{"gene":"DLG2","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":1996,"finding":"Chapsyn-110 (DLG2/PSD-93) directly binds NMDA receptor and Shaker K+ channel subunits via its PDZ domains, mediates clustering of both NMDA receptors and K+ channels in heterologous cells, and heteromultimerizes with PSD-95 to be recruited into the same receptor/channel clusters at postsynaptic sites.","method":"Heterologous cell clustering assay, co-immunoprecipitation, immunostaining in rat brain","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (clustering assay, co-IP, immunostaining), highly cited foundational paper","pmids":["8755482"],"is_preprint":false},{"year":2001,"finding":"PSD-93 localizes to postsynaptic densities of excitatory synapses in visual cortex, but also occurs along presynaptic membranes and in axonal/dendritic cytoplasm, suggesting dual roles in maintaining receptors at synapses and regulating receptor shuttling between nonsynaptic and synaptic sites.","method":"Electron microscopic immunocytochemistry with quantitative immunogold labeling","journal":"Synapse","confidence":"High","confidence_rationale":"Tier 1/2 — rigorous quantitative EM-ICC with systematic analysis across multiple compartments","pmids":["11309840"],"is_preprint":false},{"year":2001,"finding":"PSD-93 knockout in mice does not impair development or function of cerebellar parallel fiber synapses, indicating PSD-93 is not essential for synaptic development at these central synapses but may participate in specialized synaptic signaling; PSD-93 interacting proteins remain correctly localized in its absence.","method":"Targeted gene disruption (knockout mouse), electrophysiology, immunohistochemistry, electron microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal readouts (behavior, electrophysiology, morphology)","pmids":["11312293"],"is_preprint":false},{"year":2003,"finding":"PSD-93 is identified as a substrate for the Src family tyrosine kinase Fyn; Fyn phosphorylates PSD-93 in vitro at Tyr-384, phosphorylation is greatly reduced in Fyn-deficient mouse brain, and the N-terminal palmitoylation signal of PSD-93 is essential for membrane anchoring required for Fyn-mediated phosphorylation. Tyrosine-phosphorylated PSD-93 binds Csk (a negative regulator of Src kinases).","method":"In vitro kinase assay with recombinant proteins, phosphosite mutagenesis, Fyn-knockout mouse brain, co-immunoprecipitation, COS7 cell expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution, mutagenesis, genetic validation in Fyn-KO mice, multiple orthogonal methods","pmids":["13129934"],"is_preprint":false},{"year":2003,"finding":"Knockdown of spinal cord PSD-93 by intrathecal antisense oligodeoxynucleotide significantly attenuates thermal and mechanical hyperalgesia in CFA-induced inflammatory pain and peripheral nerve injury-induced neuropathic pain without affecting acute nociception or locomotion, indicating PSD-93 is required for central sensitization in chronic pain.","method":"Intrathecal antisense oligodeoxynucleotide knockdown, behavioral pain testing (CFA and nerve injury models)","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 — clean knockdown with specific behavioral phenotype, but single lab","pmids":["14581127"],"is_preprint":false},{"year":2003,"finding":"PSD-93 colocalizes and co-immunoprecipitates with NMDA receptor and nNOS in cortical neurons; PSD-93 deletion prevents NMDA receptor–nNOS complex formation, attenuates PAF-induced NMDA receptor–nitric oxide signaling neurotoxicity, and reduces cGMP elevation, placing PSD-93 as an essential scaffold linking NMDA receptors to nNOS-mediated neuronal injury.","method":"PSD-93 knockout neurons, co-immunoprecipitation, cGMP measurement, cell death assay","journal":"Experimental neurology","confidence":"High","confidence_rationale":"Tier 2 — KO neurons with defined molecular mechanism, multiple endpoints","pmids":["15296832"],"is_preprint":false},{"year":2004,"finding":"PSD-93 co-immunoprecipitates with neuronal nicotinic acetylcholine receptors (nAChRs) in superior cervical ganglion in vivo, is enriched in the PSD fraction of ganglia, and PSD-93 knockout mice show accelerated disassembly of nAChR synaptic clusters after denervation, demonstrating PSD-93 is required for stability of neuronal cholinergic synapses.","method":"Co-immunoprecipitation, subcellular fractionation, immunostaining, PSD-93 knockout mouse denervation model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, fractionation, and KO functional phenotype in vivo","pmids":["14724236"],"is_preprint":false},{"year":2004,"finding":"An alternatively spliced isoform of PSD-93 (PSD-93δ) directly binds inwardly rectifying potassium channel Kir2.1 via a type I PDZ recognition motif at the extreme C-terminus of Kir2.1; co-expression results in Kir2.1 clustering at the cell surface and suppression of channel internalization without changing channel kinetics.","method":"Yeast two-hybrid, in vitro PDZ-binding assay, co-immunoprecipitation from rat spinal cord, heterologous cell surface clustering","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple binding assays, native tissue co-IP, functional clustering readout","pmids":["15304517"],"is_preprint":false},{"year":2008,"finding":"PSD-93 and PSD-95 have opposing roles in synaptic plasticity: PSD-93 knockout mice exhibit deficits in LTP and normal LTD, whereas PSD-95 knockouts facilitate LTP and disrupt LTD, indicating these MAGUKs form distinct NMDA receptor signaling complexes that differentially regulate LTP induction.","method":"Knockout mice, hippocampal CA1 electrophysiology, LTP/LTD induction protocols","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined electrophysiological phenotype, genetic epistasis between paralogs","pmids":["18936077"],"is_preprint":false},{"year":2008,"finding":"PSD-93 and PSD-95 are distributed homogeneously throughout isolated PSDs, consistent with their function as backbone scaffold proteins that stabilize binding partners within the PSD.","method":"Immunogold labeling and rotary shadow electron microscopy of isolated PSDs","journal":"Brain cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative EM mapping, single study","pmids":["18392731"],"is_preprint":false},{"year":2010,"finding":"PSD-95 (but not PSD-93) is required for localizing NR2A-containing NMDA receptor complexes to lipid rafts; deletion of NR2A C-terminus or NR2B C-terminal valine (PDZ-binding) reduces NR1 association with rafts. Raft versus PSD PSD-95 complexes show differential composition (less CaMKIIα/SynGAP, enriched Src/Arc in rafts).","method":"Tandem affinity purification from knock-in mice, lipid raft isolation, PSD-93 and PSD-95 knockout mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — genetically encoded tags, KO validation, multiple fractions compared","pmids":["20554866"],"is_preprint":false},{"year":2011,"finding":"PSD-93 and PSD-95 are necessary for synaptic scaling but serve distinct roles: scaling down requires PSD-95 (via PDZ1/2 domains), while scaling up can be supported by either PSD-95 or PSD-93 in an age-dependent manner. Neither MAGUK drives homeostatic scaling by changes in synaptic abundance; they act as organizers using distinct protein-protein interactions.","method":"shRNA knockdown and overexpression in neurons, mEPSC recording, PSD-93/95 mutant analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — bidirectional manipulation, specific domain requirements identified, clean electrophysiological readouts","pmids":["21543610"],"is_preprint":false},{"year":2012,"finding":"ERK2 directly binds PSD-93 via an N-terminal region, and active ERK2 phosphorylates PSD-93 at Ser323 in vitro; native ERK from synaptosomal fractions also associates with PSD-93 in rat striatal neurons, and immunoprecipitated PSD-93 shows basal ERK-sensitive phosphorylation in vivo.","method":"In vitro protein-protein interaction with purified proteins, in vitro kinase assay, co-immunoprecipitation from synaptosomal fractions","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with phosphosite identification, supported by native tissue co-IP; single lab","pmids":["22618309"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of PSD-93 PDZ1 with GluD2 C-terminal peptide (GTSI) reveals two binding modes suggesting weak interaction; fluorescence polarization shows no appreciable affinity for GluD2 C-terminal octapeptide but micromolar affinity for GluN2B-derived C-terminal octapeptide, indicating PDZ1/2 preferentially bind GluN2B over GluD2.","method":"X-ray crystallography, fluorescence polarization spectroscopy","journal":"Acta crystallographica. Section D","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus quantitative binding assay, orthogonal methods","pmids":["23519667"],"is_preprint":false},{"year":2014,"finding":"PSD-93 deletion reduces phosphorylation of NR2B at Tyr1472 and the interaction between NR2B and Fyn after focal cerebral ischemia, and ischemic LTP cannot be induced in PSD-93 KO mice, demonstrating that PSD-93 mediates Fyn-dependent phosphorylation of NR2B and downstream excitotoxicity.","method":"PSD-93 knockout mouse, MCAO model, Western blot for phospho-NR2B, pharmacological inhibitors (AP-5, PP2), co-immunoprecipitation","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — KO + pharmacology + co-IP defining mechanism, multiple endpoints","pmids":["24787897"],"is_preprint":false},{"year":2018,"finding":"DLG2 regulates cell division, migration, and tumorigenesis in osteosarcoma: DLG2-deficient osteosarcoma cell lines show dysregulated cell division and migration in vitro, and osteoblast-specific Dlg2 deletion in mice accelerates osteosarcoma development in vivo.","method":"DLG2-deficient human/canine cell lines (functional assays), osteoblast-specific Dlg2 conditional knockout mouse model, cross-species comparative genomics","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple species validation, conditional KO mouse model with tumor phenotype, multiple functional assays","pmids":["30093633"],"is_preprint":false},{"year":2020,"finding":"PSD-93 directly interacts with SynGAP, and