","citation_count":3,"is_preprint":false},{"pmid":"34371146","id":"PMC_34371146","title":"Crystal structure of the PDZ4 domain of MAGI2 in complex with PBM of ARMS reveals a canonical PDZ recognition mode.","date":"2021","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/34371146","citation_count":3,"is_preprint":false},{"pmid":"40563084","id":"PMC_40563084","title":"The differential expression of MAGI2 in glomerulopathies and its application as a molecular discriminator of podocytopathies.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40563084","citation_count":2,"is_preprint":false},{"pmid":"37196468","id":"PMC_37196468","title":"Role of MAGI2-AS3 in malignant and non-malignant disorders.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/37196468","citation_count":2,"is_preprint":false},{"pmid":"40247354","id":"PMC_40247354","title":"LncRNA MAGI2-AS3 promotes the progression of atherosclerosis by sponging miR-525-5p.","date":"2025","source":"Journal of cardiothoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/40247354","citation_count":2,"is_preprint":false},{"pmid":"39523104","id":"PMC_39523104","title":"[LncRNA MAGI2-AS3 enhances cisplatin sensitivity of non-small cell lung cancer cells by regulating the miR-1269a/PTEN/AKT pathway].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39523104","citation_count":2,"is_preprint":false},{"pmid":"30535759","id":"PMC_30535759","title":"The MAGI2 gene polymorphism rs2160322 is associated with Graves' disease but not with Hashimoto's thyroiditis.","date":"2018","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30535759","citation_count":2,"is_preprint":false},{"pmid":"34375487","id":"PMC_34375487","title":"Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/34375487","citation_count":2,"is_preprint":false},{"pmid":"26030165","id":"PMC_26030165","title":"Seizure Disorder in a Patient with a 5.09 Mb 7q11.23-q21.11 Microdeletion Including the MAGI2 Gene.","date":"2014","source":"Journal of the Association of Genetic Technologists","url":"https://pubmed.ncbi.nlm.nih.gov/26030165","citation_count":2,"is_preprint":false},{"pmid":"37602452","id":"PMC_37602452","title":"Long Noncoding RNA MAGI2-AS3 Represses Cell Progression in Clear Cell Renal Cell Carcinoma by Modulating the miR-629-5p/PRDM16 Axis.","date":"2023","source":"Critical reviews in eukaryotic gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/37602452","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55193,"output_tokens":5713,"usd":0.125637,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14291,"output_tokens":5524,"usd":0.104777,"stage2_stop_reason":"end_turn"},"total_usd":0.230414,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI-2 was identified as a binding partner of PTEN via an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-2 localizes to tight junctions in epithelial cell membranes and enhances PTEN's ability to suppress Akt activation, stabilizing PTEN protein.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, functional Akt suppression assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid discovery confirmed by pull-down, co-IP, and functional Akt suppression assay; independently replicated in multiple subsequent studies\",\n      \"pmids\": [\"10760291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTEN binding to MAGI-2 is regulated by phosphorylation at threonine residues T382 and T383 in PTEN's C-terminus: phosphorylation-incompetent PTEN mutants (T382A/T383A) show dramatically reduced expression due to proteasome-mediated degradation and display significantly greater binding affinity to MAGI-2, suggesting phosphorylation status controls PTEN recruitment to cell-cell junctions via MAGI-2.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, proteasome inhibition assay, polyubiquitination detection\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with binding assay and proteasome pathway functional dissection in a single focused study\",\n      \"pmids\": [\"11431330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The beta1-adrenergic receptor (beta1AR) C-terminus binds with high affinity to the first PDZ domain of MAGI-2. Co-expression of MAGI-2 with beta1AR constitutively associates the two proteins (enhanced by agonist), markedly increases agonist-induced beta1AR internalization (opposite to PSD-95 effect), and promotes association of beta1AR with beta-catenin.