{"gene":"DLG2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1996,"finding":"Chapsyn-110/DLG2 is a MAGUK protein that directly binds NMDA receptor subunits 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 form a multimeric postsynaptic scaffold.","method":"Co-immunoprecipitation, heterologous cell clustering assay, yeast two-hybrid, subcellular fractionation","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, heterologous clustering assay, and fractionation; foundational paper replicated by subsequent work","pmids":["8755482"],"is_preprint":false},{"year":2001,"finding":"Electron microscopic immunocytochemistry demonstrated that PSD-93/DLG2 localizes to postsynaptic densities of asymmetric axo-spinous synapses in rat visual cortex, as well as along presynaptic membranes and in axonal/dendritic cytoplasm, suggesting dual roles in maintaining receptors at synapses and regulating receptor shuttling.","method":"Electron microscopic immunocytochemistry with quantitative immunogold labeling","journal":"Synapse","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct EM-ICC localization with quantitative mapping, systematic survey across multiple MAGUKs","pmids":["11309840"],"is_preprint":false},{"year":2001,"finding":"PSD-93 knockout mice show no structural or functional abnormality in cerebellar parallel fiber synapses despite PSD-93 being the only MAGUK expressed in Purkinje neurons, indicating PSD-93 is not essential for development of certain central synapses but may participate in specialized synaptic signaling.","method":"Targeted gene disruption (knockout mouse), light and electron microscopy, electrophysiology, behavioral testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and behavioral phenotype, multiple orthogonal readouts","pmids":["11312293"],"is_preprint":false},{"year":2003,"finding":"PSD-93/DLG2 is a substrate for the Src family tyrosine kinase Fyn; Fyn phosphorylates PSD-93 in vitro and in vivo at Tyr-384, an N-terminal palmitoylation signal is required for membrane anchoring where Fyn is localized, and tyrosine-phosphorylated PSD-93 binds Csk (a negative regulator of Src family kinases).","method":"Immunopurification of NMDA receptor complex, microsequencing, in vitro kinase assay with recombinant proteins, site-directed mutagenesis, Fyn-deficient mouse brain comparison, Co-IP from brain lysate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis identifying Tyr-384, validated in Fyn-KO mice and brain lysate Co-IP","pmids":["13129934"],"is_preprint":false},{"year":2003,"finding":"Knockdown of spinal cord PSD-93/DLG2 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 mechanisms downstream of NMDAR activation.","method":"Intrathecal antisense oligodeoxynucleotide knockdown in rat, behavioral pain assays (paw withdrawal thresholds), Western blot confirmation of knockdown","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with specific behavioral readout, single lab, antisense approach","pmids":["14581127"],"is_preprint":false},{"year":2003,"finding":"In neonatal hypoxia-ischemia, PSD-93 deletion does not provide neuroprotection; PSD-95 compensates by still interacting with NR2B and nNOS in PSD-93 KO mice, and PSD-95 expression is upregulated after HI in KO pups, demonstrating functional redundancy between MAGUKs at baseline.","method":"PSD-93 KO mouse model, neonatal HI model, Western blot, co-immunoprecipitation, brain injury scoring","journal":"Stroke","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined phenotypic readout and Co-IP validation; single lab","pmids":["14605317"],"is_preprint":false},{"year":2004,"finding":"PSD-93/DLG2 colocalizes and co-immunoprecipitates with NMDA receptors and neuronal nitric oxide synthase in cultured cortical neurons; PSD-93 gene disruption prevents NMDA receptor-nNOS complex formation, attenuates PAF-induced cGMP elevation, and significantly reduces PAF-triggered NMDA receptor-nitric oxide signaling-dependent neurotoxicity.","method":"Co-immunoprecipitation, targeted gene disruption (KO neurons), cGMP measurement, neurotoxicity assay","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KO functional readout, single lab","pmids":["15296832"],"is_preprint":false},{"year":2004,"finding":"Novel splice forms of PSD-93/DLG2 are expressed in mouse superior cervical ganglion (SCG); PSD-93 co-localizes with and co-immunoprecipitates neuronal nicotinic acetylcholine receptors (nAChRs) at cholinergic synapses, and PSD-93 KO mice show accelerated disassembly of nAChR synaptic clusters after denervation, establishing PSD-93 as a stabilizing scaffold at neuronal cholinergic postsynaptic densities.","method":"Immunostaining, subcellular fractionation, co-immunoprecipitation, PSD-93 KO mouse denervation model","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vivo KO with defined synaptic stability phenotype, multiple orthogonal methods","pmids":["14724236"],"is_preprint":false},{"year":2004,"finding":"An alternatively spliced isoform of PSD-93 (PSD-93δ) directly interacts with the inwardly rectifying K+ channel Kir2.1 via a type I PDZ recognition motif at the Kir2.1 C-terminus; co-expression of Kir2.1 and PSD-93δ causes cell surface clustering of Kir2.1 and suppresses