this interaction mediates SynGAP ubiquitination and proteasomal degradation following cerebral ischemia/reperfusion; the 670-685 amino acid sequence of SynGAP is essential for binding to PSD-93. PSD-93 KO mice show preserved SynGAP levels and reduced infarct volume, rescued by neither MG-132 nor MK801.","method":"Co-immunoprecipitation, PSD-93 knockout mice, MCAO model, peptide competition (Tat-SynGAP), proteasome inhibitor MG-132, NMDAR inhibitor MK801, Western blot","journal":"Translational stroke research","confidence":"High","confidence_rationale":"Tier 2 — KO + inhibitor epistasis + domain mapping + peptide competition; multiple orthogonal approaches","pmids":["32130656"],"is_preprint":false},{"year":2020,"finding":"Dlg2 knockout mice show reduced excitatory (but not inhibitory) spontaneous postsynaptic current frequency in the dorsolateral striatum, accompanied by ASD-like behavioral deficits (reduced social approach, increased self-grooming), establishing DLG2 as necessary for excitatory synaptic transmission in the striatum.","method":"Dlg2 exon 14 knockout mouse, patch-clamp electrophysiology in striatal slices, behavioral battery, in situ hybridization","journal":"Molecular autism","confidence":"High","confidence_rationale":"Tier 2 — KO with defined synaptic and behavioral phenotypes, multiple readouts","pmids":["32164788"],"is_preprint":false},{"year":2020,"finding":"DLG2 knockdown in MIN6 pancreatic beta cells impairs glucose-stimulated and non-glucose-stimulated insulin secretion, establishing DLG2 as a regulator of insulin secretion.","method":"RNA interference (siRNA knockdown) in MIN6 cells, insulin secretion assay","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with specific functional readout; single study","pmids":["32356104"],"is_preprint":false},{"year":2021,"finding":"PSD-93 binds CX3CL1 (fractalkine) at specific domains (420-535 aa of PSD-93; 357-395 aa of CX3CL1), and this interaction peaks at 6 h after ischemia/reperfusion; blockade of this interaction with a fusion peptide (Tat-CX3CL1) reduces pro-inflammatory cytokine expression and provides neuroprotection.","method":"Co-immunoprecipitation, peptide competition, MCAO model in mice, cytokine measurement","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with domain mapping, functional peptide blockade; single lab","pmids":["33599284"],"is_preprint":false},{"year":2021,"finding":"DLG2 isoform 7 (containing the L27 domain) binds LIN7A, and increased DLG2-isoform 7 expression increases LIN7A expression, reduces neuroblastoma cell proliferation and viability, and increases the BAX/BCL2 ratio (indicating apoptosis); L27 domain-lacking isoform 2 does not show these effects.","method":"Co-immunoprecipitation/binding assay, isoform overexpression in neuroblastoma cells, cell viability/proliferation assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and OE with functional readout; single lab, single study","pmids":["33726762"],"is_preprint":false},{"year":2022,"finding":"DLG2 overexpression increases expression of IL1B, IκBζ, and BAX (inflammasome components), while DLG2 silencing in THP1 cells increases IL-6 release leading to STAT3 phosphorylation in bystander cells; DLG2 restoration reduces AKT and S6 signaling, placing DLG2 as a regulator of inflammasome formation and inflammatory signaling.","method":"DLG2 overexpression and siRNA knockdown in colon cancer/THP1 cells, cytokine ELISA, Western blot for signaling proteins","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation (OE and KD) with defined molecular readouts; single lab","pmids":["35499706"],"is_preprint":false},{"year":2022,"finding":"DLG2 overexpression impairs NHEJ DNA repair genes PARP1 and FEN1 expression, reduces DNA fragmentation after UVC radiation, promotes CHK1 phosphorylation (G2/M checkpoint), and increases p53 S46-dependent apoptosis, establishing DLG2 as a regulator of DNA double-strand break repair and genomic integrity.","method":"Comet assay, H2AX phosphorylation, UVC irradiation, Western blot, Drosophila model, neuroblastoma cell lines","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays (comet, γH2AX, apoptosis), cross-species validation in Drosophila; single lab","pmids":["35217496"],"is_preprint":false},{"year":2022,"finding":"In Dlg2+/- rats, reduced DLG2 causes increased potassium channel function (reduced input resistance) that impairs supra-linear dendritic integration and associative LTP; NMDA receptor-mediated currents are paradoxically increased while AMPA currents are unaffected. Blockade of potassium channels or muscarinic M1 receptor activation rescues LTP, placing DLG2 upstream of potassium channel regulation in dendritic integration.","method":"Heterozygous Dlg2+/- rat, ex vivo patch-clamp electrophysiology, pharmacology (K+ channel blockers, M1 agonist), computational modelling","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 1-2 — electrophysiology + pharmacological rescue + computational modelling in clinically relevant model","pmids":["35115661"],"is_preprint":false},{"year":2022,"finding":"Rho-kinase/ROCK directly phosphorylates DLG2/PSD-93 at Thr612 downstream of NMDA receptor activation. Chemical LTP induction increases PSD-93 Thr612 phosphorylation, spine enlargement, and PSD-93 colocalization with PSD-95; these effects are blocked by Rho-kinase inhibition. PSD-93-interacting proteins identified by LC-MS/MS include PSD-95, NMDARs, SynGAP1, ADAM22, and LGI1; phosphorylation increases PSD-93 binding to PSD-95 and NMDARs.","method":"In vitro kinase assay (ROCK phosphorylation of PSD-93), mutagenesis of Thr612, chemical LTP in striatal slices, LC-MS/MS interactome, co-immunoprecipitation, confocal imaging","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay + phosphosite ID + MS interactome + functional LTP assay + co-IP","pmids":["36613848"],"is_preprint":false},{"year":2022,"finding":"DLG2 deficiency causes reduced density of postsynaptic densities and perforated synapses, decreased dendritic spine density in striatal (but not cortical) neurons, and compensatory increases of DLG4/PSD-95 and decreases in TrkA in the striatum, establishing a cell-type-specific role for DLG2 in maintaining striatal synapse structure.","method":"Dlg2 exon 14 KO mice, transmission electron microscopy, dendritic spine analysis, Western blot, patch-clamp (mEPSC)","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 — TEM + electrophysiology + protein quantification in KO mice, multiple orthogonal readouts","pmids":["35966008"],"is_preprint":false},{"year":2022,"finding":"DLG2 knockout in human embryonic stem cells down-regulates transcriptional programs for early neurogenesis, impairing neuronal migration, morphology, and action potential generation during differentiation to cortical excitatory neurons.","method":"DLG2 knockout hESCs, RNA-seq, neuronal differentiation assays (migration, morphology, electrophysiology)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — KO in human cells with multiple functional readouts (migration, morphology, AP generation), transcriptomics","pmids":["35031607"],"is_preprint":false},{"year":2017,"finding":"A DLG2 missense variant (F900V) associated with delayed puberty impairs the interaction between PSD-93 and Fyn, decreases GnRH expression in a GnRH neuronal cell line, linking DLG2-Fyn interaction to NMDA receptor signaling controlling GnRH secretion and pubertal timing.","method":"Exome sequencing, in vitro co-immunoprecipitation (F900V interaction with Fyn), GnRH expression assay in neuronal cell line","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional consequence in cell line; single study with human variant","pmids":["32341572"],"is_preprint":false},{"year":2017,"finding":"PSD-93 interacts with somatostatin receptor 4 (SSTR4) and affects SSTR4 membrane levels through ubiquitination; PSD-93 overexpression in APP/PS1 mice increases SSTR4 and neprilysin expression and reduces amyloid plaque load.","method":"Co-immunoprecipitation, ubiquitination assay, lentivirus-mediated PSD-93 overexpression in APP/PS1 mice, behavioral and biochemical readouts","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP + ubiquitination assay + in vivo rescue; single lab","pmids":["28697571"],"is_preprint":false},{"year":2026,"finding":"Src kinase phosphorylates PSD-93 more robustly than PSD-95 at multiple sites in vitro; phosphorylation differentially reduces affinity of PSD-93 for postsynaptic client proteins, and reduces PSD-93's ability to recruit key synaptic clients into supercomplexes (scaffolding activity), while also affecting biomolecular condensation of PSD-93 (but not PSD-95). SAXS and smFRET reveal phosphorylation alters PSD-93 dynamics but not overall supertertiary structure.","method":"In vitro kinase assay (Src kinase, multiple substrates), affinity measurements, supercomplex reconstitution, biomolecular condensation assay, SAXS, smFRET","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal structural and functional methods","pmids":["41562278"],"is_preprint":false}],"current_model":"DLG2/PSD-93 is a postsynaptic MAGUK scaffold protein that directly binds NMDA receptor subunits (preferentially GluN2B via PDZ domains), Shaker and Kir2.1 K+ channels, SynGAP, CX3CL1, and LIN7A to organize receptor-signaling complexes at excitatory synapses; it is phosphorylated by Fyn at Tyr-384 (promoting Csk recruitment), by ERK2 at Ser-323, and by Rho-kinase/ROCK at Thr-612 (which increases PSD-93 association with PSD-95 and NMDARs to regulate structural plasticity), and by Src kinase at multiple sites (reducing client-protein affinity and scaffolding activity); it controls LTP/LTD bidirectionality and synaptic scaling through distinct PDZ-domain interactions, maintains dendritic spine density and postsynaptic density structure in the striatum, regulates SynGAP ubiquitination and degradation after ischemia, and plays isoform-dependent roles in neuronal differentiation, inflammasome formation, DNA damage response, and insulin secretion."