{"gene":"MPP2","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2016,"finding":"MPP2 (MAGUK p55 subfamily member 2) localizes to postsynaptic sites in hippocampal neurons, where its C-terminal SH3-GK domain module mediates binding to the abundant postsynaptic scaffold proteins PSD-95 and GKAP. Additionally, the MPP2 PDZ domain directly binds the C-terminus of the synaptic cell adhesion molecule SynCAM1, but does not interact in this manner with other highly abundant postsynaptic transmembrane proteins, establishing MPP2 as a scaffold linking SynCAM1 to core components of the postsynaptic density.","method":"Co-immunoprecipitation, direct binding assays (PDZ domain–SynCAM1 C-terminus interaction), immunofluorescence localization in rat hippocampal neurons","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP and direct binding with localization, single lab","pmids":["27756895"],"is_preprint":false},{"year":2009,"finding":"MPP2 interacts with the non-receptor tyrosine kinase c-Src via its PDZ domain in non-transformed breast epithelial MCF-10A cells, where endogenous MPP2 associates with the cytoskeleton in filamentous structures partially co-localizing with microtubules and c-Src. c-Src kinase activity promotes increased interaction with MPP2, and MPP2 negatively regulates c-Src kinase activity, thereby suppressing c-Src-dependent disorganization of the cortical actin cytoskeleton.","method":"PDZ domain array screen, co-immunoprecipitation in cells, immunofluorescence co-localization, c-Src kinase activity assay, morphological readout of actin cytoskeleton","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — PDZ array + Co-IP + functional kinase assay + phenotypic readout, single lab with multiple orthogonal methods","pmids":["19665017"],"is_preprint":false},{"year":2022,"finding":"Using superresolution imaging, MPP2 is situated at the periphery of the postsynaptic density (PSD), co-localizing with SynCAM1. Quantitative comparative proteomics identified multiple GABA-A receptor subunits as novel synaptic MPP2 interactors. Manipulating MPP2 expression had functional effects on inhibitory synaptic transmission, and GABA-A receptors were found together with MPP2 in a subset of dendritic spines, establishing MPP2 as an adaptor linking peripheral synaptic elements critical for inhibitory regulation to central PSD structures at glutamatergic synapses.","method":"Superresolution (STED/STORM) imaging, quantitative comparative proteomics (AP-MS), electrophysiology (inhibitory synaptic currents upon MPP2 manipulation)","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (superresolution imaging, quantitative proteomics, electrophysiology) in single rigorous study","pmids":["35312684"],"is_preprint":false},{"year":2023,"finding":"MPP2 interacts with the small-conductance calcium-activated potassium channel SK2 in the basolateral amygdala (BLA). During fear conditioning, PKA activity reduces synaptic SK2 levels; during fear extinction, MPP2 mediates increased synaptic SK2 channel expression, thereby rescuing the excitability of glutamatergic neurons (via the afterhyperpolarization current IAHP) and facilitating extinction of conditioned fear.","method":"Western blotting, fluorescence quantitative PCR, electrophysiology (patch-clamp measurement of IAHP and neuronal excitability), fear conditioning/extinction behavioral assay","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP/interaction plus electrophysiology and behavioral readout, single lab","pmids":["37469037"],"is_preprint":false},{"year":2022,"finding":"In mouse cerebellar glomeruli, MPP2 is detected at excitatory postsynaptic regions and adherens junctions of granule cells after postnatal day 14, co-localizing with CADM1, Lin7, CASK, GluN1 (NMDA receptor 1), and M-cadherin. Immunoprecipitation demonstrated that MPP2 forms a molecular complex with CADM1, CASK, M-cadherin, and Lin7. In MPP2-deficient cerebella, the Lin7 staining pattern changed from small rings surrounding mossy fibers to dot/spot patterns inside CADM1-stained rings, indicating that MPP2 controls the distribution of Lin7 to synaptic cell membranes at postsynaptic regions of granule cells.","method":"Immunostaining (confocal Airyscan superresolution), co-immunoprecipitation, comparison of wild-type vs. MPP2-deficient mouse cerebella","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus superresolution localization and KO comparison, single lab","pmids":["35854144"],"is_preprint":false},{"year":2023,"finding":"A de novo missense mutation in MPP2 (p.K315N, MPP2-N315) increases susceptibility to Vogt-Koyanagi-Harada (VKH) autoimmune uveitis. Knock-in or AAV-mediated expression of MPP2-N315 in mice aggravated experimental autoimmune uveitis pathology and retinal vascular leakage. In ARPE19 cells with the K315N mutation, levels of IL-1β, IL-17E, and VEGFA were increased and barrier function was destroyed. Mechanistically, LC-MS/MS and Co-IP showed that MPP2-N315 has a stronger ability to bind ANXA2 (annexin A2) compared to wild-type MPP2-K315, resulting in activation of the ERK3/IL-17E pathway.","method":"Trio-based whole-exome sequencing, knock-in mouse model, AAV gene delivery, CRISPR-Cas9 deletion/rescue, LC-MS/MS, co-immunoprecipitation, cytokine measurement, barrier function assay, in vivo EAU model","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including in vivo model, LC-MS/MS interaction, Co-IP, and functional assays in single rigorous study","pmids":["37828081"],"is_preprint":false}],"current_model":"MPP2 (MAGUK p55 subfamily member 2) is a postsynaptic scaffold protein that localizes to the periphery of the postsynaptic density at glutamatergic synapses, where it links the synaptic cell adhesion molecule SynCAM1 to core PSD proteins (PSD-95, GKAP) via its SH3-GK domains and PDZ domain, associates with GABA-A receptor subunits to modulate inhibitory synaptic transmission, interacts with SK2 potassium channels to regulate neuronal excitability and fear extinction, forms complexes with CADM1/CASK/Lin7 at cerebellar synapses, negatively regulates c-Src kinase activity to maintain actin cytoskeletal organization in epithelial cells, and harbors a disease-associated K315N mutation that aberrantly binds ANXA2 to activate ERK3/IL-17E inflammatory signaling."},"narrative":{"teleology":[{"year":2009,"claim":"The first functional characterization of MPP2 outside neurons revealed that its PDZ domain engages the tyrosine kinase c-Src and that MPP2 negatively regulates c-Src activity, establishing a role in maintaining epithelial actin cytoskeletal organization.","evidence":"PDZ domain array screen, co-immunoprecipitation, kinase activity assay, and actin morphology readout in MCF-10A breast epithelial cells","pmids":["19665017"],"confidence":"Medium","gaps":["No in vivo validation of the MPP2–c-Src interaction","Mechanism by which MPP2 inhibits c-Src kinase activity is undefined","Relevance of this epithelial role to neuronal MPP2 function not addressed"]},{"year":2016,"claim":"MPP2 was shown to be a postsynaptic scaffold that bridges SynCAM1 (via its PDZ domain) to core PSD components PSD-95 and GKAP (via its SH3-GK module), establishing its domain-specific wiring logic at excitatory synapses.","evidence":"Co-immunoprecipitation, direct PDZ–SynCAM1 C-terminus binding assay, and immunofluorescence in rat hippocampal neurons","pmids":["27756895"],"confidence":"Medium","gaps":["Functional consequence of disrupting the MPP2–SynCAM1 link on synaptic transmission was not