\",\n      \"method\": \"Overlay assay, pull-down, co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus pull-down plus functional internalization assay in same study; PDZ domain specificity mapped\",\n      \"pmids\": [\"11526121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"High-risk HPV E6 proteins target MAGI-2 for proteasome-mediated degradation via a specific interaction with one PDZ domain of MAGI-2; co-expression of that PDZ domain alone can protect full-length MAGI-2 from E6-mediated degradation.\",\n      \"method\": \"Co-expression degradation assay, PDZ domain competition experiment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional degradation assay with domain competition; single lab, two orthogonal approaches\",\n      \"pmids\": [\"12140759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The delta2 glutamate receptor interacts with MAGI-2 (S-SCAM) at a PDZ domain; PKC-mediated phosphorylation of the receptor regulates this interaction. Co-expression of both proteins in COS7 cells caused drastic changes in delta2 receptor localization, indicating MAGI-2 controls intracellular trafficking of delta2 receptor.\",\n      \"method\": \"Co-immunoprecipitation, co-expression localization in COS7 cells, PKC phosphorylation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — co-IP and localization change shown in single lab; PKC regulation of binding demonstrated but limited mechanistic detail in abstract\",\n      \"pmids\": [\"12589829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PTEN protein levels depend on the maintenance of the beta-catenin–MAGI-2 interaction at the cell membrane, with vinculin playing a critical role by preserving adherens junction integrity. In vinculin-null cells, MAGI-2 overexpression restored PTEN protein levels, and vinculin mutants that reinstated beta-catenin–MAGI-2 interaction also restored PTEN.\",\n      \"method\": \"Vinculin-null cell transfection, MAGI-2 overexpression rescue, E-cadherin blocking antibody, co-immunoprecipitation-linked PTEN stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic and biochemical approaches in same study; null cell rescue establishes causality\",\n      \"pmids\": [\"15579911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI-2 (S-SCAM) is a component of the nephrin multiprotein complex in podocytes: GST-nephrin cytoplasmic domain pull-down from glomerular lysates specifically retrieved MAGI-2, IQGAP1, CASK, alpha-actinin, alphaII spectrin, and betaII spectrin. MAGI-2 co-localizes with nephrin in podocyte foot processes and appears at junctional complexes after podocyte migration.\",\n      \"method\": \"GST pull-down with mass spectrometry identification, immunofluorescence co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — affinity pull-down plus MS identification plus immunofluorescence co-localization; developmental expression timing characterized\",\n      \"pmids\": [\"15994232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAGI-2 (S-SCAM) localizes to inhibitory synapses in rat hippocampal neurons where its WW domains bind beta-dystroglycan (beta-DG) and its WW and second PDZ domain bind neuroligin 2. MAGI-2, beta-DG, and neuroligin 2 form a tripartite complex in vitro, and MAGI-2 functions as a linker between the dystrophin glycoprotein complex and the neurexin-neuroligin complex at inhibitory synapses.\",\n      \"method\": \"Co-immunoprecipitation from rat brain, in vitro complex reconstitution, immunofluorescence in primary hippocampal neurons, domain-binding mapping\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP from brain plus in vitro reconstitution of tripartite complex plus immunofluorescence localization\",\n      \"pmids\": [\"17059560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAGI-2 interacts with stargazin and other TARPs (transmembrane AMPA receptor regulating proteins) via the C-terminal -TTPV motif of stargazin and the PDZ1, PDZ3, and PDZ5 domains of MAGI-2. Co-immunoprecipitation confirmed the MAGI-2/stargazin interaction in vivo from mouse cerebral cortex. Stargazin expression recruits MAGI-2 to cell membranes and cell-cell contact sites in a -TTPV motif-dependent manner.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation from mouse brain, in vitro binding assay, transfection-based localization in HEK-293T cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo co-IP from mouse cortex, PDZ domain specificity mapped in vitro, functional localization demonstrated in cell-based assay\",\n      \"pmids\": [\"16870733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MAGI-2 overexpression in hepatocellular carcinoma cells inhibits migration and proliferation through PTEN upregulation: MAGI-2 increases PTEN protein stability (not mRNA), leading to downregulation of p-FAK and p-Akt. The effect was lost when PTEN was silenced or in PTEN-null cells, and restored by PTEN transfection.