},"narrative":{"teleology":[{"year":1996,"claim":"Identifying DLG2 as a PDZ-domain scaffold that clusters NMDA receptors and K+ channels at synapses and heteromultimerizes with PSD-95 established the foundational model of MAGUK-mediated receptor organization at the postsynaptic density.","evidence":"Heterologous cell clustering assays, co-immunoprecipitation, and immunostaining in rat brain","pmids":["8755482"],"confidence":"High","gaps":["Stoichiometry and hierarchy of DLG2 versus PSD-95 within native complexes undefined","Functional consequence of clustering on channel/receptor gating not tested"]},{"year":2001,"claim":"Ultrastructural mapping revealed DLG2 is concentrated at postsynaptic densities but also present presynaptically and in trafficking compartments, while genetic deletion showed it is dispensable for cerebellar synapse formation, raising the question of synapse-type-specific necessity.","evidence":"Quantitative immunogold EM in visual cortex; Dlg2 knockout mouse with electrophysiology and morphology at cerebellar synapses","pmids":["11309840","11312293"],"confidence":"High","gaps":["Which synapse types require DLG2 remained unclear","Compensatory upregulation of other MAGUKs in KO not fully assessed"]},{"year":2003,"claim":"Identification of Fyn-mediated phosphorylation at Tyr-384 and consequent Csk recruitment, together with the requirement for palmitoylation-dependent membrane anchoring, revealed the first post-translational regulatory axis controlling DLG2 scaffold function.","evidence":"In vitro kinase assays, phosphosite mutagenesis, Fyn-KO mouse brain, co-IP in COS7 cells","pmids":["13129934"],"confidence":"High","gaps":["Functional consequence of Tyr-384 phosphorylation on synaptic receptor clustering not directly measured","Identity of phosphatase reversing this modification unknown"]},{"year":2003,"claim":"Demonstration that DLG2 scaffolds NMDA receptors to nNOS, mediating excitotoxic NO signaling, and that DLG2 knockdown in spinal cord attenuates chronic pain, placed DLG2 as a druggable node linking receptor activation to downstream pathological signaling.","evidence":"PSD-93 KO neurons with cGMP/cell-death readouts; intrathecal antisense knockdown with behavioral pain models","pmids":["15296832","14581127"],"confidence":"High","gaps":["Whether disrupting DLG2-nNOS coupling spares physiological NMDAR signaling not tested","Antisense knockdown specificity not independently validated"]},{"year":2004,"claim":"DLG2 was shown to stabilize nicotinic acetylcholine receptor clusters at cholinergic synapses and to bind Kir2.1 channels via PDZ interactions, broadening its role beyond glutamatergic synapses to a general ion channel scaffold.","evidence":"Co-IP and denervation in PSD-93 KO superior cervical ganglia; yeast two-hybrid and surface clustering for Kir2.1","pmids":["14724236","15304517"],"confidence":"High","gaps":["Whether DLG2 regulates Kir2.1 surface expression in vivo not demonstrated","Mechanism by which DLG2 prevents nAChR cluster disassembly unknown"]},{"year":2008,"claim":"Opposing roles of DLG2 and PSD-95 in LTP versus LTD revealed that paralogous MAGUKs form functionally distinct NMDAR signaling complexes, resolving why both scaffolds coexist at synapses.","evidence":"Hippocampal CA1 electrophysiology in DLG2-KO and PSD-95-KO mice","pmids":["18936077"],"confidence":"High","gaps":["Molecular basis for why DLG2 favors LTP-promoting complexes not identified","Double-KO epistasis not tested"]},{"year":2011,"claim":"Establishing that DLG2 and PSD-95 serve overlapping but distinct roles in homeostatic synaptic scaling—with scaling up supported by either MAGUK and scaling down requiring PSD-95—added a non-Hebbian plasticity dimension to DLG2 function.","evidence":"shRNA knockdown and overexpression in neurons with mEPSC recording and domain mutant analysis","pmids":["21543610"],"confidence":"High","gaps":["Signaling pathway linking DLG2 to scaling-up effectors unresolved","In vivo relevance of DLG2 in homeostatic plasticity not tested"]},{"year":2012,"claim":"ERK2 was identified as a second kinase directly phosphorylating DLG2 (at Ser-323) and binding its N-terminal region, linking MAPK signaling to scaffold regulation in striatal neurons.","evidence":"In vitro kinase assay with purified proteins, co-IP from striatal synaptosomal fractions","pmids":["22618309"],"confidence":"Medium","gaps":["Functional consequence of Ser-323 phosphorylation on DLG2 interactions or plasticity not determined","Not independently replicated"]},{"year":2013,"claim":"Structural resolution of DLG2 PDZ1 bound to GluN2B-derived peptide, combined with quantitative affinity data showing preference for GluN2B over GluD2, provided the first atomic-level view of DLG2's selectivity among glutamate receptor subunits.","evidence":"X-ray crystallography and fluorescence polarization spectroscopy","pmids":["23519667"],"confidence":"High","gaps":["Full-length DLG2 structure or supramolecular arrangement within the PSD unknown","PDZ2/3 domain selectivity not structurally resolved"]},{"year":2014,"claim":"Placing DLG2 as a required scaffold for Fyn-dependent NR2B Tyr-1472 phosphorylation after cerebral ischemia defined the mechanism by which DLG2 promotes excitotoxic signaling in stroke.","evidence":"DLG2-KO mice in MCAO model with phospho-NR2B Western blot, pharmacological inhibitors, co-IP","pmids":["24787897"],"confidence":"High","gaps":["Whether DLG2 deletion is neuroprotective long-term after stroke not assessed","Contribution of DLG2-independent Fyn pathways unclear"]},{"year":2017,"claim":"A human DLG2 missense variant (F900V) disrupting PSD-93–Fyn interaction and reducing GnRH expression linked DLG2 scaffold function to neuroendocrine regulation and delayed puberty, extending its physiology beyond synaptic plasticity.","evidence":"Exome sequencing, co-IP of F900V mutant with Fyn, GnRH expression in neuronal cell line","pmids":["32341572"],"confidence":"Medium","gaps":["Single family study; replication in independent cohorts needed","In vivo GnRH neuron-specific mechanism not demonstrated"]},{"year":2018,"claim":"Demonstrating that DLG2 deficiency dysregulates cell division and migration and that osteoblast-specific Dlg2 deletion accelerates osteosarcoma established a tumor-suppressive function outside the nervous system.","evidence":"DLG2-deficient cell lines, conditional KO mouse osteosarcoma model, cross-species genomics","pmids":["30093633"],"confidence":"High","gaps":["Molecular mechanism of tumor suppression (which DLG2 interaction is critical) not defined","Relevance to human osteosarcoma patients not clinically validated"]},{"year":2020,"claim":"Identification of DLG2 as a mediator of SynGAP ubiquitination/degradation after ischemia, combined with domain mapping (SynGAP 670-685), revealed a scaffold-dependent proteostatic mechanism for excitotoxic signaling.","evidence":"Co-IP, PSD-93-KO in MCAO model, Tat-SynGAP peptide competition, proteasome/NMDAR inhibitor epistasis","pmids":["32130656"],"confidence":"High","gaps":["E3 ubiquitin ligase recruited by DLG2 for SynGAP ubiquitination not identified","Whether this mechanism operates in non-ischemic contexts unknown"]},{"year":2020,"claim":"DLG2 knockout in striatum selectively reduced excitatory synaptic frequency and produced ASD-like behaviors, while DLG2 knockdown in beta cells impaired insulin secretion, demonstrating circuit-specific and metabolic functions.","evidence":"Dlg2-KO mice with patch-clamp and behavioral battery; siRNA in MIN6 cells with insulin secretion assay","pmids":["32164788","32356104"],"confidence":"High","gaps":["Mechanism linking DLG2 to insulin granule exocytosis unknown","Which DLG2 isoform mediates striatal versus beta-cell function unresolved"]},{"year":2022,"claim":"ROCK-mediated phosphorylation of DLG2 at Thr-612 during chemical LTP was shown to strengthen DLG2 association with PSD-95 and NMDARs, directly coupling activity-dependent kinase signaling to structural plasticity of the scaffold complex.","evidence":"In vitro ROCK kinase assay, Thr612 mutagenesis, chemical LTP in striatal slices, LC-MS/MS interactome, co-IP, confocal imaging","pmids":["36613848"],"confidence":"High","gaps":["Whether Thr-612 phosphorylation is necessary for LTP in vivo not demonstrated with phospho-dead knock-in","Phosphatase opposing ROCK at this site unknown"]},{"year":2022,"claim":"DLG2 KO in human embryonic stem cells impaired transcriptional programs for neurogenesis including migration, morphology, and action potential generation, establishing a cell-autonomous role in human cortical neuron development.","evidence":"DLG2-KO hESCs differentiated to cortical excitatory neurons, RNA-seq, functional assays","pmids":["35031607"],"confidence":"High","gaps":["Whether developmental role requires PDZ-domain scaffolding or a transcriptional mechanism unclear","In vivo human relevance not validated"]},{"year":2022,"claim":"Reduced DLG2 dosage in heterozygous rats increased potassium channel function, impairing dendritic integration and LTP, rescuable by K+ channel blockers or M1 receptor activation, defining a channelopathy-like mechanism for DLG2 haploinsufficiency.","evidence":"Dlg2+/- rat, ex vivo patch-clamp, pharmacological rescue, computational modelling","pmids":["35115661"],"confidence":"High","gaps":["Identity of the specific potassium channel(s) dysregulated not determined","Whether M1 agonist rescue translates to behavioral improvement unknown"]},{"year":2022,"claim":"Parallel studies showed DLG2 modulates DNA damage repair (suppressing NHEJ via PARP1/FEN1, promoting CHK1-mediated checkpoint), inflammasome signaling (IL1B, IκBζ induction), and striatal synapse ultrastructure, revealing diverse non-canonical functions.","evidence":"Comet assay, γH2AX, UVC irradiation, Drosophila model; DLG2 OE/KD in THP1/colon cancer cells; TEM in Dlg2-KO striatum","pmids":["35217496","35499706","35966008"],"confidence":"Medium","gaps":["Whether DNA repair and inflammasome functions operate via scaffold activity or a distinct mechanism unknown","Non-neuronal roles not validated in vivo beyond overexpression"]},{"year":2026,"claim":"Src kinase phosphorylation of DLG2 at multiple sites was shown to reduce client-protein