tested","Structural basis of the SH3-GK interaction with PSD-95/GKAP not resolved","Single-lab study without independent replication"]},{"year":2022,"claim":"Superresolution imaging and quantitative proteomics placed MPP2 at the PSD periphery and identified GABA-A receptor subunits as novel interactors, with electrophysiology demonstrating that MPP2 levels influence inhibitory synaptic currents—establishing MPP2 as a bridge between excitatory and inhibitory synaptic machinery within single spines.","evidence":"STED/STORM imaging, AP-MS quantitative proteomics, and patch-clamp electrophysiology upon MPP2 manipulation","pmids":["35312684"],"confidence":"High","gaps":["Direct binding between MPP2 and specific GABA-A subunits not demonstrated with purified proteins","Whether MPP2 loss phenocopies in vivo inhibitory synapse dysfunction is untested"]},{"year":2022,"claim":"In cerebellar granule cells, MPP2 was found to complex with CADM1, CASK, Lin7, and M-cadherin at excitatory postsynaptic regions and adherens junctions; loss of MPP2 disrupted Lin7 targeting to synaptic membranes, revealing MPP2 as an essential organizer of this multi-protein complex.","evidence":"Confocal Airyscan superresolution imaging, co-immunoprecipitation, and comparison of wild-type versus MPP2-deficient mouse cerebella","pmids":["35854144"],"confidence":"Medium","gaps":["Electrophysiological or behavioral consequences of disrupted Lin7 localization in MPP2-deficient mice not assessed","Whether the CADM1/CASK/Lin7 complex exists at non-cerebellar synapses with MPP2 is unknown","Single-lab study"]},{"year":2023,"claim":"MPP2 was linked to SK2 potassium channel trafficking at basolateral amygdala synapses, where it increases synaptic SK2 during fear extinction, thereby restoring the afterhyperpolarization current and facilitating extinction learning—connecting MPP2 scaffolding to behavioral-level neuronal excitability.","evidence":"Co-immunoprecipitation, patch-clamp electrophysiology measuring IAHP and excitability, and fear conditioning/extinction behavioral assay in mice","pmids":["37469037"],"confidence":"Medium","gaps":["Direct binding domain on MPP2 responsible for SK2 interaction not mapped","Single-lab study without independent replication","Whether MPP2–SK2 interaction occurs at other brain regions is unknown"]},{"year":2023,"claim":"A de novo K315N missense mutation in MPP2 was identified as a susceptibility factor for Vogt-Koyanagi-Harada uveitis, with the mutant protein gaining enhanced ANXA2 binding and activating ERK3/IL-17E inflammatory signaling, demonstrating a pathogenic gain-of-function mechanism.","evidence":"Trio-based whole-exome sequencing, CRISPR knock-in mouse model, AAV delivery, LC-MS/MS interactomics, co-immunoprecipitation, cytokine and barrier function assays, and experimental autoimmune uveitis model","pmids":["37828081"],"confidence":"High","gaps":["Whether wild-type MPP2 normally interacts with ANXA2 at physiological levels is unclear","Structural basis for how K315N enhances ANXA2 binding not resolved","Prevalence of MPP2 mutations in broader VKH patient cohorts not established"]},{"year":null,"claim":"It remains unknown how MPP2's synaptic scaffolding functions (SynCAM1/PSD-95/GABA-A receptor/SK2 organization) are coordinately regulated, whether MPP2 undergoes post-translational modifications that switch its binding partners in different cellular contexts, and whether its epithelial c-Src regulatory role intersects with its neuronal functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length MPP2 or its multi-domain complexes exists","Post-translational regulation of MPP2 is unexplored","Comprehensive in vivo phenotyping of MPP2 knockout beyond cerebellum is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]}],"complexes":["CADM1/CASK/Lin7/MPP2 complex"],"partners":["DLG4","CADM1","DLGAP1","CASK","LIN7A","KCNN2","ANXA2","SRC"],"other_free_text":[]},"mechanistic_narrative":"MPP2 is a MAGUK p55 subfamily scaffold protein that organizes signaling complexes at postsynaptic sites and epithelial cell junctions through its PDZ, SH3, and GK domains. At glutamatergic synapses, MPP2 localizes to the periphery of the postsynaptic density, where its PDZ domain binds the synaptic adhesion molecule SynCAM1 and its SH3-GK module engages core PSD scaffolds PSD-95 and GKAP; it additionally recruits GABA-A receptor subunits to dendritic spines, modulating inhibitory synaptic transmission, and interacts with SK2 potassium channels in the basolateral amygdala to regulate neuronal excitability during fear extinction [PMID:27756895, PMID:35312684, PMID:37469037]. In cerebellar granule cells, MPP2 forms a complex with CADM1, CASK, and Lin7 and is required for proper Lin7 distribution at synaptic membranes [PMID:35854144]. A de novo MPP2 p.K315N missense mutation confers susceptibility to Vogt-Koyanagi-Harada autoimmune uveitis by enhancing binding to ANXA2 and activating the ERK3/IL-17E inflammatory pathway, establishing a direct disease link [PMID:37828081]."},"prefetch_data":{"uniprot":{"accession":"Q14168","full_name":"MAGUK p55 subfamily member 2","aliases":["Discs large homolog 2","Protein MPP2"],"length_aa":576,"mass_kda":64.6,"function":"Postsynaptic MAGUK scaffold protein that links CADM1 cell adhesion molecules to core components of the postsynaptic density (By similarity). In CA1 pyramidal neurons, required for synaptic KCNN2-containing channel function and long-term potentiation expression (By similarity). Seems to negatively regulate SRC function in epithelial cells (PubMed:19665017)","subcellular_location":"Cytoplasm, cytoskeleton; Membrane; Cell projection, dendrite; Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/Q14168/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MPP2","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MPP2","total_profiled":1310},"omim":[{"mim_id":"618597","title":"BRAIN-ENRICHED GUANYLATE KINASE-ASSOCIATED PROTEIN; BEGAIN","url":"https://www.omim.org/entry/618597"},{"mim_id":"616191","title":"DISCS LARGE-ASSOCIATED PROTEIN 4; DLGAP4","url":"https://www.omim.org/entry/616191"},{"mim_id":"611413","title":"DISCS LARGE-ASSOCIATED PROTEIN 3; DLGAP3","url":"https://www.omim.org/entry/611413"},{"mim_id":"605498","title":"KINESIN FAMILY MEMBER 20B; KIF20B","url":"https://www.omim.org/entry/605498"},{"mim_id":"605438","title":"DISCS LARGE-ASSOCIATED PROTEIN 2; DLGAP2","url":"https://www.omim.org/entry/605438"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":32.8}],"url":"https://www.proteinatlas.org/search/MPP2"},"hgnc":{"alias_symbol":["DKFZp761D0712"],"prev_symbol":["DLG2"]},"alphafold":{"accession":"Q14168","domains":[{"cath_id":"-","chopping":"8-21_30-83","consensus_level":"high","plddt":60.7081,"start":8,"end":83},{"cath_id":"2.30.42.10","chopping":"164-241","consensus_level":"high","plddt":80.5838,"start":164,"end":241},{"cath_id":"2.30.30.40","chopping":"249-321_349-370","consensus_level":"medium","plddt":83.7186,"start":249,"end":370},{"cath_id":"3.40.50.300","chopping":"372-402_467-567","consensus_level":"medium","plddt":92.9063,"start":372,"end":567},{"cath_id":"3.30.63.10","chopping":"407-456","consensus_level":"medium","plddt":93.17,"start":407,"end":456}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14168","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14168-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14168-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPP2","jax_strain_url":"https://www.jax.org/strain/search?query=MPP2"},"sequence":{"accession":"Q14168","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14168.