\",\n      \"method\": \"Transfection of myc-MAGI-2, PTEN siRNA knockdown, co-immunoprecipitation, western blot for p-FAK and p-Akt, PTEN-null cell rescue\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via siRNA knockdown and null cell rescue, molecular interaction confirmed by co-IP, multiple orthogonal readouts\",\n      \"pmids\": [\"17880912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S-SCAM/MAGI-2 is an essential scaffolding molecule for maintaining GluA2-containing AMPA receptors at synapses. Increasing S-SCAM levels in rat hippocampal neurons increased surface GluA2-containing AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlarged dendritic spines without affecting NMDAR EPSCs. Knockdown by RNAi caused loss of synaptic AMPARs and severe reduction of dendritic spine density. S-SCAM regulated AMPARs in a GluA2-dependent manner, independently of activity and PSD-95.\",\n      \"method\": \"RNA interference knockdown, overexpression in rat hippocampal neurons, electrophysiology (AMPAR and NMDAR EPSCs), surface AMPAR measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional (OE and KD) manipulation with electrophysiology, spine imaging, and receptor biochemistry; multiple orthogonal readouts in single study\",\n      \"pmids\": [\"22593065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAGI2 overexpression enhances sensitivity of BEL-7404 hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN protein stability and decreasing its degradation, leading to reduced AKT phosphorylation. The pro-apoptotic effect of MAGI-2 was reversed by PTEN siRNA, confirming PTEN dependency.\",\n      \"method\": \"Myc-MAGI2 transfection, Annexin V apoptosis assay, PTEN siRNA knockdown, western blot for PTEN protein levels and p-AKT\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue by PTEN siRNA plus MAGI-2/PTEN interaction confirmed, single lab\",\n      \"pmids\": [\"23754155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Magi-2 knockout mice develop progressive proteinuria, podocyte foot process effacement, loss of nephrin expression, podocyte hypertrophy, and die of renal failure by 3 months. MAGI-2 is required for kidney filter integrity and podocyte survival; parietal epithelial cells (PECs) are activated to form glomerular lesions following rapid podocyte loss.\",\n      \"method\": \"Homologous recombination knockout mouse, immunohistochemistry, electron microscopy, proteinuria assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive KO mouse with defined molecular and cellular phenotype, multiple histological and functional readouts\",\n      \"pmids\": [\"25271328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Homozygous deletion of Magi2 in mice causes neonatal lethality due to podocyte morphological abnormalities and anuria. Loss of MAGI-2 function leads to significant decreases in nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, and enhanced expression of cathepsin L, which is critical for actin cytoskeleton rearrangement in podocytes.\",\n      \"method\": \"Constitutive knockout mouse, immunohistological analysis, expression analysis of slit diaphragm components\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with specific molecular downstream effects (dendrin nuclear translocation, cathepsin L upregulation) identified; independently replicates MAGI-2 kidney function\",\n      \"pmids\": [\"25108225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGI-2 interacts with the USH1G protein SANS through SANS's sterile alpha motif (SAM) domain via an internal PDZ-binding motif, and this interaction is regulated by CK2 phosphorylation of SANS. MAGI-2 participates in clathrin-dependent endocytosis; phosphorylated SANS tightly regulates MAGI-2-mediated endocytosis. SANS-MAGI-2-mediated endocytosis also regulates ciliogenesis. The SANS-MAGI-2 complex localizes to the periciliary membrane complex in retinal photoreceptors. USH1G patient mutations in SANS that eliminate MAGI-2 binding deregulate endocytosis and disrupt photoreceptor cell function.