affinity, impair supercomplex assembly, and alter biomolecular condensation without changing supertertiary structure, establishing phosphorylation as a general rheostat for DLG2 scaffolding capacity.","evidence":"In vitro Src kinase assay, affinity measurements, supercomplex reconstitution, condensation assay, SAXS, smFRET","pmids":["41562278"],"confidence":"High","gaps":["In vivo relevance of Src-mediated DLG2 regulation at synapses not demonstrated","Which specific phosphosites are most functionally consequential not resolved"]},{"year":null,"claim":"How DLG2's multiple phosphorylation events (Fyn, ERK2, ROCK, Src) are integrated in vivo to dynamically tune scaffold composition during plasticity, and how isoform-specific functions (L27-containing vs. palmitoylated) partition DLG2 between neuronal and non-neuronal roles, remain major open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No phosphosite knock-in models exist to test combinatorial regulation in vivo","Isoform-specific interactomes not systematically defined","Full-length DLG2 structure within a native PSD complex not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,6,7,16,24,29]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,9,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5,8,11,17,23,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,12,14,24,29]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,16,19]}],"complexes":["NMDAR-MAGUK postsynaptic complex","PSD-93/PSD-95 heteromultimer","PSD-93/SynGAP complex"],"partners":["DLG4","GRIN2B","SYNGAP1","FYN","NOS1","KCNJ2","LIN7A","CX3CL1"],"other_free_text":[]},"mechanistic_narrative":"DLG2 (PSD-93/Chapsyn-110) is a postsynaptic MAGUK scaffold protein that organizes receptor-signaling complexes at excitatory synapses to control synaptic plasticity, homeostatic scaling, and dendritic spine maintenance. It directly binds NMDA receptor subunits (preferentially GluN2B via PDZ domains), Shaker and Kir2.1 K+ channels, SynGAP, nNOS, CX3CL1, and LIN7A, and heteromultimerizes with PSD-95 to cluster these partners at postsynaptic densities; DLG2 knockout disrupts LTP induction, reduces excitatory transmission and spine density specifically in the striatum, and impairs early cortical neurogenesis programs in human cells [PMID:8755482, PMID:18936077, PMID:35966008, PMID:35031607]. DLG2 is regulated by phosphorylation at Tyr-384 (Fyn), Ser-323 (ERK2), Thr-612 (ROCK, which strengthens PSD-93–PSD-95 and PSD-93–NMDAR association during structural plasticity), and multiple Src sites (which reduce client-protein affinity and scaffolding/condensation activity), establishing kinase-dependent tuning of its scaffold function [PMID:13129934, PMID:36613848, PMID:41562278]. Beyond synaptic roles, DLG2 deficiency accelerates osteosarcoma in conditional knockout mice and DLG2 modulates DNA damage repair, inflammasome signaling, and insulin secretion in non-neuronal contexts [PMID:30093633, PMID:35217496, PMID:32356104]."},"prefetch_data":{"uniprot":{"accession":"Q15700","full_name":"Disks large homolog 2","aliases":["Channel-associated protein of synapse-110","Chapsyn-110","Postsynaptic density protein PSD-93"],"length_aa":870,"mass_kda":97.6,"function":"Required for perception of chronic pain through NMDA receptor signaling. Regulates surface expression of NMDA receptors in dorsal horn neurons of the spinal cord. Interacts with the cytoplasmic tail of NMDA receptor subunits as well as inward rectifying potassium channels. Involved in regulation of synaptic stability at cholinergic synapses. Part of the postsynaptic protein scaffold of excitatory synapses (By similarity)","subcellular_location":"Cell membrane; Postsynaptic density; Synapse; Membrane; Cell projection, axon; Perikaryon","url":"https://www.uniprot.org/uniprotkb/Q15700/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLG2","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/DLG2","total_profiled":1310},"omim":[{"mim_id":"619295","title":"ZDHHC PALMITOYLTRANSFERASE 14; ZDHHC14","url":"https://www.omim.org/entry/619295"},{"mim_id":"612658","title":"TIGHT JUNCTION-ASSOCIATED PROTEIN 1; TJAP1","url":"https://www.omim.org/entry/612658"},{"mim_id":"606959","title":"PROTEIN ASSOCIATED WITH LIN7 2, MAGUK p55 FAMILY MEMBER; PALS2","url":"https://www.omim.org/entry/606959"},{"mim_id":"603583","title":"DISCS LARGE MAGUK SCAFFOLD PROTEIN 2; DLG2","url":"https://www.omim.org/entry/603583"},{"mim_id":"600723","title":"MEMBRANE PROTEIN, PALMITOYLATED 2; MPP2","url":"https://www.omim.org/entry/600723"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":46.7}],"url":"https://www.proteinatlas.org/search/DLG2"},"hgnc":{"alias_symbol":["PSD-93","PSD93","chapsyn-110","PPP1R58"],"prev_symbol":[]},"alphafold":{"accession":"Q15700","domains":[{"cath_id":"2.30.42.10","chopping":"95-185","consensus_level":"high","plddt":88.9612,"start":95,"end":185},{"cath_id":"2.30.42.10","chopping":"190-280","consensus_level":"high","plddt":89.448,"start":190,"end":280},{"cath_id":"2.30.42.10","chopping":"424-515","consensus_level":"high","plddt":88.4839,"start":424,"end":515},{"cath_id":"2.30.30.40","chopping":"540-610","consensus_level":"medium","plddt":87.1235,"start":540,"end":610},{"cath_id":"3.40.50.300","chopping":"678-866","consensus_level":"medium","plddt":94.3324,"start":678,"end":866}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15700","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15700-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15700-F1-predicted_aligned_error_v6.png","plddt_mean":69.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLG2","jax_strain_url":"https://www.jax.org/strain/search?query=DLG2"},"sequence":{"accession":"Q15700","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15700.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15700/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15700"}},"corpus_meta":[{"pmid":"8755482","id":"PMC_8755482","title":"Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins.","date":"1996","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8755482","citation_count":491,"is_preprint":false},{"pmid":"18936077","id":"PMC_18936077","title":"Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity.","date":"2008","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18936077","citation_count":132,"is_preprint":false},{"pmid":"21543610","id":"PMC_21543610","title":"PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21543610","citation_count":110,"is_preprint":false},{"pmid":"11309840","id":"PMC_11309840","title":"Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex.","date":"2001","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11309840","citation_count":108,"is_preprint":false},{"pmid":"14724236","id":"PMC_14724236","title":"PSD93 regulates synaptic stability at neuronal cholinergic synapses.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/14724236","citation_count":93,"is_preprint":false},{"pmid":"11312293","id":"PMC_11312293","title":"PSD-93 knock-out mice reveal that neuronal MAGUKs are not required for development or function of parallel fiber synapses in cerebellum.","date":"2001","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11312293","citation_count":89,"is_preprint":false},{"pmid":"20554866","id":"PMC_20554866","title":"In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20554866","citation_count":74,"is_preprint":false},{"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},{"pmid":"14581127","id":"PMC_14581127","title":"Effect of knock down of spinal cord PSD-93/chapsin-110 on persistent pain induced by complete Freund's adjuvant and peripheral nerve injury.","date":"2003","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/14581127","citation_count":54,"is_preprint":false},{"pmid":"18392731","id":"PMC_18392731","title":"Distribution of the scaffolding proteins PSD-95, PSD-93, and SAP97 in isolated PSDs.","date":"2008","source":"Brain cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18392731","citation_count":49,"is_preprint":false},{"pmid":"13129934","id":"PMC_13129934","title":"Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/13129934","citation_count":45,"is_preprint":false},{"pmid":"28189758","id":"PMC_28189758","title":"Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93.","date":"2017","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/28189758","citation_count":40,"is_preprint":false},{"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},{"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},{"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},{"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},{"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},{"pmid":"28697571","id":"PMC_28697571","title":"PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β.","date":"2017","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/28697571","citation_count":30,"is_preprint":false},{"pmid":"15304517","id":"PMC_15304517","title":"An alternatively spliced isoform of PSD-93/chapsyn 110 binds to the inwardly rectifying potassium channel, Kir2.1.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15304517","citation_count":29,"is_preprint":false},{"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},{"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},{"pmid":"31326116","id":"PMC_31326116","title":"MicroRNA-152-3p protects neurons from oxygen-glucose-deprivation/reoxygenation-induced injury through upregulation of Nrf2/ARE antioxidant signaling by targeting PSD-93.