{"gene":"MAGI2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2000,"finding":"MAGI2 (renamed from AIP-1/atrophin interacting protein 1) binds PTEN through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI2, and this interaction enhances PTEN's ability to suppress Akt activation and stabilizes PTEN protein at the cell membrane.","method":"Yeast two-hybrid screening, 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 — reciprocal co-IP plus functional readout (Akt suppression), replicated across multiple subsequent studies","pmids":["10760291"],"is_preprint":false},{"year":2001,"finding":"PTEN binding to MAGI2 is regulated by phosphorylation at threonine 382 and 383 of PTEN; phosphorylation-incompetent PTEN mutants (T382A/T383A) show dramatically enhanced binding affinity to MAGI2 but reduced protein stability via proteasome-dependent polyubiquitination, suggesting PTEN recruitment to cell-cell junctions is regulated through C-terminal phosphorylation.","method":"Site-directed mutagenesis, pulldown assay, ubiquitination assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis combined with biochemical assays demonstrating the mechanistic link between phosphorylation state and MAGI2 binding affinity","pmids":["11431330"],"is_preprint":false},{"year":2001,"finding":"MAGI2 binds the beta1-adrenergic receptor (beta1AR) carboxyl terminus through its first PDZ domain, with the last few amino acids of the beta1AR C-terminus being the key determinants; this interaction is enhanced by agonist stimulation and markedly increases beta1AR internalization. MAGI2 also promotes physical association of beta1AR with beta-catenin.","method":"Overlay and pulldown assays, co-immunoprecipitation, immunofluorescence co-localization, domain-specific binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pulldown, co-IP, immunofluorescence) with defined functional consequence (enhanced internalization)","pmids":["11526121"],"is_preprint":false},{"year":2002,"finding":"High-risk HPV E6 proteins target MAGI2 for proteasome-mediated degradation through interaction with a specific PDZ domain of MAGI2; co-expression of this PDZ domain can protect full-length MAGI2 from E6-mediated degradation.","method":"Co-expression and degradation assays, domain competition experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — functional degradation assay with domain-level mechanistic detail, single lab","pmids":["12140759"],"is_preprint":false},{"year":2004,"finding":"Vinculin maintains PTEN protein levels by preserving the interaction of beta-catenin with MAGI2 at adherens junctions; loss of vinculin disrupts the beta-catenin–MAGI2 interaction, leading to PTEN destabilization and degradation.","method":"Genetic rescue experiments (vinculin-null cells), co-immunoprecipitation, transfection with vinculin mutants and E-cadherin fusion constructs, MAGI2 overexpression rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic and biochemical methods establishing the vinculin→beta-catenin→MAGI2→PTEN pathway","pmids":["15579911"],"is_preprint":false},{"year":2005,"finding":"MAGI2 (S-SCAM) is a component of the nephrin multiprotein complex at glomerular slit diaphragms; it is pulled down by the GST-nephrin cytoplasmic domain from glomerular lysates and co-localizes with nephrin in podocyte foot processes.","method":"GST pulldown with mass spectrometry, immunofluorescence co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — MS-confirmed pulldown combined with in vivo co-localization; replicated in subsequent knockout studies","pmids":["15994232"],"is_preprint":false},{"year":2003,"finding":"PKC-mediated phosphorylation of the delta2 glutamate receptor regulates its interaction with MAGI2 (S-SCAM), and co-expression of delta2 receptor with MAGI2 dramatically alters receptor localization in cells.","method":"Co-immunoprecipitation, co-expression in COS7 cells, immunolocalization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP with pharmacological evidence for phosphorylation regulation of the interaction","pmids":["12589829"],"is_preprint":false},{"year":2006,"finding":"MAGI2 (S-SCAM) localizes at inhibitory synapses and interacts with beta-dystroglycan (beta-DG) through its WW domains; MAGI2 WW domains and its second PDZ domain interact with neuroligin 2. Beta-DG, neuroligin 2, and MAGI2 form a tripartite complex in vitro, linking the dystrophin glycoprotein complex to the neurexin-neuroligin complex at inhibitory synapses.","method":"Yeast two-hybrid, co-immunoprecipitation from rat brain, in vitro complex reconstitution, immunofluorescence in hippocampal neurons","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple methods including in vitro reconstitution of tripartite complex and in vivo co-IP, clear domain mapping","pmids":["17059560"],"is_preprint":false},{"year":2006,"finding":"MAGI2 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 MAGI2; MAGI2 co-immunoprecipitates with stargazin in vivo from mouse cerebral cortex and stargazin expression recruits MAGI2 to cell membranes.","method":"Yeast two-hybrid, co-immunoprecipitation from mouse brain, in vitro domain mapping, co-expression in HEK-293T cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — in vivo co-IP confirmed by in vitro domain mapping and cell-based co-localization, multiple orthogonal approaches","pmids":["16870733"],"is_preprint":false},{"year":2007,"finding":"MAGI2 overexpression inhibits cell migration and proliferation in hepatocarcinoma cells by upregulating PTEN protein stability (not mRNA), leading to downregulation of p-FAK and p-Akt; the effect is attenuated in PTEN-null cells and rescued by PTEN transfection, confirming PTEN-dependent mechanism.","method":"Transfection/overexpression, migration and proliferation assays, western blot, siRNA knockdown of PTEN, co-immunoprecipitation","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 — functional KO/KD plus genetic rescue establishing PTEN dependence, single lab","pmids":["17880912"],"is_preprint":false},{"year":2008,"finding":"Hemizygous deletion within the MAGI2 gene (encoding the synaptic scaffolding protein) is associated with infantile spasms; MAGI2 interacts with Stargazin, a protein associated with epilepsy in the stargazer mouse.","method":"High-resolution genomic mapping of chromosomal deletions in patients, candidate gene analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic mapping identifies MAGI2 locus; interaction with Stargazin based on prior literature","pmids":["18565486"],"is_preprint":false},{"year":2012,"finding":"MAGI2 (S-SCAM) is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors; increasing MAGI2 levels selectively increases surface AMPAR levels and enlarges dendritic spines, while MAGI2 knockdown causes loss of synaptic AMPARs and severe reduction in dendritic spine density in rat hippocampal neurons. MAGI2 regulates AMPARs in a GluA2-dependent, activity-independent manner, and its overexpression hampers NMDA-induced AMPAR internalization and prevents LTD induction.","method":"RNAi knockdown, overexpression in hippocampal neurons, electrophysiology (AMPAR-mediated EPSC), dendritic spine imaging, surface AMPAR quantification","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — bidirectional loss- and gain-of-function with multiple orthogonal readouts (electrophysiology, spine morphology, surface receptor levels), clearly defined mechanism","pmids":["22593065"],"is_preprint":false},{"year":2013,"finding":"MiR-134/487b/655 cluster directly targets MAGI2 mRNA, suppressing MAGI2 expression to destabilize PTEN and promote TGF-β1-induced EMT and gefitinib resistance in lung adenocarcinoma cells.","method":"miRNA array, qRT-PCR, overexpression/knockdown of miRNAs, western blot for MAGI2 and PTEN, EMT markers, drug resistance assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct targeting demonstrated with functional consequences, but mechanism is indirect (miRNA suppresses MAGI2 which then destabilizes PTEN)","pmids":["24258346"],"is_preprint":false},{"year":2014,"finding":"MAGI2 is required for kidney filtration barrier integrity and podocyte survival in mice; MAGI2-null mice develop progressive proteinuria, podocyte foot process effacement, loss of nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, enhanced cathepsin L expression, and die of renal failure by 3 months.","method":"Homologous recombination knockout mice, immunohistochemistry, electron microscopy, proteinuria measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined molecular and cellular phenotypes, replicated in two independent KO mouse studies","pmids":["25271328"],"is_preprint":false},{"year":2014,"finding":"MAGI2-null mice show neonatal lethality with podocyte morphological abnormalities; loss of MAGI2 causes significant decreases in nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, and enhanced cathepsin L expression, which is critical for rearrangement of the actin cytoskeleton in podocytes.","method":"Homozygous gene deletion mouse model, immunohistological analysis, ultrastructural analysis","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — independent KO mouse study confirming and extending mechanistic findings of PMID 25271328","pmids":["25108225"],"is_preprint":false},{"year":2014,"finding":"Phosphorylation of the Usher syndrome protein SANS by CK2 at an internal PDZ-binding motif in its SAM domain regulates SANS-MAGI2 complex assembly; phosphorylated SANS tightly regulates MAGI2-mediated clathrin-dependent endocytosis, which in turn regulates ciliogenesis. USH1G patient mutations in SANS that eliminate MAGI2 binding deregulate endocytosis and disrupt photoreceptor cell function.","method":"Co-immunoprecipitation, RNAi depletion, kinase assay (CK2), endocytosis assays, localization in retinal photoreceptor cells, patient mutation analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including patient mutations, kinase regulation, and defined cellular phenotype (endocytosis, ciliogenesis)","pmids":["24608321"],"is_preprint":false},{"year":2015,"finding":"MAGI2 is a transcriptional target of WT1 (Wilms' tumor suppressor) in podocytes, and is required for normal development of the embryonic zebrafish kidney as shown by functional assays in zebrafish.","method":"ChIP-seq, cDNA microarray, zebrafish functional assays (morpholino knockdown)","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — integrated cistromic and transcriptomic analyses with in vivo functional validation in zebrafish","pmids":["25556170"],"is_preprint":false},{"year":2016,"finding":"MAGI2 mutations (frameshift and duplication) cause congenital nephrotic syndrome by disrupting podocyte MAGI2 expression, consistent with its essential role in interacting with nephrin and regulating podocyte cytoskeleton and slit diaphragm dynamics.","method":"Whole-exome sequencing of patients, immunohistochemistry of patient kidney sections","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — disease-causing mutations identified with confirmed protein loss in patient tissue, mechanistic interpretation based on prior functional data","pmids":["27932480"],"is_preprint":false},{"year":2019,"finding":"MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor RapGEF2; co-expression of RapGEF2 with wild-type but not MAGI2 CNS variants enhances Rap1 GTPase activation. Podocyte-specific RapGEF2 deletion in mice causes glomerulosclerosis similar to MAGI2 knockout, and pharmacological Rap1 activation rescues actin cytoskeletal defects in human podocytes expressing MAGI2 CNS mutations.","method":"Co-immunoprecipitation, Rap1 activation assays, podocyte-specific conditional knockout mice, pharmacological rescue, patient kidney immunostaining","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo genetic models, biochemical pathway validation, and pharmacological rescue establish the MAGI2-RapGEF2-Rap1 signaling axis","pmids":["31171376"],"is_preprint":false}],"current_model":"MAGI2 is a multi-PDZ domain scaffold protein that assembles multiprotein complexes at cell junctions (tight junctions, adherens junctions, synapses, and the kidney slit diaphragm), where it stabilizes PTEN by direct PDZ-domain interaction (PDZ2) to suppress PI3K-Akt signaling; forms complexes with nephrin and RapGEF2 to activate Rap1 GTPase signaling essential for podocyte integrity; scaffolds neurotransmitter receptors (AMPA receptors via TARPs, beta1AR, delta2 GluR, NMDA receptors) at synapses to regulate receptor trafficking and synaptic strength; and is regulated by phosphorylation (of its binding partners, e.g. PTEN T382/T383 and SANS-CK2) and by HPV E6-mediated proteasomal degradation."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying how PTEN is stabilized at cell membranes, this work established that MAGI2 directly binds PTEN through a PDZ2–PDZ-binding motif interaction, enhancing PTEN-mediated Akt suppression and defining MAGI2 as a PTEN scaffold.