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, RNAi knockdown, endocytosis assay, immunolocalization in retina, patient mutation functional analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, co-IP, RNAi with functional endocytosis readout, patient mutation validation, immunolocalization) in single study\",\n      \"pmids\": [\"24608321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WT1 (Wilms' tumor suppressor) directly transcriptionally regulates Magi2 expression in podocytes, as identified by chromatin immunoprecipitation sequencing (ChIP-seq) of glomeruli combined with transcriptomic analysis of WT1 knockout mice. Functional assays in zebrafish confirmed Magi2 is required for normal embryonic kidney development.\",\n      \"method\": \"ChIP-seq from glomeruli, cDNA microarray of WT1 knockout mice, zebrafish morpholino knockdown\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq identifies WT1 binding at Magi2 locus; zebrafish functional knockdown validates requirement, single lab\",\n      \"pmids\": [\"25556170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor RapGEF2, and this complex activates the small GTPase Rap1 in podocytes. MAGI2 congenital nephrotic syndrome (CNS) variants fail to form this complex and do not enhance Rap1 activation. Podocyte-specific RapGEF2 deletion in mice produces spontaneous glomerulosclerosis similar to MAGI2 KO. MAGI2 CNS variant-expressing human podocytes show severe actin cytoskeletal disorganization that is rescued by pharmacological Rap1 activation.\",\n      \"method\": \"Co-immunoprecipitation, Rap1 activation assay, podocyte-specific RapGEF2 conditional KO mouse, RNAi knockdown, pharmacological Rap1 activation rescue, immunostaining of patient kidney sections\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including KO mouse, patient mutation co-IP, Rap1 activity assay, and pharmacological rescue; mechanistic pathway placement established\",\n      \"pmids\": [\"31171376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Podocyte-specific deficiency of MAGI-2 in mice abrogates localization of Nephrin and Neph1 at the slit diaphragm independently of other scaffold proteins. The PDZ domains of MAGI-2 are required for its interaction with slit diaphragm backbone proteins Nephrin and Neph1, as shown by co-immunoprecipitation and pull-down assays.\",\n      \"method\": \"Podocyte-specific MAGI-2 knockout mouse, co-immunoprecipitation, pull-down, immunofluorescence, super-resolution microscopy\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with specific molecular phenotype, PDZ domain requirement confirmed by biochemical assays; multiple orthogonal approaches\",\n      \"pmids\": [\"33144214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAGI2 can autonomously undergo liquid-liquid phase separation. Multivalent interactions among the MAGI2-Dendrin-CD2AP complex drive formation of highly dense slit diaphragm condensates that recruit Nephrin. A nephrotic syndrome-associated mutation of MAGI2 interferes with condensate formation and impairs Nephrin enrichment.\",\n      \"method\": \"In vitro phase separation assay, biochemical reconstitution of MAGI2-Dendrin-CD2AP complex, biophysical assays, cell biology condensate visualization, disease mutant analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of phase separation, complex reconstitution, and disease mutant functional validation; multiple orthogonal biochemical and biophysical methods\",\n      \"pmids\": [\"34330769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the MAGI2 PDZ4 domain in complex with the PDZ-binding motif (PBM) of ARMS (ankyrin repeat-rich membrane spanning protein) was solved, revealing a canonical PDZ/PBM interaction at the αB/βB groove. Serial mutagenesis validated key contact residues. The conserved 'GLGF' motif in PSD-95-PDZ3 changes to 'GFGF' in the MAGI2-PDZ4/ARMS-PBM complex.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, site-directed mutagenesis\",\n      \"journal\": \"Neurochemistry international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis validation; rigorous structural and biochemical characterization in one study\",\n      \"pmids\": [\"34371146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAGI2 deficiency induced by high-glucose activates TGF-β signaling, which decreases expression of anti-apoptotic proteins in podocytes. AAV-mediated enforced expression of MAGI2 in db/db mice protected podocytes from apoptosis and improved renal function, placing MAGI2 upstream of TGF-β-Smad3/nephrin pathway in podocyte survival.