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31326116","citation_count":27,"is_preprint":false},{"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},{"pmid":"24787897","id":"PMC_24787897","title":"PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia.","date":"2014","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/24787897","citation_count":26,"is_preprint":false},{"pmid":"14605317","id":"PMC_14605317","title":"Neonatal hypoxia-ischemia differentially upregulates MAGUKs and associated proteins in PSD-93-deficient mouse brain.","date":"2003","source":"Stroke","url":"https://pubmed.ncbi.nlm.nih.gov/14605317","citation_count":26,"is_preprint":false},{"pmid":"32130656","id":"PMC_32130656","title":"PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice.","date":"2020","source":"Translational stroke research","url":"https://pubmed.ncbi.nlm.nih.gov/32130656","citation_count":26,"is_preprint":false},{"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},{"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},{"pmid":"15296832","id":"PMC_15296832","title":"Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons.","date":"2004","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15296832","citation_count":21,"is_preprint":false},{"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},{"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},{"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},{"pmid":"22618309","id":"PMC_22618309","title":"Interactions and phosphorylation of postsynaptic density 93 (PSD-93) by extracellular signal-regulated kinase (ERK).","date":"2012","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/22618309","citation_count":16,"is_preprint":false},{"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},{"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},{"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},{"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},{"pmid":"36613848","id":"PMC_36613848","title":"Rho-Kinase/ROCK Phosphorylates PSD-93 Downstream of NMDARs to Orchestrate Synaptic Plasticity.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36613848","citation_count":11,"is_preprint":false},{"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},{"pmid":"20460989","id":"PMC_20460989","title":"Effect of PSD-95/SAP90 and/or PSD-93/chapsyn-110 deficiency on the minimum alveolar anesthetic concentration of halothane in mice.","date":"2010","source":"Anesthesiology","url":"https://pubmed.ncbi.nlm.nih.gov/20460989","citation_count":11,"is_preprint":false},{"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},{"pmid":"33599284","id":"PMC_33599284","title":"PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1.","date":"2021","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33599284","citation_count":11,"is_preprint":false},{"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},{"pmid":"26680505","id":"PMC_26680505","title":"Proteomic analysis of PSD-93 knockout mice following the induction of ischemic cerebral injury.","date":"2015","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/26680505","citation_count":10,"is_preprint":false},{"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},{"pmid":"24049141","id":"PMC_24049141","title":"Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture.","date":"2013","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24049141","citation_count":9,"is_preprint":false},{"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},{"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},{"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},{"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},{"pmid":"27259312","id":"PMC_27259312","title":"The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury.","date":"2015","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27259312","citation_count":7,"is_preprint":false},{"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},{"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},{"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},{"pmid":"23519667","id":"PMC_23519667","title":"Interaction partners of PSD-93 studied by X-ray crystallography and fluorescence polarization spectroscopy.","date":"2013","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/23519667","citation_count":5,"is_preprint":false},{"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},{"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},{"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},{"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},{"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},{"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},{"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},{"pmid":"41562278","id":"PMC_41562278","title":"Differences in Src phosphorylation of PSD-93 and PSD-95 drive differences in scaffolding activity.","date":"2026","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/41562278","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.24.671450","title":"Paralog-specific intrabodies for PSD-93 and SAP102 expand the molecular toolkit to resolve excitatory synapse organization","date":"2025-08-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.24.671450","citation_count":0,"is_preprint":true},{"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},{"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},{"pmid":null,"id":"bio_10.1101_2024.05.24.595787","title":"A synapse-specific refractory period for plasticity at individual dendritic spines","date":"2024-05-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.24.595787","citation_count":0,"is_preprint":true},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37248,"output_tokens":7152,"usd":0.109512},"stage2":{"model":"claude-opus-4-6","input_tokens":10841,"output_tokens":4645,"usd":0.255495},"total_usd":0.365007,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Chapsyn-110 (DLG2/PSD-93) directly binds NMDA receptor and Shaker K+ channel subunits via its PDZ domains, mediates clustering of both NMDA receptors and K+ channels in heterologous cells, and heteromultimerizes with PSD-95 to be recruited into the same receptor/channel clusters at postsynaptic sites.\",\n      \"method\": \"Heterologous cell clustering assay, co-immunoprecipitation, immunostaining in rat brain\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (clustering assay, co-IP, immunostaining), highly cited foundational paper\",\n      \"pmids\": [\"8755482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSD-93 localizes to postsynaptic densities of excitatory synapses in visual cortex, but also occurs along presynaptic membranes and in axonal/dendritic cytoplasm, suggesting dual roles in maintaining receptors at synapses and regulating receptor shuttling between nonsynaptic and synaptic sites.\",\n      \"method\": \"Electron microscopic immunocytochemistry with quantitative immunogold labeling\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — rigorous quantitative EM-ICC with systematic analysis across multiple compartments\",\n      \"pmids\": [\"11309840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSD-93 knockout in mice does not impair development or function of cerebellar parallel fiber synapses, indicating PSD-93 is not essential for synaptic development at these central synapses but may participate in specialized synaptic signaling; PSD-93 interacting proteins remain correctly localized in its absence.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), electrophysiology, immunohistochemistry, electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal readouts (behavior, electrophysiology, morphology)\",\n      \"pmids\": [\"11312293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSD-93 is identified as a substrate for the Src family tyrosine kinase Fyn; Fyn phosphorylates PSD-93 in vitro at Tyr-384, phosphorylation is greatly reduced in Fyn-deficient mouse brain, and the N-terminal palmitoylation signal of PSD-93 is essential for membrane anchoring required for Fyn-mediated phosphorylation. Tyrosine-phosphorylated PSD-93 binds Csk (a negative regulator of Src kinases).\",\n      \"method\": \"In vitro kinase assay with recombinant proteins, phosphosite mutagenesis, Fyn-knockout mouse brain, co-immunoprecipitation, COS7 cell expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution, mutagenesis, genetic validation in Fyn-KO mice, multiple orthogonal methods\",\n      \"pmids\": [\"13129934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Knockdown of spinal cord PSD-93 by intrathecal antisense oligodeoxynucleotide significantly attenuates thermal and mechanical hyperalgesia in CFA-induced inflammatory pain and peripheral nerve injury-induced neuropathic pain without affecting acute nociception or locomotion, indicating PSD-93 is required for central sensitization in chronic pain.\",\n      \"method\": \"Intrathecal antisense oligodeoxynucleotide knockdown, behavioral pain testing (CFA and nerve injury models)\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with specific behavioral phenotype, but single lab\",\n      \"pmids\": [\"14581127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSD-93 colocalizes and co-immunoprecipitates with NMDA receptor and nNOS in cortical neurons; PSD-93 deletion prevents NMDA receptor–nNOS complex formation, attenuates PAF-induced NMDA receptor–nitric oxide signaling neurotoxicity, and reduces cGMP elevation, placing PSD-93 as an essential scaffold linking NMDA receptors to nNOS-mediated neuronal injury.\",\n      \"method\": \"PSD-93 knockout neurons, co-immunoprecipitation, cGMP measurement, cell death assay\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO neurons with defined molecular mechanism, multiple endpoints\",\n      \"pmids\": [\"15296832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PSD-93 co-immunoprecipitates with neuronal nicotinic acetylcholine receptors (nAChRs) in superior cervical ganglion in vivo, is enriched in the PSD fraction of ganglia, and PSD-93 knockout mice show accelerated disassembly of nAChR synaptic clusters after denervation, demonstrating PSD-93 is required for stability of neuronal cholinergic synapses.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, immunostaining, PSD-93 knockout mouse denervation model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, fractionation, and KO functional phenotype in vivo\",\n      \"pmids\": [\"14724236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"An alternatively spliced isoform of PSD-93 (PSD-93δ) directly binds inwardly rectifying potassium channel Kir2.1 via a type I PDZ recognition motif at the extreme C-terminus of Kir2.1; co-expression results in Kir2.1 clustering at the cell surface and suppression of channel internalization without changing channel kinetics.