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and functional Akt suppression assays in mammalian cells","pmids":["10760291"],"confidence":"High","gaps":["Structural basis of PDZ2–PTEN interaction unresolved","In vivo significance of MAGI2-PTEN axis not yet tested in animal models"]},{"year":2001,"claim":"Addressing how the MAGI2–PTEN interaction is regulated, phosphorylation at PTEN T382/T383 was shown to control binding affinity to MAGI2 — dephosphorylated PTEN binds MAGI2 more tightly but becomes susceptible to proteasomal degradation, revealing a phosphorylation-dependent switch governing PTEN junctional recruitment.","evidence":"Site-directed mutagenesis, pulldown assays, and ubiquitination assays","pmids":["11431330"],"confidence":"High","gaps":["Kinase(s) responsible for T382/T383 phosphorylation in vivo not identified","Whether this regulation operates at specific junction types unclear"]},{"year":2001,"claim":"Extending MAGI2's scaffolding repertoire beyond PTEN, its PDZ1 domain was shown to bind the β1-adrenergic receptor C-terminus in an agonist-enhanced manner, promoting receptor internalization and linking MAGI2 to GPCR trafficking.","evidence":"Overlay assays, pulldown, co-immunoprecipitation, and immunofluorescence in transfected cells","pmids":["11526121"],"confidence":"High","gaps":["Physiological significance of MAGI2–β1AR interaction in cardiac tissue not tested","Whether MAGI2 scaffolds other GPCRs unknown"]},{"year":2002,"claim":"Revealing a mechanism by which HPV subverts cell polarity, high-risk HPV E6 proteins were shown to target MAGI2 for proteasome-mediated degradation via a specific PDZ domain interaction, which could be blocked by competitive expression of that domain.","evidence":"Co-expression and degradation assays with domain competition in cultured cells","pmids":["12140759"],"confidence":"Medium","gaps":["In vivo relevance during HPV-driven carcinogenesis not demonstrated","Which E3 ligase mediates E6-directed MAGI2 ubiquitination not identified"]},{"year":2004,"claim":"Establishing the junctional pathway that stabilizes PTEN, vinculin was shown to maintain the β-catenin–MAGI2 interaction at adherens junctions; loss of vinculin disrupts this complex, causing PTEN destabilization and degradation.","evidence":"Genetic rescue in vinculin-null cells, co-immunoprecipitation, and MAGI2 overexpression rescue","pmids":["15579911"],"confidence":"High","gaps":["Direct vs. indirect nature of vinculin's effect on MAGI2 assembly unclear","Whether this pathway operates in all epithelial tissues not tested"]},{"year":2005,"claim":"Identifying MAGI2 as a slit diaphragm component, it was found in the nephrin multiprotein complex at glomerular podocyte foot processes, establishing a non-neuronal scaffolding role for MAGI2 in kidney filtration.","evidence":"GST-nephrin pulldown with mass spectrometry and immunofluorescence co-localization in kidney sections","pmids":["15994232"],"confidence":"High","gaps":["Functional consequence of MAGI2 loss in podocytes not yet shown","Binding domains mediating MAGI2–nephrin interaction not mapped"]},{"year":2006,"claim":"Defining MAGI2's synaptic scaffolding architecture, two key interactions were mapped: MAGI2 bridges β-dystroglycan (via WW domains) and neuroligin-2 (via PDZ2) into a tripartite complex at inhibitory synapses, and separately interacts with stargazin/TARPs (via PDZ1/3/5) to scaffold AMPA receptor complexes at excitatory synapses.","evidence":"Yeast two-hybrid, co-immunoprecipitation from rodent brain, in vitro complex reconstitution, domain mapping in HEK-293T cells","pmids":["17059560","16870733"],"confidence":"High","gaps":["Functional consequence of disrupting the tripartite complex at inhibitory synapses not tested","Whether MAGI2 simultaneously engages all these partners in a single complex unknown"]},{"year":2008,"claim":"Linking MAGI2 to human neurological disease, hemizygous MAGI2 deletion was identified in patients with infantile spasms, consistent with its role in scaffolding stargazin/epilepsy-associated proteins.","evidence":"High-resolution genomic mapping of chromosomal deletions in patients with infantile spasms","pmids":["18565486"],"confidence":"Medium","gaps":["Causal role not proven by functional rescue","Whether MAGI2 haploinsufficiency alone is sufficient for epilepsy or requires additional hits unclear"]},{"year":2012,"claim":"Resolving the functional role of MAGI2 at excitatory synapses, bidirectional manipulation showed that MAGI2 is essential for maintaining surface GluA2-containing AMPA receptors and dendritic spine density, and its overexpression blocks NMDA-induced AMPAR internalization and LTD.","evidence":"RNAi knockdown and overexpression in rat hippocampal neurons with electrophysiology, spine imaging, and surface receptor quantification","pmids":["22593065"],"confidence":"High","gaps":["Whether MAGI2 regulation of AMPARs involves direct GluA2 binding or is entirely TARP-mediated not fully resolved","In vivo behavioral consequences of synaptic MAGI2 loss not tested"]},{"year":2014,"claim":"Demonstrating MAGI2's essential role in kidney filtration, two independent MAGI2-knockout mouse studies showed progressive proteinuria, podocyte foot process effacement, loss of nephrin and dendrin from slit diaphragms, dendrin nuclear translocation, upregulated cathepsin L, and renal failure, establishing MAGI2 as indispensable for podocyte integrity.","evidence":"Homologous recombination knockout mice analyzed by electron microscopy, immunohistochemistry, and proteinuria measurement","pmids":["25271328","25108225"],"confidence":"High","gaps":["Molecular mechanism linking MAGI2 loss to dendrin nuclear translocation not defined","Whether MAGI2 loss causes a primary signaling defect or structural disassembly is unclear"]},{"year":2014,"claim":"Connecting MAGI2 to sensory cell function, CK2 phosphorylation of the Usher syndrome protein SANS was shown to regulate SANS–MAGI2 complex assembly, controlling MAGI2-mediated clathrin-dependent endocytosis required for ciliogenesis; patient mutations in SANS that abolish MAGI2 binding deregulate endocytosis and disrupt photoreceptor function.","evidence":"Co-immunoprecipitation, CK2 kinase assays, endocytosis assays, patient mutation analysis in retinal photoreceptor cells","pmids":["24608321"],"confidence":"High","gaps":["Whether MAGI2 directly participates in clathrin coat assembly or acts indirectly through cargo sorting not resolved","Role of MAGI2 in other ciliated cell types not tested"]},{"year":2016,"claim":"Confirming clinical relevance, MAGI2 loss-of-function mutations (frameshift, duplication) were identified as a cause of congenital nephrotic syndrome in