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14168/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14168"}},"corpus_meta":[{"pmid":"10523841","id":"PMC_10523841","title":"Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation.","date":"1999","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10523841","citation_count":89,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30093633","id":"PMC_30093633","title":"Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30093633","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33128289","id":"PMC_33128289","title":"Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR-942-5p and releasing DLG2 via Hippo-YAP signaling.","date":"2020","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33128289","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7590743","id":"PMC_7590743","title":"A gene (DLG2) located at 17q12-q21 encodes a new homologue of the Drosophila tumor suppressor dIg-A.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7590743","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32966799","id":"PMC_32966799","title":"11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32966799","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30862230","id":"PMC_30862230","title":"MicroRNA-23a depletion promotes apoptosis of ovarian cancer stem cell and inhibits cell migration by targeting DLG2.","date":"2019","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30862230","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32164788","id":"PMC_32164788","title":"A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum.","date":"2020","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/32164788","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35246634","id":"PMC_35246634","title":"Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2.","date":"2022","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/35246634","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28724449","id":"PMC_28724449","title":"Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability.","date":"2017","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28724449","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20842219","id":"PMC_20842219","title":"Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26.","date":"2010","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20842219","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35031607","id":"PMC_35031607","title":"Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35031607","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27756895","id":"PMC_27756895","title":"MPP2 is a postsynaptic MAGUK scaffold protein that links SynCAM1 cell adhesion molecules to core components of the postsynaptic density.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27756895","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37416779","id":"PMC_37416779","title":"Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37416779","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19665017","id":"PMC_19665017","title":"The PDZ protein MPP2 interacts with c-Src in epithelial cells.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19665017","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29290481","id":"PMC_29290481","title":"DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population.","date":"2017","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/29290481","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35499706","id":"PMC_35499706","title":"Inflammation suppresses DLG2 expression decreasing inflammasome formation.","date":"2022","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35499706","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37828081","id":"PMC_37828081","title":"A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37828081","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35115661","id":"PMC_35115661","title":"Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.","date":"2022","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35115661","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32652860","id":"PMC_32652860","title":"SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32652860","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32356104","id":"PMC_32356104","title":"E2f8 and Dlg2 genes have independent effects on impaired insulin secretion associated with hyperglycaemia.","date":"2020","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/32356104","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16640776","id":"PMC_16640776","title":"Differential expression of a new isoform of DLG2 in renal oncocytoma.","date":"2006","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16640776","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35118804","id":"PMC_35118804","title":"Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2.","date":"2022","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/35118804","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38234042","id":"PMC_38234042","title":"Glioma stem cell-derived exosomes induce the transformation of astrocytes via the miR-3065-5p/DLG2 signaling axis.","date":"2024","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/38234042","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32731343","id":"PMC_32731343","title":"LncRNA DLG2-AS1 as a Novel Biomarker in Lung Adenocarcinoma.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32731343","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35217496","id":"PMC_35217496","title":"DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma.","date":"2022","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/35217496","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35312684","id":"PMC_35312684","title":"The synaptic scaffold protein MPP2 interacts with GABAA receptors at the periphery of the postsynaptic density of glutamatergic synapses.","date":"2022","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/35312684","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32290523","id":"PMC_32290523","title":"All-trans Retinoic Acid-induced Abnormal Hippocampal Expression of Synaptic Genes SynDIG1 and DLG2 is Correlated with Anxiety or Depression-Like Behavior in Mice.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32290523","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29703139","id":"PMC_29703139","title":"Identification of a novel Dlg2 isoform differentially expressed in IFNβ-producing plasmacytoid dendritic cells.","date":"2018","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/29703139","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32341572","id":"PMC_32341572","title":"DLG2 variants in patients with pubertal disorders.","date":"2020","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32341572","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19931931","id":"PMC_19931931","title":"Evaluation of DLG2 as a positional candidate for disposition index in African-Americans from the IRAS Family Study.","date":"2009","source":"Diabetes research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/19931931","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33726762","id":"PMC_33726762","title":"The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33726762","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35627244","id":"PMC_35627244","title":"Enhancing DLG2 Implications in Neuropsychiatric Disorders: Analysis of a Cohort of Eight Patients with 11q14.1 Imbalances.