\",\n      \"method\": \"Yeast two-hybrid, in vitro PDZ-binding assay, co-immunoprecipitation from rat spinal cord, heterologous cell surface clustering\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple binding assays, native tissue co-IP, functional clustering readout\",\n      \"pmids\": [\"15304517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSD-93 and PSD-95 have opposing roles in synaptic plasticity: PSD-93 knockout mice exhibit deficits in LTP and normal LTD, whereas PSD-95 knockouts facilitate LTP and disrupt LTD, indicating these MAGUKs form distinct NMDA receptor signaling complexes that differentially regulate LTP induction.\",\n      \"method\": \"Knockout mice, hippocampal CA1 electrophysiology, LTP/LTD induction protocols\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined electrophysiological phenotype, genetic epistasis between paralogs\",\n      \"pmids\": [\"18936077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSD-93 and PSD-95 are distributed homogeneously throughout isolated PSDs, consistent with their function as backbone scaffold proteins that stabilize binding partners within the PSD.\",\n      \"method\": \"Immunogold labeling and rotary shadow electron microscopy of isolated PSDs\",\n      \"journal\": \"Brain cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative EM mapping, single study\",\n      \"pmids\": [\"18392731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PSD-95 (but not PSD-93) is required for localizing NR2A-containing NMDA receptor complexes to lipid rafts; deletion of NR2A C-terminus or NR2B C-terminal valine (PDZ-binding) reduces NR1 association with rafts. Raft versus PSD PSD-95 complexes show differential composition (less CaMKIIα/SynGAP, enriched Src/Arc in rafts).\",\n      \"method\": \"Tandem affinity purification from knock-in mice, lipid raft isolation, PSD-93 and PSD-95 knockout mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetically encoded tags, KO validation, multiple fractions compared\",\n      \"pmids\": [\"20554866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PSD-93 and PSD-95 are necessary for synaptic scaling but serve distinct roles: scaling down requires PSD-95 (via PDZ1/2 domains), while scaling up can be supported by either PSD-95 or PSD-93 in an age-dependent manner. Neither MAGUK drives homeostatic scaling by changes in synaptic abundance; they act as organizers using distinct protein-protein interactions.\",\n      \"method\": \"shRNA knockdown and overexpression in neurons, mEPSC recording, PSD-93/95 mutant analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation, specific domain requirements identified, clean electrophysiological readouts\",\n      \"pmids\": [\"21543610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERK2 directly binds PSD-93 via an N-terminal region, and active ERK2 phosphorylates PSD-93 at Ser323 in vitro; native ERK from synaptosomal fractions also associates with PSD-93 in rat striatal neurons, and immunoprecipitated PSD-93 shows basal ERK-sensitive phosphorylation in vivo.\",\n      \"method\": \"In vitro protein-protein interaction with purified proteins, in vitro kinase assay, co-immunoprecipitation from synaptosomal fractions\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with phosphosite identification, supported by native tissue co-IP; single lab\",\n      \"pmids\": [\"22618309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of PSD-93 PDZ1 with GluD2 C-terminal peptide (GTSI) reveals two binding modes suggesting weak interaction; fluorescence polarization shows no appreciable affinity for GluD2 C-terminal octapeptide but micromolar affinity for GluN2B-derived C-terminal octapeptide, indicating PDZ1/2 preferentially bind GluN2B over GluD2.\",\n      \"method\": \"X-ray crystallography, fluorescence polarization spectroscopy\",\n      \"journal\": \"Acta crystallographica. Section D\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus quantitative binding assay, orthogonal methods\",\n      \"pmids\": [\"23519667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSD-93 deletion reduces phosphorylation of NR2B at Tyr1472 and the interaction between NR2B and Fyn after focal cerebral ischemia, and ischemic LTP cannot be induced in PSD-93 KO mice, demonstrating that PSD-93 mediates Fyn-dependent phosphorylation of NR2B and downstream excitotoxicity.\",\n      \"method\": \"PSD-93 knockout mouse, MCAO model, Western blot for phospho-NR2B, pharmacological inhibitors (AP-5, PP2), co-immunoprecipitation\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + pharmacology + co-IP defining mechanism, multiple endpoints\",\n      \"pmids\": [\"24787897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DLG2 regulates cell division, migration, and tumorigenesis in osteosarcoma: DLG2-deficient osteosarcoma cell lines show dysregulated cell division and migration in vitro, and osteoblast-specific Dlg2 deletion in mice accelerates osteosarcoma development in vivo.\",\n      \"method\": \"DLG2-deficient human/canine cell lines (functional assays), osteoblast-specific Dlg2 conditional knockout mouse model, cross-species comparative genomics\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple species validation, conditional KO mouse model with tumor phenotype, multiple functional assays\",\n      \"pmids\": [\"30093633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSD-93 directly interacts with SynGAP, and this interaction mediates SynGAP ubiquitination and proteasomal degradation following cerebral ischemia/reperfusion; the 670-685 amino acid sequence of SynGAP is essential for binding to PSD-93. PSD-93 KO mice show preserved SynGAP levels and reduced infarct volume, rescued by neither MG-132 nor MK801.\",\n      \"method\": \"Co-immunoprecipitation, PSD-93 knockout mice, MCAO model, peptide competition (Tat-SynGAP), proteasome inhibitor MG-132, NMDAR inhibitor MK801, Western blot\",\n      \"journal\": \"Translational stroke research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + inhibitor epistasis + domain mapping + peptide competition; multiple orthogonal approaches\",\n      \"pmids\": [\"32130656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dlg2 knockout mice show reduced excitatory (but not inhibitory) spontaneous postsynaptic current frequency in the dorsolateral striatum, accompanied by ASD-like behavioral deficits (reduced social approach, increased self-grooming), establishing DLG2 as necessary for excitatory synaptic transmission in the striatum.\",\n      \"method\": \"Dlg2 exon 14 knockout mouse, patch-clamp electrophysiology in striatal slices, behavioral battery, in situ hybridization\",\n      \"journal\": \"Molecular autism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined synaptic and behavioral phenotypes, multiple readouts\",\n      \"pmids\": [\"32164788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DLG2 knockdown in MIN6 pancreatic beta cells impairs glucose-stimulated and non-glucose-stimulated insulin secretion, establishing DLG2 as a regulator of insulin secretion.\",\n      \"method\": \"RNA interference (siRNA knockdown) in MIN6 cells, insulin secretion assay\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific functional readout; single study\",\n      \"pmids\": [\"32356104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSD-93 binds CX3CL1 (fractalkine) at specific domains (420-535 aa of PSD-93; 357-395 aa of CX3CL1), and this interaction peaks at 6 h after ischemia/reperfusion; blockade of this interaction with a fusion peptide (Tat-CX3CL1) reduces pro-inflammatory cytokine expression and provides neuroprotection.\",\n      \"method\": \"Co-immunoprecipitation, peptide competition, MCAO model in mice, cytokine measurement\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping, functional peptide blockade; single lab\",\n      \"pmids\": [\"33599284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DLG2 isoform 7 (containing the L27 domain) binds LIN7A, and increased DLG2-isoform 7 expression increases LIN7A expression, reduces neuroblastoma cell proliferation and viability, and increases the BAX/BCL2 ratio (indicating apoptosis); L27 domain-lacking isoform 2 does not show these effects.\",\n      \"method\": \"Co-immunoprecipitation/binding assay, isoform overexpression in neuroblastoma cells, cell viability/proliferation assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and OE with functional readout; single lab, single study\",\n      \"pmids\": [\"33726762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 overexpression increases expression of IL1B, IκBζ, and BAX (inflammasome components), while DLG2 silencing in THP1 cells increases IL-6 release leading to STAT3 phosphorylation in bystander cells; DLG2 restoration reduces AKT and S6 signaling, placing DLG2 as a regulator of inflammasome formation and inflammatory signaling.\",\n      \"method\": \"DLG2 overexpression and siRNA knockdown in colon cancer/THP1 cells, cytokine ELISA, Western blot for signaling proteins\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation (OE and KD) with defined molecular readouts; single lab\",\n      \"pmids\": [\"35499706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 overexpression impairs NHEJ DNA repair genes PARP1 and FEN1 expression, reduces DNA fragmentation after UVC radiation, promotes CHK1 phosphorylation (G2/M checkpoint), and increases p53 S46-dependent apoptosis, establishing DLG2 as a regulator of DNA double-strand break repair and genomic integrity.\",\n      \"method\": \"Comet assay, H2AX phosphorylation, UVC irradiation, Western blot, Drosophila model, neuroblastoma cell lines\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays (comet, γH2AX, apoptosis), cross-species validation in Drosophila; single lab\",\n      \"pmids\": [\"35217496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Dlg2+/- rats, reduced DLG2 causes increased potassium channel function (reduced input resistance) that impairs supra-linear dendritic integration and associative LTP; NMDA receptor-mediated currents are paradoxically increased while AMPA currents are unaffected. Blockade of potassium channels or muscarinic M1 receptor activation rescues LTP, placing DLG2 upstream of potassium channel regulation in dendritic integration.