humans, with absent MAGI2 protein in patient kidney tissue.","evidence":"Whole-exome sequencing of patients with congenital nephrotic syndrome and immunohistochemistry of patient kidneys","pmids":["27932480"],"confidence":"Medium","gaps":["Number of families studied is small","Genotype-phenotype correlation across different MAGI2 mutations not established"]},{"year":2019,"claim":"Identifying the signaling pathway downstream of MAGI2 in podocytes, MAGI2 was shown to form a complex with RapGEF2 to activate Rap1 GTPase; disease-causing MAGI2 mutations disrupt this activation, podocyte-specific RapGEF2 deletion phenocopies MAGI2 loss, and pharmacological Rap1 activation rescues actin defects caused by MAGI2 mutations.","evidence":"Co-immunoprecipitation, Rap1 activation assays, podocyte-specific conditional knockout mice, pharmacological rescue in human podocytes","pmids":["31171376"],"confidence":"High","gaps":["Whether the MAGI2–RapGEF2–Rap1 axis operates in neurons or other cell types unknown","Structural basis of MAGI2–RapGEF2 interaction not determined"]},{"year":null,"claim":"Key unresolved questions include how MAGI2 coordinates its multiple PDZ domain interactions simultaneously, whether the PTEN-stabilizing and Rap1-activating functions are integrated or independent at podocyte junctions, and what molecular mechanisms link MAGI2 haploinsufficiency to epileptogenesis in humans.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length MAGI2 or multi-partner complexes","Relative contribution of PTEN stabilization vs. Rap1 activation to podocyte survival not dissected","Causal mechanism linking MAGI2 loss to infantile spasms not functionally validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,7,8,11,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4,5,7,8,11]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,9,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,8,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,5,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,14,16]}],"complexes":["Nephrin slit diaphragm complex","β-dystroglycan–neuroligin-2 complex","TARP/stargazin–AMPAR complex"],"partners":["PTEN","CTNNB1","NPHS1","RAPGEF2","NLGN2","DAG1","CACNG2","USH1G"],"other_free_text":[]},"mechanistic_narrative":"MAGI2 is a multi-PDZ domain scaffold protein that organizes signaling complexes at cell junctions and synapses, functioning in epithelial barrier integrity, synaptic receptor maintenance, and tumor suppression. At adherens junctions and the kidney slit diaphragm, MAGI2 stabilizes PTEN protein (via PDZ2-mediated binding regulated by PTEN C-terminal phosphorylation) to suppress PI3K-Akt signaling, and scaffolds nephrin and RapGEF2 to activate Rap1 GTPase signaling essential for podocyte cytoskeletal integrity; loss-of-function mutations in MAGI2 cause congenital nephrotic syndrome in humans [PMID:10760291, PMID:11431330, PMID:25271328, PMID:31171376, PMID:27932480]. At synapses, MAGI2 interacts with TARPs/stargazin, neuroligin-2, and β-dystroglycan to maintain surface AMPA receptor pools and dendritic spine density in a GluA2-dependent, activity-independent manner, and its hemizygous deletion is associated with infantile spasms [PMID:22593065, PMID:16870733, PMID:17059560, PMID:18565486]. MAGI2 is also targeted for proteasomal degradation by high-risk HPV E6 proteins and is subject to miRNA-mediated downregulation, linking its loss to epithelial-mesenchymal transition and drug resistance in cancer [PMID:12140759, PMID:24258346]."},"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; GLIDR","url":"https://www.omim.org/entry/621292"},{"mim_id":"617609","title":"NEPHROTIC SYNDROME, TYPE 15; NPHS15","url":"https://www.omim.org/entry/617609"},{"mim_id":"615943","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 3; MAGI3","url":"https://www.omim.org/entry/615943"},{"mim_id":"613729","title":"CHROMOSOME 7q11.23 DELETION SYNDROME, DISTAL, 1.2-MB","url":"https://www.omim.org/entry/613729"},{"mim_id":"612258","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE 3; MAST3","url":"https://www.omim.org/entry/612258"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":25.9}],"url":"https://www.proteinatlas.org/search/MAGI2"},"hgnc":{"alias_symbol":["AIP1","ARIP1","KIAA0705","ACVRIP1","MAGI-2"],"prev_symbol":[]},"alphafold":{"accession":"Q86UL8","domains":[{"cath_id":"2.30.42.10","chopping":"12-138_188-209","consensus_level":"high","plddt":83.9447,"start":12,"end":209},{"cath_id":"-","chopping":"309-390","consensus_level":"medium","plddt":78.8624,"start":309,"end":390},{"cath_id":"2.30.42.10","chopping":"423-509","consensus_level":"high","plddt":89.1787,"start":423,"end":509},{"cath_id":"2.30.42.10","chopping":"603-682","consensus_level":"high","plddt":85.366,"start":603,"end":682},{"cath_id":"2.30.42.10","chopping":"775-862","consensus_level":"high","plddt":88.8609,"start":775,"end":862},{"cath_id":"2.30.42.10","chopping":"920-940_950-1008","consensus_level":"high","plddt":87.3755,"start":920,"end":1008},{"cath_id":"2.30.42.10","chopping":"1146-1227","consensus_level":"high","plddt":90.8817,"start":1146,"end":1227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86UL8-F1-predicted_aligned_error_v6.png","plddt_mean":60.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAGI2","jax_strain_url":"https://www.jax.org/strain/search?query=MAGI2"},"sequence":{"accession":"Q86UL8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86UL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86UL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86UL8"}},"corpus_meta":[{"pmid":"14505569","id":"PMC_14505569","title":"AIP1/ALIX 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CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35524333","citation_count":26,"is_preprint":false},{"pmid":"32450008","id":"PMC_32450008","title":"Long noncoding RNA MAGI2-AS3/miR-218-5p/GDPD5/SEC61A1 axis drives cellular proliferation and migration and confers cisplatin resistance in nasopharyngeal carcinoma.","date":"2020","source":"International forum of allergy & rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/32450008","citation_count":26,"is_preprint":false},{"pmid":"32681706","id":"PMC_32681706","title":"MAGI2-AS3 suppresses MYC signaling to inhibit cell proliferation and migration in ovarian cancer through targeting miR-525-5p/MXD1 axis.","date":"2020","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32681706","citation_count":25,"is_preprint":false},{"pmid":"17335497","id":"PMC_17335497","title":"Actin organization and root hair