\",\n      \"method\": \"AAV transduction in db/db mice, high-glucose in vitro model, western blot for TGF-β signaling components and apoptotic proteins, renal function measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV rescue combined with in vitro mechanistic dissection; TGF-β pathway epistasis established but single lab\",\n      \"pmids\": [\"37950637\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGI2 is a multi-PDZ/WW domain scaffold protein that stabilizes PTEN at the cell membrane (through PDZ2–PTEN C-terminal PDZ-binding motif interaction, regulated by PTEN phosphorylation at T382/T383) to suppress PI3K/Akt signaling; in podocytes it assembles a slit diaphragm condensate via liquid-liquid phase separation with Dendrin and CD2AP to anchor Nephrin and Neph1, activates Rap1 through a complex with RapGEF2, and functions downstream of the WT1 transcription factor, while in neurons it scaffolds AMPA receptor (GluA2-containing) maintenance, TARP/stargazin trafficking via PDZ1/3/5, beta1-adrenergic receptor internalization via PDZ1, and inhibitory synapse organization by linking beta-dystroglycan and neuroligin 2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAGI2 is a multi-PDZ/WW domain scaffold protein that organizes membrane-associated signaling complexes at cell-cell junctions, the podocyte slit diaphragm, and neuronal synapses [#0, #6, #10]. A core function is stabilization of the tumor suppressor PTEN: the second PDZ domain of MAGI2 engages the PTEN C-terminal PDZ-binding motif, an interaction tuned by PTEN phosphorylation at T382/T383, which enhances PTEN protein stability and suppresses Akt activation [#0, #1]. This stabilization depends on an intact beta-catenin–MAGI2 interface at adherens junctions maintained by vinculin [#5], and in hepatocellular carcinoma cells MAGI2 overexpression curbs migration and proliferation and sensitizes cells to apoptosis through PTEN-dependent downregulation of p-FAK and p-Akt [#9, #11]. In podocytes, MAGI2 is a transcriptional target of WT1 and is essential for kidney filter integrity: its loss in mice causes proteinuria, foot process effacement, loss of nephrin, and renal failure [#12, #13, #15]. There it scaffolds the slit diaphragm by binding Nephrin and Neph1 through its PDZ domains [#17], drives formation of slit diaphragm condensates via liquid-liquid phase separation with Dendrin and CD2AP that recruit Nephrin [#18], and activates the small GTPase Rap1 through a complex with RapGEF2 to maintain podocyte actin organization [#16]; congenital nephrotic syndrome variants disrupt these assemblies [#16, #18]. In neurons, MAGI2 maintains GluA2-containing AMPA receptors at synapses and controls dendritic spine density [#10], traffics TARPs/stargazin via PDZ1/3/5 [#8], links beta-dystroglycan and neuroligin 2 to organize inhibitory synapses [#7], and mediates beta1-adrenergic receptor internalization via PDZ1 [#2]. MAGI2 also participates in CK2-regulated, SANS-dependent clathrin endocytosis required for photoreceptor ciliogenesis, where USH1G patient mutations abolish MAGI2 binding [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established MAGI2's founding molecular role by showing it binds and stabilizes PTEN, linking a junctional scaffold to PI3K/Akt suppression.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and Akt suppression assay in epithelial cells\",\n      \"pmids\": [\"10760291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how PTEN recruitment is dynamically regulated\", \"Physiological context beyond epithelial tight junctions unaddressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the regulatory switch for the MAGI2-PTEN interaction, showing PTEN C-terminal phosphorylation at T382/T383 controls binding affinity and protects PTEN from proteasomal degradation.\",\n      \"evidence\": \"Site-directed mutagenesis, co-IP, proteasome inhibition, polyubiquitination detection\",\n      \"pmids\": [\"11431330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for T382/T383 phosphorylation not identified\", \"In vivo relevance of the phospho-switch untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extended MAGI2 beyond PTEN by mapping a high-affinity beta1AR–PDZ1 interaction that promotes receptor internalization, establishing MAGI2 as a GPCR trafficking scaffold.\",\n      \"evidence\": \"Overlay assay, pull-down, reciprocal co-IP, internalization assay\",\n      \"pmids\": [\"11526121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous neuronal/cardiac context not examined\", \"Mechanism coupling MAGI2 to the internalization machinery unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed MAGI2 as a viral oncoprotein target, with high-risk HPV E6 driving its proteasomal degradation through a single PDZ domain.