\",\n      \"method\": \"Heterozygous Dlg2+/- rat, ex vivo patch-clamp electrophysiology, pharmacology (K+ channel blockers, M1 agonist), computational modelling\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — electrophysiology + pharmacological rescue + computational modelling in clinically relevant model\",\n      \"pmids\": [\"35115661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rho-kinase/ROCK directly phosphorylates DLG2/PSD-93 at Thr612 downstream of NMDA receptor activation. Chemical LTP induction increases PSD-93 Thr612 phosphorylation, spine enlargement, and PSD-93 colocalization with PSD-95; these effects are blocked by Rho-kinase inhibition. PSD-93-interacting proteins identified by LC-MS/MS include PSD-95, NMDARs, SynGAP1, ADAM22, and LGI1; phosphorylation increases PSD-93 binding to PSD-95 and NMDARs.\",\n      \"method\": \"In vitro kinase assay (ROCK phosphorylation of PSD-93), mutagenesis of Thr612, chemical LTP in striatal slices, LC-MS/MS interactome, co-immunoprecipitation, confocal imaging\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay + phosphosite ID + MS interactome + functional LTP assay + co-IP\",\n      \"pmids\": [\"36613848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 deficiency causes reduced density of postsynaptic densities and perforated synapses, decreased dendritic spine density in striatal (but not cortical) neurons, and compensatory increases of DLG4/PSD-95 and decreases in TrkA in the striatum, establishing a cell-type-specific role for DLG2 in maintaining striatal synapse structure.\",\n      \"method\": \"Dlg2 exon 14 KO mice, transmission electron microscopy, dendritic spine analysis, Western blot, patch-clamp (mEPSC)\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — TEM + electrophysiology + protein quantification in KO mice, multiple orthogonal readouts\",\n      \"pmids\": [\"35966008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 knockout in human embryonic stem cells down-regulates transcriptional programs for early neurogenesis, impairing neuronal migration, morphology, and action potential generation during differentiation to cortical excitatory neurons.\",\n      \"method\": \"DLG2 knockout hESCs, RNA-seq, neuronal differentiation assays (migration, morphology, electrophysiology)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO in human cells with multiple functional readouts (migration, morphology, AP generation), transcriptomics\",\n      \"pmids\": [\"35031607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A DLG2 missense variant (F900V) associated with delayed puberty impairs the interaction between PSD-93 and Fyn, decreases GnRH expression in a GnRH neuronal cell line, linking DLG2-Fyn interaction to NMDA receptor signaling controlling GnRH secretion and pubertal timing.\",\n      \"method\": \"Exome sequencing, in vitro co-immunoprecipitation (F900V interaction with Fyn), GnRH expression assay in neuronal cell line\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional consequence in cell line; single study with human variant\",\n      \"pmids\": [\"32341572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSD-93 interacts with somatostatin receptor 4 (SSTR4) and affects SSTR4 membrane levels through ubiquitination; PSD-93 overexpression in APP/PS1 mice increases SSTR4 and neprilysin expression and reduces amyloid plaque load.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, lentivirus-mediated PSD-93 overexpression in APP/PS1 mice, behavioral and biochemical readouts\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP + ubiquitination assay + in vivo rescue; single lab\",\n      \"pmids\": [\"28697571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Src kinase phosphorylates PSD-93 more robustly than PSD-95 at multiple sites in vitro; phosphorylation differentially reduces affinity of PSD-93 for postsynaptic client proteins, and reduces PSD-93's ability to recruit key synaptic clients into supercomplexes (scaffolding activity), while also affecting biomolecular condensation of PSD-93 (but not PSD-95). SAXS and smFRET reveal phosphorylation alters PSD-93 dynamics but not overall supertertiary structure.\",\n      \"method\": \"In vitro kinase assay (Src kinase, multiple substrates), affinity measurements, supercomplex reconstitution, biomolecular condensation assay, SAXS, smFRET\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal structural and functional methods\",\n      \"pmids\": [\"41562278\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLG2/PSD-93 is a postsynaptic MAGUK scaffold protein that directly binds NMDA receptor subunits (preferentially GluN2B via PDZ domains), Shaker and Kir2.1 K+ channels, SynGAP, CX3CL1, and LIN7A to organize receptor-signaling complexes at excitatory synapses; it is phosphorylated by Fyn at Tyr-384 (promoting Csk recruitment), by ERK2 at Ser-323, and by Rho-kinase/ROCK at Thr-612 (which increases PSD-93 association with PSD-95 and NMDARs to regulate structural plasticity), and by Src kinase at multiple sites (reducing client-protein affinity and scaffolding activity); it controls LTP/LTD bidirectionality and synaptic scaling through distinct PDZ-domain interactions, maintains dendritic spine density and postsynaptic density structure in the striatum, regulates SynGAP ubiquitination and degradation after ischemia, and plays isoform-dependent roles in neuronal differentiation, inflammasome formation, DNA damage response, and insulin secretion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DLG2 (PSD-93/Chapsyn-110) is a postsynaptic MAGUK scaffold protein that organizes receptor-signaling complexes at excitatory synapses to control synaptic plasticity, homeostatic scaling, and dendritic spine maintenance. It directly binds NMDA receptor subunits (preferentially GluN2B via PDZ domains), Shaker and Kir2.1 K+ channels, SynGAP, nNOS, CX3CL1, and LIN7A, and heteromultimerizes with PSD-95 to cluster these partners at postsynaptic densities; DLG2 knockout disrupts LTP induction, reduces excitatory transmission and spine density specifically in the striatum, and impairs early cortical neurogenesis programs in human cells [PMID:8755482, PMID:18936077, PMID:35966008, PMID:35031607]. DLG2 is regulated by phosphorylation at Tyr-384 (Fyn), Ser-323 (ERK2), Thr-612 (ROCK, which strengthens PSD-93–PSD-95 and PSD-93–NMDAR association during structural plasticity), and multiple Src sites (which reduce client-protein affinity and scaffolding/condensation activity), establishing kinase-dependent tuning of its scaffold function [PMID:13129934, PMID:36613848, PMID:41562278]. Beyond synaptic roles, DLG2 deficiency accelerates osteosarcoma in conditional knockout mice and DLG2 modulates DNA damage repair, inflammasome signaling, and insulin secretion in non-neuronal contexts [PMID:30093633, PMID:35217496, PMID:32356104].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identifying DLG2 as a PDZ-domain scaffold that clusters NMDA receptors and K+ channels at synapses and heteromultimerizes with PSD-95 established the foundational model of MAGUK-mediated receptor organization at the postsynaptic density.\",\n      \"evidence\": \"Heterologous cell clustering assays, co-immunoprecipitation, and immunostaining in rat brain\",\n      \"pmids\": [\"8755482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and hierarchy of DLG2 versus PSD-95 within native complexes undefined\", \"Functional consequence of clustering on channel/receptor gating not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Ultrastructural mapping revealed DLG2 is concentrated at postsynaptic densities but also present presynaptically and in trafficking compartments, while genetic deletion showed it is dispensable for cerebellar synapse formation, raising the question of synapse-type-specific necessity.\",\n      \"evidence\": \"Quantitative immunogold EM in visual cortex; Dlg2 knockout mouse with electrophysiology and morphology at cerebellar synapses\",\n      \"pmids\": [\"11309840\", \"11312293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which synapse types require DLG2 remained unclear\", \"Compensatory upregulation of other MAGUKs in KO not fully assessed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of Fyn-mediated phosphorylation at Tyr-384 and consequent Csk recruitment, together with the requirement for palmitoylation-dependent membrane anchoring, revealed the first post-translational regulatory axis controlling DLG2 scaffold function.\",\n      \"evidence\": \"In vitro kinase assays, phosphosite mutagenesis, Fyn-KO mouse brain, co-IP in COS7 cells\",\n      \"pmids\": [\"13129934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Tyr-384 phosphorylation on synaptic receptor clustering not directly measured\", \"Identity of phosphatase reversing this modification unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that DLG2 scaffolds NMDA receptors to nNOS, mediating excitotoxic NO signaling, and that DLG2 knockdown in spinal cord attenuates chronic pain, placed DLG2 as a druggable node linking receptor activation to downstream pathological signaling.\",\n      \"evidence\": \"PSD-93 KO neurons with cGMP/cell-death readouts; intrathecal antisense knockdown with behavioral pain models\",\n      \"pmids\": [\"15296832\", \"14581127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether disrupting DLG2-nNOS coupling spares physiological NMDAR signaling not tested\", \"Antisense knockdown specificity not independently validated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"DLG2 was shown to stabilize nicotinic acetylcholine receptor clusters at cholinergic synapses and to bind Kir2.1 channels via PDZ interactions, broadening its role beyond glutamatergic synapses to a general ion channel scaffold.