development are disrupted by ethanol-induced overexpression of Arabidopsis actin interacting protein 1 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24608321","citation_count":23,"is_preprint":false},{"pmid":"17601348","id":"PMC_17601348","title":"Regulation of HTLV-1 Gag budding by Vps4A, Vps4B, and AIP1/Alix.","date":"2007","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/17601348","citation_count":23,"is_preprint":false},{"pmid":"20101691","id":"PMC_20101691","title":"Deletion of 7q11.21-q11.23 and infantile spasms without deletion of MAGI2.","date":"2010","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20101691","citation_count":23,"is_preprint":false},{"pmid":"12813014","id":"PMC_12813014","title":"AIP1: a new player in TNF signaling.","date":"2003","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12813014","citation_count":23,"is_preprint":false},{"pmid":"32723865","id":"PMC_32723865","title":"Catastrophic actin filament bursting by cofilin, Aip1, and coronin.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32723865","citation_count":22,"is_preprint":false},{"pmid":"31171376","id":"PMC_31171376","title":"Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.","date":"2019","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/31171376","citation_count":22,"is_preprint":false},{"pmid":"34002044","id":"PMC_34002044","title":"LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma.","date":"2021","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34002044","citation_count":22,"is_preprint":false},{"pmid":"33761624","id":"PMC_33761624","title":"Novel insights for lncRNA MAGI2-AS3 in solid tumors.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/33761624","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51201,"output_tokens":4574,"usd":0.111106},"stage2":{"model":"claude-opus-4-6","input_tokens":8058,"output_tokens":3589,"usd":0.195022},"total_usd":0.306128,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGI2 (renamed from AIP-1/atrophin interacting protein 1) binds PTEN through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI2, and this interaction enhances PTEN's ability to suppress Akt activation and stabilizes PTEN protein at the cell membrane.\",\n      \"method\": \"Yeast two-hybrid screening, 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 — reciprocal co-IP plus functional readout (Akt suppression), replicated across multiple subsequent studies\",\n      \"pmids\": [\"10760291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTEN binding to MAGI2 is regulated by phosphorylation at threonine 382 and 383 of PTEN; phosphorylation-incompetent PTEN mutants (T382A/T383A) show dramatically enhanced binding affinity to MAGI2 but reduced protein stability via proteasome-dependent polyubiquitination, suggesting PTEN recruitment to cell-cell junctions is regulated through C-terminal phosphorylation.\",\n      \"method\": \"Site-directed mutagenesis, pulldown assay, ubiquitination assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis combined with biochemical assays demonstrating the mechanistic link between phosphorylation state and MAGI2 binding affinity\",\n      \"pmids\": [\"11431330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MAGI2 binds the beta1-adrenergic receptor (beta1AR) carboxyl terminus through its first PDZ domain, with the last few amino acids of the beta1AR C-terminus being the key determinants; this interaction is enhanced by agonist stimulation and markedly increases beta1AR internalization. MAGI2 also promotes physical association of beta1AR with beta-catenin.\",\n      \"method\": \"Overlay and pulldown assays, co-immunoprecipitation, immunofluorescence co-localization, domain-specific binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pulldown, co-IP, immunofluorescence) with defined functional consequence (enhanced internalization)\",\n      \"pmids\": [\"11526121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"High-risk HPV E6 proteins target MAGI2 for proteasome-mediated degradation through interaction with a specific PDZ domain of MAGI2; co-expression of this PDZ domain can protect full-length MAGI2 from E6-mediated degradation.\",\n      \"method\": \"Co-expression and degradation assays, domain competition experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional degradation assay with domain-level mechanistic detail, single lab\",\n      \"pmids\": [\"12140759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Vinculin maintains PTEN protein levels by preserving the interaction of beta-catenin with MAGI2 at adherens junctions; loss of vinculin disrupts the beta-catenin–MAGI2 interaction, leading to PTEN destabilization and degradation.\",\n      \"method\": \"Genetic rescue experiments (vinculin-null cells), co-immunoprecipitation, transfection with vinculin mutants and E-cadherin fusion constructs, MAGI2 overexpression rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic and biochemical methods establishing the vinculin→beta-catenin→MAGI2→PTEN pathway\",\n      \"pmids\": [\"15579911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MAGI2 (S-SCAM) is a component of the nephrin multiprotein complex at glomerular slit diaphragms; it is pulled down by the GST-nephrin cytoplasmic domain from glomerular lysates and co-localizes with nephrin in podocyte foot processes.\",\n      \"method\": \"GST pulldown with mass spectrometry, 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 2 — MS-confirmed pulldown combined with in vivo co-localization; replicated in subsequent knockout studies\",\n      \"pmids\": [\"15994232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PKC-mediated phosphorylation of the delta2 glutamate receptor regulates its interaction with MAGI2 (S-SCAM), and co-expression of delta2 receptor with MAGI2 dramatically alters receptor localization in cells.\",\n      \"method\": \"Co-immunoprecipitation, co-expression in COS7 cells, immunolocalization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP with pharmacological evidence for phosphorylation regulation of the interaction\",\n      \"pmids\": [\"12589829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAGI2 (S-SCAM) localizes at inhibitory synapses and interacts with beta-dystroglycan (beta-DG) through its WW domains; MAGI2 WW domains and its second PDZ domain interact with neuroligin 2. Beta-DG, neuroligin 2, and MAGI2 form a tripartite complex in vitro, linking the dystrophin glycoprotein complex to the neurexin-neuroligin complex at inhibitory synapses.