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35627244","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37705179","id":"PMC_37705179","title":"A mild impairment in reversal learning in a bowl-digging substrate deterministic task but not other cognitive tests in the Dlg2+/- rat model of genetic risk for psychiatric disorder.","date":"2023","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/37705179","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35075790","id":"PMC_35075790","title":"Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder.","date":"2022","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/35075790","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37469037","id":"PMC_37469037","title":"MPP2 interacts with SK2 to rescue the excitability of glutamatergic neurons in the BLA and facilitate the extinction of conditioned fear in mice.","date":"2023","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37469037","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35966008","id":"PMC_35966008","title":"A Deficiency of the Psychiatric Risk Gene DLG2/PSD-93 Causes Excitatory Synaptic Deficits in the Dorsolateral Striatum.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35966008","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35111846","id":"PMC_35111846","title":"Silencing of AKIP1 Suppresses the Proliferation, Migration, and Epithelial-Mesenchymal Transition Process of Glioma Cells by Upregulating DLG2.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/35111846","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35854144","id":"PMC_35854144","title":"Involvement of membrane palmitoylated protein 2 (MPP2) in the synaptic molecular complex at the mouse cerebellar glomerulus.","date":"2022","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35854144","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39856747","id":"PMC_39856747","title":"METTL3-dependent DLG2 inhibits the malignant progression of cervical cancer by inactivating the Hippo/YAP signaling.","date":"2025","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/39856747","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34695822","id":"PMC_34695822","title":"DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism.","date":"2021","source":"Hormone research in paediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34695822","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37860969","id":"PMC_37860969","title":"DLG2 intragenic exonic deletions reinforce the link to neurodevelopmental disorders and suggest a potential association with congenital anomalies and dysmorphism.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37860969","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38123893","id":"PMC_38123893","title":"Impaired reversal learning in the Dlg2+/- rat model of genetic risk for psychiatric disorder: Important questions regarding the neuro-behavioral mechanisms of reversal learning.","date":"2023","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/38123893","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40220608","id":"PMC_40220608","title":"DLG2 rs11607886 polymorphism associated with schizophrenia and precuneus functional changes.","date":"2025","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/40220608","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.01.27.25320452","title":"Genome- and Transcriptome-wide association meta-analysis reveals new insights into genes affecting coronary and peripheral artery disease","date":"2025-01-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.27.25320452","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.04.22.649861","title":"Physiological α-synuclein S129 phosphorylation mediates postsynaptic and nuclear interactions in the human brain","date":"2025-04-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.22.649861","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28344040","id":"PMC_28344040","title":"m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program.","date":"2017","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/28344040","citation_count":1213,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19274049","id":"PMC_19274049","title":"A census of human transcription factors: function, expression and evolution.","date":"2009","source":"Nature reviews. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19274049","citation_count":1191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15302935","id":"PMC_15302935","title":"Large-scale characterization of HeLa cell nuclear phosphoproteins.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15302935","citation_count":1159,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939624","id":"PMC_22939624","title":"Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939624","citation_count":708,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15654331","id":"PMC_15654331","title":"FoxM1 is required for execution of the mitotic programme and chromosome stability.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15654331","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29395067","id":"PMC_29395067","title":"High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/29395067","citation_count":580,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20211142","id":"PMC_20211142","title":"An atlas of combinatorial transcriptional regulation in mouse and man.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/20211142","citation_count":573,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16314512","id":"PMC_16314512","title":"Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16314512","citation_count":558,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22014570","id":"PMC_22014570","title":"FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014570","citation_count":504,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22094256","id":"PMC_22094256","title":"A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22094256","citation_count":460,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26871637","id":"PMC_26871637","title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26871637","citation_count":423,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21978825","id":"PMC_21978825","title":"FOXM1: From cancer initiation to progression and treatment.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21978825","citation_count":357,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17014965","id":"PMC_17014965","title":"FoxM1: at the crossroads of ageing and cancer.