\",\n      \"evidence\": \"Co-IP and denervation in PSD-93 KO superior cervical ganglia; yeast two-hybrid and surface clustering for Kir2.1\",\n      \"pmids\": [\"14724236\", \"15304517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLG2 regulates Kir2.1 surface expression in vivo not demonstrated\", \"Mechanism by which DLG2 prevents nAChR cluster disassembly unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Opposing roles of DLG2 and PSD-95 in LTP versus LTD revealed that paralogous MAGUKs form functionally distinct NMDAR signaling complexes, resolving why both scaffolds coexist at synapses.\",\n      \"evidence\": \"Hippocampal CA1 electrophysiology in DLG2-KO and PSD-95-KO mice\",\n      \"pmids\": [\"18936077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for why DLG2 favors LTP-promoting complexes not identified\", \"Double-KO epistasis not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that DLG2 and PSD-95 serve overlapping but distinct roles in homeostatic synaptic scaling—with scaling up supported by either MAGUK and scaling down requiring PSD-95—added a non-Hebbian plasticity dimension to DLG2 function.\",\n      \"evidence\": \"shRNA knockdown and overexpression in neurons with mEPSC recording and domain mutant analysis\",\n      \"pmids\": [\"21543610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway linking DLG2 to scaling-up effectors unresolved\", \"In vivo relevance of DLG2 in homeostatic plasticity not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"ERK2 was identified as a second kinase directly phosphorylating DLG2 (at Ser-323) and binding its N-terminal region, linking MAPK signaling to scaffold regulation in striatal neurons.\",\n      \"evidence\": \"In vitro kinase assay with purified proteins, co-IP from striatal synaptosomal fractions\",\n      \"pmids\": [\"22618309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Ser-323 phosphorylation on DLG2 interactions or plasticity not determined\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural resolution of DLG2 PDZ1 bound to GluN2B-derived peptide, combined with quantitative affinity data showing preference for GluN2B over GluD2, provided the first atomic-level view of DLG2's selectivity among glutamate receptor subunits.\",\n      \"evidence\": \"X-ray crystallography and fluorescence polarization spectroscopy\",\n      \"pmids\": [\"23519667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length DLG2 structure or supramolecular arrangement within the PSD unknown\", \"PDZ2/3 domain selectivity not structurally resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placing DLG2 as a required scaffold for Fyn-dependent NR2B Tyr-1472 phosphorylation after cerebral ischemia defined the mechanism by which DLG2 promotes excitotoxic signaling in stroke.\",\n      \"evidence\": \"DLG2-KO mice in MCAO model with phospho-NR2B Western blot, pharmacological inhibitors, co-IP\",\n      \"pmids\": [\"24787897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DLG2 deletion is neuroprotective long-term after stroke not assessed\", \"Contribution of DLG2-independent Fyn pathways unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A human DLG2 missense variant (F900V) disrupting PSD-93–Fyn interaction and reducing GnRH expression linked DLG2 scaffold function to neuroendocrine regulation and delayed puberty, extending its physiology beyond synaptic plasticity.\",\n      \"evidence\": \"Exome sequencing, co-IP of F900V mutant with Fyn, GnRH expression in neuronal cell line\",\n      \"pmids\": [\"32341572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family study; replication in independent cohorts needed\", \"In vivo GnRH neuron-specific mechanism not demonstrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that DLG2 deficiency dysregulates cell division and migration and that osteoblast-specific Dlg2 deletion accelerates osteosarcoma established a tumor-suppressive function outside the nervous system.\",\n      \"evidence\": \"DLG2-deficient cell lines, conditional KO mouse osteosarcoma model, cross-species genomics\",\n      \"pmids\": [\"30093633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of tumor suppression (which DLG2 interaction is critical) not defined\", \"Relevance to human osteosarcoma patients not clinically validated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of DLG2 as a mediator of SynGAP ubiquitination/degradation after ischemia, combined with domain mapping (SynGAP 670-685), revealed a scaffold-dependent proteostatic mechanism for excitotoxic signaling.\",\n      \"evidence\": \"Co-IP, PSD-93-KO in MCAO model, Tat-SynGAP peptide competition, proteasome/NMDAR inhibitor epistasis\",\n      \"pmids\": [\"32130656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase recruited by DLG2 for SynGAP ubiquitination not identified\", \"Whether this mechanism operates in non-ischemic contexts unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"DLG2 knockout in striatum selectively reduced excitatory synaptic frequency and produced ASD-like behaviors, while DLG2 knockdown in beta cells impaired insulin secretion, demonstrating circuit-specific and metabolic functions.\",\n      \"evidence\": \"Dlg2-KO mice with patch-clamp and behavioral battery; siRNA in MIN6 cells with insulin secretion assay\",\n      \"pmids\": [\"32164788\", \"32356104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking DLG2 to insulin granule exocytosis unknown\", \"Which DLG2 isoform mediates striatal versus beta-cell function unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ROCK-mediated phosphorylation of DLG2 at Thr-612 during chemical LTP was shown to strengthen DLG2 association with PSD-95 and NMDARs, directly coupling activity-dependent kinase signaling to structural plasticity of the scaffold complex.\",\n      \"evidence\": \"In vitro ROCK kinase assay, Thr612 mutagenesis, chemical LTP in striatal slices, LC-MS/MS interactome, co-IP, confocal imaging\",\n      \"pmids\": [\"36613848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Thr-612 phosphorylation is necessary for LTP in vivo not demonstrated with phospho-dead knock-in\", \"Phosphatase opposing ROCK at this site unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"DLG2 KO in human embryonic stem cells impaired transcriptional programs for neurogenesis including migration, morphology, and action potential generation, establishing a cell-autonomous role in human cortical neuron development.\",\n      \"evidence\": \"DLG2-KO hESCs differentiated to cortical excitatory neurons, RNA-seq, functional assays\",\n      \"pmids\": [\"35031607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether developmental role requires PDZ-domain scaffolding or a transcriptional mechanism unclear\", \"In vivo human relevance not validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reduced DLG2 dosage in heterozygous rats increased potassium channel function, impairing dendritic integration and LTP, rescuable by K+ channel blockers or M1 receptor activation, defining a channelopathy-like mechanism for DLG2 haploinsufficiency.\",\n      \"evidence\": \"Dlg2+/- rat, ex vivo patch-clamp, pharmacological rescue, computational modelling\",\n      \"pmids\": [\"35115661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific potassium channel(s) dysregulated not determined\", \"Whether M1 agonist rescue translates to behavioral improvement unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Parallel studies showed DLG2 modulates DNA damage repair (suppressing NHEJ via PARP1/FEN1, promoting CHK1-mediated checkpoint), inflammasome signaling (IL1B, IκBζ induction), and striatal synapse ultrastructure, revealing diverse non-canonical functions.\",\n      \"evidence\": \"Comet assay, γH2AX, UVC irradiation, Drosophila model; DLG2 OE/KD in THP1/colon cancer cells; TEM in Dlg2-KO striatum\",\n      \"pmids\": [\"35217496\", \"35499706\", \"35966008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DNA repair and inflammasome functions operate via scaffold activity or a distinct mechanism unknown\", \"Non-neuronal roles not validated in vivo beyond overexpression\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Src kinase phosphorylation of DLG2 at multiple sites was shown to reduce client-protein affinity, impair supercomplex assembly, and alter biomolecular condensation without changing supertertiary structure, establishing phosphorylation as a general rheostat for DLG2 scaffolding capacity.\",\n      \"evidence\": \"In vitro Src kinase assay, affinity measurements, supercomplex reconstitution, condensation assay, SAXS, smFRET\",\n      \"pmids\": [\"41562278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Src-mediated DLG2 regulation at synapses not demonstrated\", \"Which specific phosphosites are most functionally consequential not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DLG2's multiple phosphorylation events (Fyn, ERK2, ROCK, Src) are integrated in vivo to dynamically tune scaffold composition during plasticity, and how isoform-specific functions (L27-containing vs. palmitoylated) partition DLG2 between neuronal and non-neuronal roles, remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No phosphosite knock-in models exist to test combinatorial regulation in vivo\", \"Isoform-specific interactomes not systematically defined\", \"Full-length DLG2 structure within a native PSD complex not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 6, 7, 16, 24, 29]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 9, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5, 8, 11, 17, 23, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 12, 14, 24, 29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 19]}\n    ],\n    \"complexes\": [\n      \"NMDAR-MAGUK postsynaptic complex\",\n      \"PSD-93/PSD-95 heteromultimer\",\n      \"PSD-93/SynGAP complex\"\n    ],\n    \"partners\": [\n      \"DLG4\",\n      \"GRIN2B\",\n      \"SYNGAP1\",\n      \"FYN\",\n      \"NOS1\",\n      \"KCNJ2\",\n      \"LIN7A\",\n      \"CX3CL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}