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from rat brain, in vitro complex reconstitution, immunofluorescence in hippocampal neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including in vitro reconstitution of tripartite complex and in vivo co-IP, clear domain mapping\",\n      \"pmids\": [\"17059560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAGI2 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 MAGI2; MAGI2 co-immunoprecipitates with stargazin in vivo from mouse cerebral cortex and stargazin expression recruits MAGI2 to cell membranes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from mouse brain, in vitro domain mapping, co-expression in HEK-293T cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo co-IP confirmed by in vitro domain mapping and cell-based co-localization, multiple orthogonal approaches\",\n      \"pmids\": [\"16870733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MAGI2 overexpression inhibits cell migration and proliferation in hepatocarcinoma cells by upregulating PTEN protein stability (not mRNA), leading to downregulation of p-FAK and p-Akt; the effect is attenuated in PTEN-null cells and rescued by PTEN transfection, confirming PTEN-dependent mechanism.\",\n      \"method\": \"Transfection/overexpression, migration and proliferation assays, western blot, siRNA knockdown of PTEN, co-immunoprecipitation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KO/KD plus genetic rescue establishing PTEN dependence, single lab\",\n      \"pmids\": [\"17880912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hemizygous deletion within the MAGI2 gene (encoding the synaptic scaffolding protein) is associated with infantile spasms; MAGI2 interacts with Stargazin, a protein associated with epilepsy in the stargazer mouse.\",\n      \"method\": \"High-resolution genomic mapping of chromosomal deletions in patients, candidate gene analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic mapping identifies MAGI2 locus; interaction with Stargazin based on prior literature\",\n      \"pmids\": [\"18565486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAGI2 (S-SCAM) is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors; increasing MAGI2 levels selectively increases surface AMPAR levels and enlarges dendritic spines, while MAGI2 knockdown causes loss of synaptic AMPARs and severe reduction in dendritic spine density in rat hippocampal neurons. MAGI2 regulates AMPARs in a GluA2-dependent, activity-independent manner, and its overexpression hampers NMDA-induced AMPAR internalization and prevents LTD induction.\",\n      \"method\": \"RNAi knockdown, overexpression in hippocampal neurons, electrophysiology (AMPAR-mediated EPSC), dendritic spine imaging, surface AMPAR quantification\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional loss- and gain-of-function with multiple orthogonal readouts (electrophysiology, spine morphology, surface receptor levels), clearly defined mechanism\",\n      \"pmids\": [\"22593065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MiR-134/487b/655 cluster directly targets MAGI2 mRNA, suppressing MAGI2 expression to destabilize PTEN and promote TGF-β1-induced EMT and gefitinib resistance in lung adenocarcinoma cells.\",\n      \"method\": \"miRNA array, qRT-PCR, overexpression/knockdown of miRNAs, western blot for MAGI2 and PTEN, EMT markers, drug resistance assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct targeting demonstrated with functional consequences, but mechanism is indirect (miRNA suppresses MAGI2 which then destabilizes PTEN)\",\n      \"pmids\": [\"24258346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGI2 is required for kidney filtration barrier integrity and podocyte survival in mice; MAGI2-null mice develop progressive proteinuria, podocyte foot process effacement, loss of nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, enhanced cathepsin L expression, and die of renal failure by 3 months.\",\n      \"method\": \"Homologous recombination knockout mice, immunohistochemistry, electron microscopy, proteinuria measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined molecular and cellular phenotypes, replicated in two independent KO mouse studies\",\n      \"pmids\": [\"25271328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGI2-null mice show neonatal lethality with podocyte morphological abnormalities; loss of MAGI2 causes significant decreases in nephrin and dendrin at the slit diaphragm, nuclear translocation of dendrin, and enhanced cathepsin L expression, which is critical for rearrangement of the actin cytoskeleton in podocytes.\",\n      \"method\": \"Homozygous gene deletion mouse model, immunohistological analysis, ultrastructural analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent KO mouse study confirming and extending mechanistic findings of PMID 25271328\",\n      \"pmids\": [\"25108225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Phosphorylation of the Usher syndrome protein SANS by CK2 at an internal PDZ-binding motif in its SAM domain regulates SANS-MAGI2 complex assembly; phosphorylated SANS tightly regulates MAGI2-mediated clathrin-dependent endocytosis, which in turn regulates ciliogenesis. USH1G patient mutations in SANS that eliminate MAGI2 binding deregulate endocytosis and disrupt photoreceptor cell function.\",\n      \"method\": \"Co-immunoprecipitation, RNAi depletion, kinase assay (CK2), endocytosis assays, localization in retinal photoreceptor cells, patient mutation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including patient mutations, kinase regulation, and defined cellular phenotype (endocytosis, ciliogenesis)\",\n      \"pmids\": [\"24608321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAGI2 is a transcriptional target of WT1 (Wilms' tumor suppressor) in podocytes, and is required for normal development of the embryonic zebrafish kidney as shown by functional assays in zebrafish.\",\n      \"method\": \"ChIP-seq, cDNA microarray, zebrafish functional assays (morpholino knockdown)\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — integrated cistromic and transcriptomic analyses with in vivo functional validation in zebrafish\",\n      \"pmids\": [\"25556170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAGI2 mutations (frameshift and duplication) cause congenital nephrotic syndrome by disrupting podocyte MAGI2 expression, consistent with its essential role in interacting with nephrin and regulating podocyte cytoskeleton and slit diaphragm dynamics.