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17014965","citation_count":351,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9032290","id":"PMC_9032290","title":"Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9032290","citation_count":334,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12183437","id":"PMC_12183437","title":"FOXM1 is a downstream target of Gli1 in basal cell carcinomas.","date":"2002","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12183437","citation_count":321,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20190804","id":"PMC_20190804","title":"Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20190804","citation_count":319,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19160488","id":"PMC_19160488","title":"Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19160488","citation_count":303,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15958562","id":"PMC_15958562","title":"Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15958562","citation_count":299,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16489016","id":"PMC_16489016","title":"The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16489016","citation_count":299,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20531406","id":"PMC_20531406","title":"A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers.","date":"2010","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/20531406","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16585184","id":"PMC_16585184","title":"FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16585184","citation_count":284,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18020943","id":"PMC_18020943","title":"FOXM1, a typical proliferation-associated transcription factor.","date":"2007","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18020943","citation_count":283,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21712406","id":"PMC_21712406","title":"FoxM1: a master regulator of tumor metastasis.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21712406","citation_count":269,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25206,"output_tokens":2110,"usd":0.053634},"stage2":{"model":"claude-opus-4-6","input_tokens":5366,"output_tokens":2445,"usd":0.131933},"total_usd":0.39182,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":37082,"output_tokens":2750,"usd":0.076248},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5594,"output_tokens":2348,"usd":0.130005}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"MPP2 (M phase phosphoprotein 2), a forkhead domain transcription factor, was identified as a direct interaction partner of HPV16 E7 protein both in vitro and in vivo in mammalian cells. MPP2 enhances E7/Ha-Ras co-transformation of rat embryo fibroblasts, and HPV16 E7 (but not non-transforming E7 mutants or low-risk HPV6 E7) stimulates MPP2-specific transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, co-immunoprecipitation in mammalian cells, rat embryo fibroblast co-transformation assay, transcriptional activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal in vitro/in vivo binding plus functional transformation assay, single lab\",\n      \"pmids\": [\"10523841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MPP2 interacts with c-Src via its PDZ domain in non-transformed breast epithelial MCF-10A cells, where endogenous MPP2 associates with the cytoskeleton in filamentous structures partially co-localizing with microtubules and c-Src. c-Src kinase activity promotes increased interaction with MPP2. MPP2 negatively regulates c-Src kinase activity in cells and suppresses c-Src-dependent disorganization of the cortical actin cytoskeleton.\",\n      \"method\": \"PDZ domain array screen, co-immunoprecipitation, immunofluorescence/colocalization, kinase activity assay, actin cytoskeleton morphology analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (PDZ array, Co-IP, functional kinase assay), single lab\",\n      \"pmids\": [\"19665017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MPP2 (MAGUK p55 subfamily member 2) localizes to postsynaptic sites in hippocampal neurons and binds to postsynaptic scaffold proteins PSD-95 and GKAP via its C-terminal SH3-GK domain module. MPP2 also directly interacts with the SynCAM1 cell adhesion molecule via its PDZ domain, and does not interact in this manner with other abundant postsynaptic transmembrane proteins, establishing MPP2 as a scaffold linking SynCAM1 to core postsynaptic density proteins.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assay, immunofluorescence colocalization in rat hippocampal neurons, domain-specific interaction mapping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, direct PDZ-domain pulldown, subcellular localization with functional context, multiple interaction partners mapped\",\n      \"pmids\": [\"27756895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MPP2 is situated at the periphery of the postsynaptic density (PSD) at glutamatergic synapses (like SynCAM1), as shown by superresolution imaging. Quantitative comparative proteomics identified multiple GABAA receptor subunits as novel MPP2 interactors. Manipulating MPP2 expression had effects on inhibitory synaptic transmission. GABAA receptors co-localize with MPP2 in a subset of dendritic spines, establishing MPP2 as an adaptor linking peripheral synaptic elements for inhibitory regulation to central PSD structures.\",\n      \"method\": \"Superresolution STORM imaging, quantitative comparative proteomics, electrophysiology (inhibitory synaptic currents), immunofluorescence colocalization\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — superresolution structure, quantitative proteomics interactome, and functional electrophysiology in one study\",\n      \"pmids\": [\"35312684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MPP2 forms a molecular complex with CADM1, CASK, M-cadherin, and Lin7 at the excitatory postsynaptic region and adherens junctions of cerebellar granule cells at the cerebellar glomerulus. In MPP2-deficient mice, the Lin7 staining pattern changes from small rings (surrounding mossy fibers) to a dot/spot pattern, indicating MPP2 influences the distribution of Lin7 to synaptic cell membranes.\",\n      \"method\": \"Immunoprecipitation, immunostaining (Airyscan confocal), MPP2-deficient mouse comparison\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus loss-of-function localization consequence in vivo, single lab\",\n      \"pmids\": [\"35854144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MPP2 interacts with small-conductance calcium-activated potassium channel subtype 2 (SK2) in the basolateral amygdala (BLA). During fear extinction, increased MPP2 levels mediate increased expression of synaptic SK2 channels, rescuing the excitability of glutamatergic BLA neurons and promoting fear extinction.\",\n      \"method\": \"Western blotting, fluorescence quantitative PCR, patch-clamp electrophysiology (IAHP measurement), fear conditioning/extinction behavioral assay\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology plus in vivo behavioral functional readout, single lab\",\n      \"pmids\": [\"37469037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The MPP2-K315N (MPP2-N315) de novo missense mutation has a stronger ability to directly bind ANXA2 (Annexin A2) than wild-type MPP2-K315, as shown by LC-MS/MS and Co-IP. This altered interaction results in activation of the ERK3/IL-17E pathway, increased cytokines (IL-1β, IL-17E, VEGFA), and destruction of barrier function in ARPE19 cells.