\",\n      \"evidence\": \"Co-expression degradation assay with PDZ domain competition\",\n      \"pmids\": [\"12140759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MAGI2 loss for HPV transformation not established\", \"Single-lab, two-approach study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed MAGI2 controls neurotransmitter receptor trafficking, binding delta2 glutamate receptor in a PKC-phosphorylation-dependent manner.\",\n      \"evidence\": \"Co-IP and co-expression localization in COS7 cells with PKC phosphorylation assay\",\n      \"pmids\": [\"12589829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mechanistic detail beyond localization change\", \"Not validated in neurons\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected junctional architecture to PTEN stability, demonstrating that vinculin-maintained beta-catenin–MAGI2 interaction at adherens junctions is required to sustain PTEN protein.\",\n      \"evidence\": \"Vinculin-null cell rescue, E-cadherin blocking antibody, co-IP-linked PTEN stability assay\",\n      \"pmids\": [\"15579911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of the beta-catenin–MAGI2 contact undefined\", \"Did not address tissue-specific dependence\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed MAGI2 within the podocyte slit diaphragm by identifying it as a component of the nephrin multiprotein complex, opening its renal biology.\",\n      \"evidence\": \"GST-nephrin pull-down with mass spectrometry and immunofluorescence in glomeruli\",\n      \"pmids\": [\"15994232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional requirement in podocytes not yet tested\", \"Direct vs indirect nephrin association unresolved at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined MAGI2's role at inhibitory synapses, showing it bridges beta-dystroglycan and neuroligin 2 via its WW and PDZ domains into a tripartite complex.\",\n      \"evidence\": \"Co-IP from rat brain, in vitro reconstitution, domain mapping, neuronal immunofluorescence\",\n      \"pmids\": [\"17059560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for inhibitory transmission not measured\", \"Stoichiometry of the tripartite complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the PDZ determinants for AMPA receptor regulation by mapping MAGI2 binding to the stargazin/TARP -TTPV motif through PDZ1/3/5.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP from mouse cortex, in vitro binding, cell-based localization\",\n      \"pmids\": [\"16870733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological effect on synaptic AMPAR currents not yet shown\", \"Selectivity among multiple PDZ domains not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established MAGI2 as a tumor-suppressive scaffold in cancer cells, with anti-migratory and anti-proliferative effects strictly dependent on PTEN stabilization.\",\n      \"evidence\": \"MAGI2 transfection, PTEN siRNA and PTEN-null rescue, p-FAK/p-Akt western blot in HCC cells\",\n      \"pmids\": [\"17880912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tumor relevance not addressed\", \"Whether MAGI2 is downregulated in primary tumors untested here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a functional, activity- and PSD-95-independent requirement for MAGI2 in maintaining GluA2-containing AMPA receptors and dendritic spines.\",\n      \"evidence\": \"Bidirectional RNAi/overexpression with electrophysiology, spine imaging, surface AMPAR measurement in hippocampal neurons\",\n      \"pmids\": [\"22593065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from MAGI2 to GluA2 surface retention not fully defined\", \"In vivo behavioral consequence not examined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided definitive genetic proof that MAGI2 is essential for kidney filter integrity and podocyte survival through constitutive knockout phenotypes, identifying downstream dendrin nuclear translocation and cathepsin L upregulation.\",\n      \"evidence\": \"Two independent constitutive Magi2 KO mice with histology, EM, proteinuria, and slit diaphragm component analysis\",\n      \"pmids\": [\"25271328\", \"25108225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs systemic contribution not separated by constitutive KO\", \"Mechanism triggering dendrin translocation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked MAGI2 to a ciliopathy pathway, showing CK2-regulated SANS binding directs MAGI2-mediated clathrin endocytosis required for ciliogenesis and photoreceptor function.