\",\n      \"method\": \"Whole-exome sequencing of patients, immunohistochemistry of patient kidney sections\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disease-causing mutations identified with confirmed protein loss in patient tissue, mechanistic interpretation based on prior functional data\",\n      \"pmids\": [\"27932480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor RapGEF2; co-expression of RapGEF2 with wild-type but not MAGI2 CNS variants enhances Rap1 GTPase activation. Podocyte-specific RapGEF2 deletion in mice causes glomerulosclerosis similar to MAGI2 knockout, and pharmacological Rap1 activation rescues actin cytoskeletal defects in human podocytes expressing MAGI2 CNS mutations.\",\n      \"method\": \"Co-immunoprecipitation, Rap1 activation assays, podocyte-specific conditional knockout mice, pharmacological rescue, patient kidney immunostaining\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo genetic models, biochemical pathway validation, and pharmacological rescue establish the MAGI2-RapGEF2-Rap1 signaling axis\",\n      \"pmids\": [\"31171376\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGI2 is a multi-PDZ domain scaffold protein that assembles multiprotein complexes at cell junctions (tight junctions, adherens junctions, synapses, and the kidney slit diaphragm), where it stabilizes PTEN by direct PDZ-domain interaction (PDZ2) to suppress PI3K-Akt signaling; forms complexes with nephrin and RapGEF2 to activate Rap1 GTPase signaling essential for podocyte integrity; scaffolds neurotransmitter receptors (AMPA receptors via TARPs, beta1AR, delta2 GluR, NMDA receptors) at synapses to regulate receptor trafficking and synaptic strength; and is regulated by phosphorylation (of its binding partners, e.g. PTEN T382/T383 and SANS-CK2) and by HPV E6-mediated proteasomal degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAGI2 is a multi-PDZ domain scaffold protein that organizes signaling complexes at cell junctions and synapses, functioning in epithelial barrier integrity, synaptic receptor maintenance, and tumor suppression. At adherens junctions and the kidney slit diaphragm, MAGI2 stabilizes PTEN protein (via PDZ2-mediated binding regulated by PTEN C-terminal phosphorylation) to suppress PI3K-Akt signaling, and scaffolds nephrin and RapGEF2 to activate Rap1 GTPase signaling essential for podocyte cytoskeletal integrity; loss-of-function mutations in MAGI2 cause congenital nephrotic syndrome in humans [PMID:10760291, PMID:11431330, PMID:25271328, PMID:31171376, PMID:27932480]. At synapses, MAGI2 interacts with TARPs/stargazin, neuroligin-2, and β-dystroglycan to maintain surface AMPA receptor pools and dendritic spine density in a GluA2-dependent, activity-independent manner, and its hemizygous deletion is associated with infantile spasms [PMID:22593065, PMID:16870733, PMID:17059560, PMID:18565486]. MAGI2 is also targeted for proteasomal degradation by high-risk HPV E6 proteins and is subject to miRNA-mediated downregulation, linking its loss to epithelial-mesenchymal transition and drug resistance in cancer [PMID:12140759, PMID:24258346].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying how PTEN is stabilized at cell membranes, this work established that MAGI2 directly binds PTEN through a PDZ2–PDZ-binding motif interaction, enhancing PTEN-mediated Akt suppression and defining MAGI2 as a PTEN scaffold.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and functional Akt suppression assays in mammalian cells\",\n      \"pmids\": [\"10760291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PDZ2–PTEN interaction unresolved\", \"In vivo significance of MAGI2-PTEN axis not yet tested in animal models\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Addressing how the MAGI2–PTEN interaction is regulated, phosphorylation at PTEN T382/T383 was shown to control binding affinity to MAGI2 — dephosphorylated PTEN binds MAGI2 more tightly but becomes susceptible to proteasomal degradation, revealing a phosphorylation-dependent switch governing PTEN junctional recruitment.\",\n      \"evidence\": \"Site-directed mutagenesis, pulldown assays, and ubiquitination assays\",\n      \"pmids\": [\"11431330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) responsible for T382/T383 phosphorylation in vivo not identified\", \"Whether this regulation operates at specific junction types unclear\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Extending MAGI2's scaffolding repertoire beyond PTEN, its PDZ1 domain was shown to bind the β1-adrenergic receptor C-terminus in an agonist-enhanced manner, promoting receptor internalization and linking MAGI2 to GPCR trafficking.\",\n      \"evidence\": \"Overlay assays, pulldown, co-immunoprecipitation, and immunofluorescence in transfected cells\",\n      \"pmids\": [\"11526121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of MAGI2–β1AR interaction in cardiac tissue not tested\", \"Whether MAGI2 scaffolds other GPCRs unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealing a mechanism by which HPV subverts cell polarity, high-risk HPV E6 proteins were shown to target MAGI2 for proteasome-mediated degradation via a specific PDZ domain interaction, which could be blocked by competitive expression of that domain.\",\n      \"evidence\": \"Co-expression and degradation assays with domain competition in cultured cells\",\n      \"pmids\": [\"12140759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance during HPV-driven carcinogenesis not demonstrated\", \"Which E3 ligase mediates E6-directed MAGI2 ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing the junctional pathway that stabilizes PTEN, vinculin was shown to maintain the β-catenin–MAGI2 interaction at adherens junctions; loss of vinculin disrupts this complex, causing PTEN destabilization and degradation.\",\n      \"evidence\": \"Genetic rescue in vinculin-null cells, co-immunoprecipitation, and MAGI2 overexpression rescue\",\n      \"pmids\": [\"15579911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect nature of vinculin's effect on MAGI2 assembly unclear\", \"Whether this pathway operates in all epithelial tissues not tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying MAGI2 as a slit diaphragm component, it was found in the nephrin multiprotein complex at glomerular podocyte foot processes, establishing a non-neuronal scaffolding role for MAGI2 in kidney filtration.