\",\n      \"method\": \"Trio-based whole-exome sequencing, LC-MS/MS proteomics, co-immunoprecipitation, CRISPR-Cas9 knockout followed by re-expression of WT or mutant MPP2, knock-in mouse model (EAU), cytokine ELISA, barrier function assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — LC-MS/MS interactome, Co-IP, CRISPR-based functional rescue, and in vivo knock-in model; multiple orthogonal methods\",\n      \"pmids\": [\"37828081\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPP2 is a postsynaptic MAGUK scaffold protein that localizes to the periphery of the postsynaptic density, where it links the cell adhesion molecule SynCAM1 to core PSD proteins (PSD-95, GKAP) via its SH3-GK domain and PDZ domain respectively, interacts with GABAA receptor subunits to modulate inhibitory synaptic transmission, binds SK2 potassium channels to regulate neuronal excitability, and interacts with ANXA2 (with a pathogenic K315N mutation activating the ERK3/IL-17E pathway); outside the synapse, MPP2 binds c-Src via its PDZ domain to suppress Src kinase activity and actin cytoskeletal disorganization, and was originally identified as a forkhead transcription factor whose activity is stimulated by HPV16 E7 to enhance cellular transformation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe query gene is **MPP2** = MAGUK p55 subfamily member 2 (membrane protein palmitoylated 2), a postsynaptic scaffold protein with PDZ/SH3/GK domains.\n\n**ALIAS COLLISION WARNING:** Many papers in the corpus describe **DLG2** (Discs Large Homolog 2 / PSD-93), which is a *different* MAGUK family member. DLG2 is NOT MPP2. Additionally, many papers in the gene2pubmed list describe **FOXM1** (Forkhead Box M1), which was previously called \"MPP2\" as an alias but is a completely different protein (transcription factor). These must be EXCLUDED.\n\nPapers about the canonical MPP2 protein (MAGUK p55 subfamily member 2):\n- PMID:27756895 ✅ KEEP — explicitly about MPP2 (MAGUK p55 subfamily member 2) at synapses\n- PMID:19665017 ✅ KEEP — explicitly about MPP2 (Membrane Protein Palmitoylated 2), PDZ protein\n- PMID:35312684 ✅ KEEP — explicitly about MPP2 (membrane protein palmitoylated 2), MAGUK scaffold\n- PMID:37469037 ✅ KEEP — explicitly about MPP2 interacting with SK2 in BLA\n- PMID:35854144 ✅ KEEP — explicitly about MPP2 in cerebellar glomerulus\n- PMID:37828081 ✅ KEEP — explicitly about MPP2 p.K315N mutation in VKH disease\n- PMID:10523841 ✅ KEEP — explicitly about MPP2 (M phase phosphoprotein 2, fork head domain... wait — this paper calls MPP2 a \"fork head domain transcription factor M phase phosphoprotein 2\" — this is the FOXM1 alias collision. EXCLUDE.\n\nAll DLG2 papers: EXCLUDE (different gene)\nAll FOXM1 papers (gene2pubmed list): EXCLUDE (alias collision)\nPMID:10523841: The paper describes \"MPP2\" as a \"fork head domain transcription factor\" = FOXM1 alias. EXCLUDE.\nLarge-scale genomics/interactome papers (PMID:12477932, 15302935, 26496610, 33961781, 22939629, etc.): These are general proteomics papers; any MPP2 mention would be incidental. EXCLUDE from discoveries (no specific mechanistic findings about MPP2).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"MPP2 (MAGUK p55 subfamily member 2) localizes to postsynaptic sites in hippocampal neurons, where its C-terminal SH3-GK domain module mediates binding to the abundant postsynaptic scaffold proteins PSD-95 and GKAP. Additionally, the MPP2 PDZ domain directly binds the C-terminus of the synaptic cell adhesion molecule SynCAM1, but does not interact in this manner with other highly abundant postsynaptic transmembrane proteins, establishing MPP2 as a scaffold linking SynCAM1 to core components of the postsynaptic density.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays (PDZ domain–SynCAM1 C-terminus interaction), immunofluorescence localization in rat hippocampal neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP and direct binding with localization, single lab\",\n      \"pmids\": [\"27756895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MPP2 interacts with the non-receptor tyrosine kinase c-Src via its PDZ domain in non-transformed breast epithelial MCF-10A cells, where endogenous MPP2 associates with the cytoskeleton in filamentous structures partially co-localizing with microtubules and c-Src. c-Src kinase activity promotes increased interaction with MPP2, and MPP2 negatively regulates c-Src kinase activity, thereby suppressing c-Src-dependent disorganization of the cortical actin cytoskeleton.\",\n      \"method\": \"PDZ domain array screen, co-immunoprecipitation in cells, immunofluorescence co-localization, c-Src kinase activity assay, morphological readout of actin cytoskeleton\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — PDZ array + Co-IP + functional kinase assay + phenotypic readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19665017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using superresolution imaging, MPP2 is situated at the periphery of the postsynaptic density (PSD), co-localizing with SynCAM1. Quantitative comparative proteomics identified multiple GABA-A receptor subunits as novel synaptic MPP2 interactors. Manipulating MPP2 expression had functional effects on inhibitory synaptic transmission, and GABA-A receptors were found together with MPP2 in a subset of dendritic spines, establishing MPP2 as an adaptor linking peripheral synaptic elements critical for inhibitory regulation to central PSD structures at glutamatergic synapses.\",\n      \"method\": \"Superresolution (STED/STORM) imaging, quantitative comparative proteomics (AP-MS), electrophysiology (inhibitory synaptic currents upon MPP2 manipulation)\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (superresolution imaging, quantitative proteomics, electrophysiology) in single rigorous study\",\n      \"pmids\": [\"35312684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MPP2 interacts with the small-conductance calcium-activated potassium channel SK2 in the basolateral amygdala (BLA). During fear conditioning, PKA activity reduces synaptic SK2 levels; during fear extinction, MPP2 mediates increased synaptic SK2 channel expression, thereby rescuing the excitability of glutamatergic neurons (via the afterhyperpolarization current IAHP) and facilitating extinction of conditioned fear.\",\n      \"method\": \"Western blotting, fluorescence quantitative PCR, electrophysiology (patch-clamp measurement of IAHP and neuronal excitability), fear conditioning/extinction behavioral assay\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP/interaction plus electrophysiology and behavioral readout, single lab\",\n      \"pmids\": [\"37469037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse cerebellar glomeruli, MPP2 is detected at excitatory postsynaptic regions and adherens junctions of granule cells after postnatal day 14, co-localizing with CADM1, Lin7, CASK, GluN1 (NMDA receptor 1), and M-cadherin. Immunoprecipitation demonstrated that MPP2 forms a molecular complex with CADM1, CASK, M-cadherin, and Lin7. In MPP2-deficient cerebella, the Lin7 staining pattern changed from small rings surrounding mossy fibers to dot/spot patterns inside CADM1-stained rings, indicating that MPP2 controls the distribution of Lin7 to synaptic cell membranes at postsynaptic regions of granule cells.\",\n      \"method\": \"Immunostaining (confocal Airyscan superresolution), co-immunoprecipitation, comparison of wild-type vs. MPP2-deficient mouse cerebella\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus superresolution localization and KO comparison, single lab\",\n      \"pmids\": [\"35854144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A de novo missense mutation in MPP2 (p.K315N, MPP2-N315) increases susceptibility to Vogt-Koyanagi-Harada (VKH) autoimmune uveitis. Knock-in or AAV-mediated expression of MPP2-N315 in mice aggravated experimental autoimmune uveitis pathology and retinal vascular leakage. In ARPE19 cells with the K315N mutation, levels of IL-1β, IL-17E, and VEGFA were increased and barrier function was destroyed. Mechanistically, LC-MS/MS and Co-IP showed that MPP2-N315 has a stronger ability to bind ANXA2 (annexin A2) compared to wild-type MPP2-K315, resulting in activation of the ERK3/IL-17E pathway.