\",\n      \"evidence\": \"Y2H, co-IP, RNAi endocytosis assay, retinal immunolocalization, USH1G patient mutation analysis\",\n      \"pmids\": [\"24608321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic cargo regulated by SANS-MAGI2 not defined\", \"Direct role of MAGI2 in the endocytic machinery mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed Magi2 downstream of the master podocyte transcription factor WT1, providing a transcriptional basis for its glomerular expression and a developmental requirement.\",\n      \"evidence\": \"Glomerular ChIP-seq, WT1 KO microarray, zebrafish morpholino knockdown\",\n      \"pmids\": [\"25556170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct WT1 binding element not functionally dissected\", \"Single-lab transcriptional regulation evidence\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how MAGI2 anchors the slit diaphragm, showing podocyte-specific loss abrogates Nephrin and Neph1 localization and that its PDZ domains directly engage these backbone proteins.\",\n      \"evidence\": \"Podocyte-specific KO mouse, co-IP, pull-down, super-resolution microscopy\",\n      \"pmids\": [\"33144214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffolding is sufficient or requires partner cooperativity untested in this study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the signaling output of MAGI2 in podocytes, showing it forms a RapGEF2 complex to activate Rap1 and maintain actin organization, with disease variants failing to activate Rap1.\",\n      \"evidence\": \"Co-IP, Rap1 activity assay, podocyte-specific RapGEF2 KO mouse, CNS variant analysis, pharmacological Rap1 rescue\",\n      \"pmids\": [\"31171376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the MAGI2-RapGEF2 complex is spatially coupled to the slit diaphragm unclear\", \"Rap1 effectors driving actin remodeling not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the biophysical principle of slit diaphragm assembly, showing MAGI2 undergoes liquid-liquid phase separation with Dendrin and CD2AP to form condensates that enrich Nephrin, disrupted by a nephrotic syndrome mutation.\",\n      \"evidence\": \"In vitro phase separation and complex reconstitution, biophysical assays, cellular condensate imaging, disease mutant analysis\",\n      \"pmids\": [\"34330769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of condensates in podocytes not established\", \"Regulation of condensate dynamics unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided atomic-resolution insight into MAGI2 ligand recognition by solving the PDZ4–ARMS PBM crystal structure and revealing a variant binding-groove motif.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis validation of contact residues\",\n      \"pmids\": [\"34371146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the MAGI2-ARMS interaction in cells untested\", \"Specificity rules across the other PDZ domains not generalized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed MAGI2 upstream of TGF-beta signaling in diabetic podocyte injury, with enforced MAGI2 expression protecting podocytes and improving renal function in db/db mice.\",\n      \"evidence\": \"AAV MAGI2 transduction in db/db mice, high-glucose in vitro model, TGF-beta/apoptotic protein western blots\",\n      \"pmids\": [\"37950637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from MAGI2 to TGF-beta pathway not defined\", \"Single-lab in vivo evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAGI2's distinct multidomain assemblies are selected and coordinated across tissues — junctional PTEN stabilization, podocyte condensate/Rap1 signaling, and synaptic receptor scaffolding — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of full-length MAGI2 with multiple ligands\", \"Regulatory logic governing tissue-specific partner choice unknown\", \"Whether PTEN and slit-diaphragm functions intersect in podocytes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 8, 17, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 6, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"slit diaphragm (MAGI2-Dendrin-CD2AP condensate)\",\n      \"nephrin multiprotein complex\",\n      \"MAGI2-RapGEF2 complex\",\n      \"beta-dystroglycan-MAGI2-neuroligin 2 complex\"\n    ],\n    \"partners\": [\n      \"PTEN\",\n      \"Nephrin\",\n      \"Neph1\",\n      \"RapGEF2\",\n      \"CD2AP\",\n      \"stargazin\",\n      \"neuroligin 2\",\n      \"beta-catenin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}