\",\n      \"evidence\": \"GST-nephrin pulldown with mass spectrometry and immunofluorescence co-localization in kidney sections\",\n      \"pmids\": [\"15994232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MAGI2 loss in podocytes not yet shown\", \"Binding domains mediating MAGI2–nephrin interaction not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining MAGI2's synaptic scaffolding architecture, two key interactions were mapped: MAGI2 bridges β-dystroglycan (via WW domains) and neuroligin-2 (via PDZ2) into a tripartite complex at inhibitory synapses, and separately interacts with stargazin/TARPs (via PDZ1/3/5) to scaffold AMPA receptor complexes at excitatory synapses.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation from rodent brain, in vitro complex reconstitution, domain mapping in HEK-293T cells\",\n      \"pmids\": [\"17059560\", \"16870733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of disrupting the tripartite complex at inhibitory synapses not tested\", \"Whether MAGI2 simultaneously engages all these partners in a single complex unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking MAGI2 to human neurological disease, hemizygous MAGI2 deletion was identified in patients with infantile spasms, consistent with its role in scaffolding stargazin/epilepsy-associated proteins.\",\n      \"evidence\": \"High-resolution genomic mapping of chromosomal deletions in patients with infantile spasms\",\n      \"pmids\": [\"18565486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role not proven by functional rescue\", \"Whether MAGI2 haploinsufficiency alone is sufficient for epilepsy or requires additional hits unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolving the functional role of MAGI2 at excitatory synapses, bidirectional manipulation showed that MAGI2 is essential for maintaining surface GluA2-containing AMPA receptors and dendritic spine density, and its overexpression blocks NMDA-induced AMPAR internalization and LTD.\",\n      \"evidence\": \"RNAi knockdown and overexpression in rat hippocampal neurons with electrophysiology, spine imaging, and surface receptor quantification\",\n      \"pmids\": [\"22593065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI2 regulation of AMPARs involves direct GluA2 binding or is entirely TARP-mediated not fully resolved\", \"In vivo behavioral consequences of synaptic MAGI2 loss not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating MAGI2's essential role in kidney filtration, two independent MAGI2-knockout mouse studies showed progressive proteinuria, podocyte foot process effacement, loss of nephrin and dendrin from slit diaphragms, dendrin nuclear translocation, upregulated cathepsin L, and renal failure, establishing MAGI2 as indispensable for podocyte integrity.\",\n      \"evidence\": \"Homologous recombination knockout mice analyzed by electron microscopy, immunohistochemistry, and proteinuria measurement\",\n      \"pmids\": [\"25271328\", \"25108225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking MAGI2 loss to dendrin nuclear translocation not defined\", \"Whether MAGI2 loss causes a primary signaling defect or structural disassembly is unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting MAGI2 to sensory cell function, CK2 phosphorylation of the Usher syndrome protein SANS was shown to regulate SANS–MAGI2 complex assembly, controlling MAGI2-mediated clathrin-dependent endocytosis required for ciliogenesis; patient mutations in SANS that abolish MAGI2 binding deregulate endocytosis and disrupt photoreceptor function.\",\n      \"evidence\": \"Co-immunoprecipitation, CK2 kinase assays, endocytosis assays, patient mutation analysis in retinal photoreceptor cells\",\n      \"pmids\": [\"24608321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAGI2 directly participates in clathrin coat assembly or acts indirectly through cargo sorting not resolved\", \"Role of MAGI2 in other ciliated cell types not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirming clinical relevance, MAGI2 loss-of-function mutations (frameshift, duplication) were identified as a cause of congenital nephrotic syndrome in humans, with absent MAGI2 protein in patient kidney tissue.\",\n      \"evidence\": \"Whole-exome sequencing of patients with congenital nephrotic syndrome and immunohistochemistry of patient kidneys\",\n      \"pmids\": [\"27932480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Number of families studied is small\", \"Genotype-phenotype correlation across different MAGI2 mutations not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying the signaling pathway downstream of MAGI2 in podocytes, MAGI2 was shown to form a complex with RapGEF2 to activate Rap1 GTPase; disease-causing MAGI2 mutations disrupt this activation, podocyte-specific RapGEF2 deletion phenocopies MAGI2 loss, and pharmacological Rap1 activation rescues actin defects caused by MAGI2 mutations.\",\n      \"evidence\": \"Co-immunoprecipitation, Rap1 activation assays, podocyte-specific conditional knockout mice, pharmacological rescue in human podocytes\",\n      \"pmids\": [\"31171376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the MAGI2–RapGEF2–Rap1 axis operates in neurons or other cell types unknown\", \"Structural basis of MAGI2–RapGEF2 interaction not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how MAGI2 coordinates its multiple PDZ domain interactions simultaneously, whether the PTEN-stabilizing and Rap1-activating functions are integrated or independent at podocyte junctions, and what molecular mechanisms link MAGI2 haploinsufficiency to epileptogenesis in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length MAGI2 or multi-partner complexes\", \"Relative contribution of PTEN stabilization vs. Rap1 activation to podocyte survival not dissected\", \"Causal mechanism linking MAGI2 loss to infantile spasms not functionally validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 7, 8, 11, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4, 5, 7, 8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 9, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 5, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 14, 16]}\n    ],\n    \"complexes\": [\n      \"Nephrin slit diaphragm complex\",\n      \"β-dystroglycan–neuroligin-2 complex\",\n      \"TARP/stargazin–AMPAR complex\"\n    ],\n    \"partners\": [\n      \"PTEN\",\n      \"CTNNB1\",\n      \"NPHS1\",\n      \"RAPGEF2\",\n      \"NLGN2\",\n      \"DAG1\",\n      \"CACNG2\",\n      \"USH1G\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}