\",\n      \"method\": \"Trio-based whole-exome sequencing, knock-in mouse model, AAV gene delivery, CRISPR-Cas9 deletion/rescue, LC-MS/MS, co-immunoprecipitation, cytokine measurement, barrier function assay, in vivo EAU model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including in vivo model, LC-MS/MS interaction, Co-IP, and functional assays in single rigorous study\",\n      \"pmids\": [\"37828081\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPP2 (MAGUK p55 subfamily member 2) is a postsynaptic scaffold protein that localizes to the periphery of the postsynaptic density at glutamatergic synapses, where it links the synaptic cell adhesion molecule SynCAM1 to core PSD proteins (PSD-95, GKAP) via its SH3-GK domains and PDZ domain, associates with GABA-A receptor subunits to modulate inhibitory synaptic transmission, interacts with SK2 potassium channels to regulate neuronal excitability and fear extinction, forms complexes with CADM1/CASK/Lin7 at cerebellar synapses, negatively regulates c-Src kinase activity to maintain actin cytoskeletal organization in epithelial cells, and harbors a disease-associated K315N mutation that aberrantly binds ANXA2 to activate ERK3/IL-17E inflammatory signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MPP2 is a MAGUK p55 subfamily scaffold protein that organizes postsynaptic architecture and modulates both excitatory and inhibitory synaptic signaling. At glutamatergic synapses, MPP2 localizes to the periphery of the postsynaptic density where its PDZ domain binds the cell adhesion molecule SynCAM1/CADM1 and its SH3-GK module links to core PSD scaffolds PSD-95 and GKAP, while it also recruits GABAA receptor subunits to modulate inhibitory transmission and interacts with SK2 potassium channels to regulate neuronal excitability in the amygdala [PMID:27756895, PMID:35312684, PMID:37469037]. Outside the synapse, MPP2 binds c-Src via its PDZ domain and suppresses Src kinase activity and actin cytoskeletal disorganization [PMID:19665017]. A de novo K315N missense mutation in MPP2 enhances binding to ANXA2 and activates the ERK3/IL-17E inflammatory pathway, disrupting epithelial barrier function [PMID:37828081].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"The initial identification of MPP2 revealed it as a forkhead-domain transcription factor that physically interacts with HPV16 E7, establishing its first link to oncogenic signaling and cellular transformation.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation, and rat embryo fibroblast co-transformation assay\",\n      \"pmids\": [\"10523841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous transcriptional targets of MPP2 remain unidentified\",\n        \"No independent replication of the HPV16 E7 interaction\",\n        \"Forkhead domain function not characterized outside HPV context\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that MPP2 directly binds and negatively regulates c-Src kinase via its PDZ domain established a non-transcriptional scaffolding role for MPP2 at the cytoskeleton, showing it restrains Src-dependent actin disorganization.\",\n      \"evidence\": \"PDZ domain array screen, co-immunoprecipitation, kinase activity assay, and actin cytoskeleton morphology analysis in MCF-10A cells\",\n      \"pmids\": [\"19665017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of PDZ–c-Src interaction not resolved\",\n        \"Physiological consequence of MPP2-Src regulation in vivo unknown\",\n        \"Single cell type (MCF-10A) studied\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of MPP2 as a postsynaptic scaffold that bridges SynCAM1 (via PDZ domain) to PSD-95 and GKAP (via SH3-GK module) redefined MPP2 as a synaptic organizer linking cell adhesion to core postsynaptic density architecture.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, PDZ-domain pulldown, and immunofluorescence colocalization in rat hippocampal neurons\",\n      \"pmids\": [\"27756895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of MPP2 loss on SynCAM1-dependent synaptogenesis not tested\",\n        \"Stoichiometry and competitive binding among PDZ ligands unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Superresolution imaging and proteomics placed MPP2 at the PSD periphery and uncovered GABAA receptor subunits as novel interactors, with electrophysiology demonstrating MPP2 influences inhibitory synaptic transmission — extending its role beyond excitatory scaffolding to cross-talk between excitatory and inhibitory synaptic compartments.\",\n      \"evidence\": \"STORM superresolution imaging, quantitative comparative proteomics, electrophysiology of inhibitory currents, and immunofluorescence in hippocampal neurons\",\n      \"pmids\": [\"35312684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding interface between MPP2 and GABAA receptor subunits not mapped\",\n        \"Behavioral consequences of altered inhibitory transmission through MPP2 not assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that MPP2 forms a complex with CADM1, CASK, M-cadherin, and Lin7 at cerebellar glomeruli, and that MPP2 deficiency redistributes Lin7 from ring to dot patterns, established MPP2 as necessary for proper synaptic membrane organization in the cerebellum.\",\n      \"evidence\": \"Immunoprecipitation, Airyscan confocal imaging, and MPP2-deficient mouse analysis\",\n      \"pmids\": [\"35854144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Electrophysiological or behavioral phenotype of MPP2-deficient mice at cerebellar synapses not reported\",\n        \"Mechanism by which MPP2 organizes Lin7 membrane distribution unknown\",\n        \"Single lab observation without independent confirmation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that MPP2 interacts with SK2 channels in the basolateral amygdala and that fear extinction upregulates MPP2 to increase synaptic SK2 expression connected MPP2 scaffolding to regulation of neuronal excitability and a specific behavioral circuit.\",\n      \"evidence\": \"Western blotting, qPCR, patch-clamp electrophysiology measuring IAHP, and fear conditioning/extinction behavioral assay in rodents\",\n      \"pmids\": [\"37469037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding domain between MPP2 and SK2 not mapped\",\n        \"Causal manipulation of MPP2 specifically in BLA not performed\",\n        \"Single lab study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of the de novo K315N mutation in MPP2, which strengthens ANXA2 binding and activates the ERK3/IL-17E inflammatory axis disrupting epithelial barrier function, established the first pathogenic variant of MPP2 and revealed an unexpected role in immune-inflammatory signaling.\",\n      \"evidence\": \"Trio-based whole-exome sequencing, LC-MS/MS proteomics, co-immunoprecipitation, CRISPR-Cas9 knockout/re-expression, knock-in mouse EAU model, cytokine ELISA, barrier function assay in ARPE19 cells\",\n      \"pmids\": [\"37828081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How K315N structurally enhances ANXA2 binding is unresolved\",\n        \"Whether the ERK3/IL-17E pathway is relevant in neuronal contexts unknown\",\n        \"Prevalence and penetrance of K315N in uveitis populations not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how MPP2's multiple PDZ-domain interactions (SynCAM1, c-Src, GABAA receptors, SK2) are coordinated or competed at single synapses, what MPP2's endogenous transcriptional targets are, and whether the inflammatory signaling function revealed by K315N reflects a normal physiological role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of full-length MPP2 or its multi-protein complexes\",\n        \"Comprehensive behavioral phenotyping of MPP2 knockout mice not reported\",\n        \"Relationship between synaptic scaffolding and transcription factor functions unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"SynCAM1–MPP2–PSD-95–GKAP postsynaptic complex\",\n      \"CADM1–MPP2–CASK–Lin7 complex\"\n    ],\n    \"partners\": [\n      \"DLG4\",\n      \"CADM1\",\n      \"DLGAP1\",\n      \"CASK\",\n      \"LIN7A\",\n      \"SRC\",\n      \"ANXA2\",\n      \"KCNN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MPP2 is a MAGUK p55 subfamily scaffold protein that organizes signaling complexes at postsynaptic sites and epithelial cell junctions through its PDZ, SH3, and GK domains. At glutamatergic synapses, MPP2 localizes to the periphery of the postsynaptic density, where its PDZ domain binds the synaptic adhesion molecule SynCAM1 and its SH3-GK module engages core PSD scaffolds PSD-95 and GKAP; it additionally recruits GABA-A receptor subunits to dendritic spines, modulating inhibitory synaptic transmission, and interacts with SK2 potassium channels in the basolateral amygdala to regulate neuronal excitability during fear extinction [PMID:27756895, PMID:35312684, PMID:37469037]. In cerebellar granule cells, MPP2 forms a complex with CADM1, CASK, and Lin7 and is required for proper Lin7 distribution at synaptic membranes [PMID:35854144]. A de novo MPP2 p.K315N missense mutation confers susceptibility to Vogt-Koyanagi-Harada autoimmune uveitis by enhancing binding to ANXA2 and activating the ERK3/IL-17E inflammatory pathway, establishing a direct disease link [PMID:37828081].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"The first functional characterization of MPP2 outside neurons revealed that its PDZ domain engages the tyrosine kinase c-Src and that MPP2 negatively regulates c-Src activity, establishing a role in maintaining epithelial actin cytoskeletal organization.\",\n      \"evidence\": \"PDZ domain array screen, co-immunoprecipitation, kinase activity assay, and actin morphology readout in MCF-10A breast epithelial cells\",\n      \"pmids\": [\"19665017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vivo validation of the MPP2–c-Src interaction\",\n        \"Mechanism by which MPP2 inhibits c-Src kinase activity is undefined\",\n        \"Relevance of this epithelial role to neuronal MPP2 function not addressed\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"MPP2 was shown to be a postsynaptic scaffold that bridges SynCAM1 (via its PDZ domain) to core PSD components PSD-95 and GKAP (via its SH3-GK module), establishing its domain-specific wiring logic at excitatory synapses.\",\n      \"evidence\": \"Co-immunoprecipitation, direct PDZ–SynCAM1 C-terminus binding assay, and immunofluorescence in rat hippocampal neurons\",\n      \"pmids\": [\"27756895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of disrupting the MPP2–SynCAM1 link on synaptic transmission was not tested\",\n        \"Structural basis of the SH3-GK interaction with PSD-95/GKAP not resolved\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Superresolution imaging and quantitative proteomics placed MPP2 at the PSD periphery and identified GABA-A receptor subunits as novel interactors, with electrophysiology demonstrating that MPP2 levels influence inhibitory synaptic currents—establishing MPP2 as a bridge between excitatory and inhibitory synaptic machinery within single spines.\",\n      \"evidence\": \"STED/STORM imaging, AP-MS quantitative proteomics, and patch-clamp electrophysiology upon MPP2 manipulation\",\n      \"pmids\": [\"35312684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding between MPP2 and specific GABA-A subunits not demonstrated with purified proteins\",\n        \"Whether MPP2 loss phenocopies in vivo inhibitory synapse dysfunction is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In cerebellar granule cells, MPP2 was found to complex with CADM1, CASK, Lin7, and M-cadherin at excitatory postsynaptic regions and adherens junctions; loss of MPP2 disrupted Lin7 targeting to synaptic membranes, revealing MPP2 as an essential organizer of this multi-protein complex.\",\n      \"evidence\": \"Confocal Airyscan superresolution imaging, co-immunoprecipitation, and comparison of wild-type versus MPP2-deficient mouse cerebella\",\n      \"pmids\": [\"35854144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Electrophysiological or behavioral consequences of disrupted Lin7 localization in MPP2-deficient mice not assessed\",\n        \"Whether the CADM1/CASK/Lin7 complex exists at non-cerebellar synapses with MPP2 is unknown\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MPP2 was linked to SK2 potassium channel trafficking at basolateral amygdala synapses, where it increases synaptic SK2 during fear extinction, thereby restoring the afterhyperpolarization current and facilitating extinction learning—connecting MPP2 scaffolding to behavioral-level neuronal excitability.\",\n      \"evidence\": \"Co-immunoprecipitation, patch-clamp electrophysiology measuring IAHP and excitability, and fear conditioning/extinction behavioral assay in mice\",\n      \"pmids\": [\"37469037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding domain on MPP2 responsible for SK2 interaction not mapped\",\n        \"Single-lab study without independent replication\",\n        \"Whether MPP2–SK2 interaction occurs at other brain regions is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A de novo K315N missense mutation in MPP2 was identified as a susceptibility factor for Vogt-Koyanagi-Harada uveitis, with the mutant protein gaining enhanced ANXA2 binding and activating ERK3/IL-17E inflammatory signaling, demonstrating a pathogenic gain-of-function mechanism.\",\n      \"evidence\": \"Trio-based whole-exome sequencing, CRISPR knock-in mouse model, AAV delivery, LC-MS/MS interactomics, co-immunoprecipitation, cytokine and barrier function assays, and experimental autoimmune uveitis model\",\n      \"pmids\": [\"37828081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether wild-type MPP2 normally interacts with ANXA2 at physiological levels is unclear\",\n        \"Structural basis for how K315N enhances ANXA2 binding not resolved\",\n        \"Prevalence of MPP2 mutations in broader VKH patient cohorts not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how MPP2's synaptic scaffolding functions (SynCAM1/PSD-95/GABA-A receptor/SK2 organization) are coordinately regulated, whether MPP2 undergoes post-translational modifications that switch its binding partners in different cellular contexts, and whether its epithelial c-Src regulatory role intersects with its neuronal functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of full-length MPP2 or its multi-domain complexes exists\",\n        \"Post-translational regulation of MPP2 is unexplored\",\n        \"Comprehensive in vivo phenotyping of MPP2 knockout beyond cerebellum is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"CADM1/CASK/Lin7/MPP2 complex\"\n    ],\n    \"partners\": [\n      \"DLG4\",\n      \"CADM1\",\n      \"DLGAP1\",\n      \"CASK\",\n      \"LIN7A\",\n      \"KCNN2\",\n      \"ANXA2\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}