channel internalization without affecting channel kinetics.","method":"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation from rat spinal cord, heterologous cell expression with surface clustering assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — yeast two-hybrid, in vitro binding, Co-IP from native tissue, and functional cell surface assay; single lab with multiple orthogonal methods","pmids":["15304517"],"is_preprint":false},{"year":2008,"finding":"PSD-93 KO mice exhibit normal AMPA and NMDA receptor-mediated synaptic transmission but show deficits in LTP induction without affecting LTD, demonstrating that PSD-93 and PSD-95 have opposing roles in LTP in hippocampal CA1 and likely organize distinct NMDA receptor signaling complexes.","method":"PSD-93 KO and PSD-95 KO mouse electrophysiology, field recordings in hippocampal slices, multiple LTP/LTD induction protocols","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined synaptic plasticity phenotype using multiple induction protocols, replicated across two mutant lines","pmids":["18936077"],"is_preprint":false},{"year":2008,"finding":"PSD-93 is homogeneously distributed throughout isolated postsynaptic densities (similar distribution to PSD-95), consistent with PSD-93 forming part of a backbone scaffold that stabilizes binding partners within the PSD.","method":"EM immunogold labeling and quantitative mapping of isolated PSDs on glass coverslips","journal":"Brain cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct EM immunogold quantitative mapping, single lab, no functional manipulation","pmids":["18392731"],"is_preprint":false},{"year":2010,"finding":"In vivo, PSD-95 (not PSD-93) is the critical scaffold for localizing NR2A-containing NMDA receptor complexes to lipid rafts; PSD-93 KO does not alter NR2A raft localization, while PSD-95 KO reduces NR2A association with rafts, indicating differential roles in organizing NMDA receptor signaling complexes across membrane microdomains.","method":"Tandem affinity purification (TAP-tag knockin mice), lipid raft isolation, PSD-95 and PSD-93 KO mice, immunoblot","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetically encoded TAP tags, KO mouse comparison, fractionation; multiple orthogonal approaches in single study","pmids":["20554866"],"is_preprint":false},{"year":2011,"finding":"PSD-93 is required for scaling up of synaptic strength (homeostatic synaptic potentiation) in a manner that depends on neuronal age and can substitute for PSD-95 in this process; synaptic PSD-93 abundance is not bidirectionally regulated by activity (unlike PSD-95 and SAP102), yet it is functionally necessary for scaling up via distinct protein-protein interactions from those used by PSD-95 in scaling down.","method":"Lentiviral shRNA knockdown, overexpression in cortical neurons, mEPSC recording, immunofluorescence quantification","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD/OE with specific electrophysiological phenotype, single lab","pmids":["21543610"],"is_preprint":false},{"year":2012,"finding":"PSD-93 is a direct substrate of ERK2; purified ERK2 physically interacts with an N-terminal region of PSD-93 and phosphorylates it at Ser-323 in vitro; native ERK co-associates with PSD-93 in striatal synaptosomal fractions and immunoprecipitated PSD-93 shows basal ERK-sensitive phosphorylation in vivo.","method":"In vitro protein-protein interaction assay with purified proteins, in vitro kinase assay, site-directed mutagenesis, synaptosomal co-immunoprecipitation","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with phosphosite identification, Co-IP from native tissue; single lab","pmids":["22618309"],"is_preprint":false},{"year":2013,"finding":"Crystal structure and fluorescence polarization spectroscopy of PSD-93 PDZ1 with a GluD2 C-terminal peptide (GTSI) revealed two different binding modes of weak affinity; the two N-terminal PDZ domains of PSD-93 show no appreciable binding to a GluD2-derived octapeptide but micromolar affinity for a GluN2B-derived C-terminal octapeptide, indicating PDZ1/2 of PSD-93 preferentially engage GluN2B over GluD2.","method":"X-ray crystallography, fluorescence polarization spectroscopy (in vitro binding assay)","journal":"Acta crystallographica Section D","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus quantitative binding measurements; single lab with two orthogonal methods","pmids":["23519667"],"is_preprint":false},{"year":2014,"finding":"PSD-93 deletion reduces ischemic infarct volume and neurological deficits in adult mice after MCAO; PSD-93 KO decreased Fyn-mediated phosphorylation of NR2B at Tyr1472 and reduced NR2B-Fyn interaction after ischemia, and prevented induction of ischemic LTP; Src family inhibitor PP2 phenocopied the KO effect, placing PSD-93 upstream of Fyn-NR2B phosphorylation in excitotoxic signaling.","method":"PSD-93 KO mouse MCAO model, electrophysiology (ischemic LTP), phospho-Western blot, Co-IP, pharmacological inhibition with AP-5 and PP2","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined phenotype, epistasis via pharmacological inhibitors, phospho-specific Western blot; multiple orthogonal methods single lab","pmids":["24787897"],"is_preprint":false},{"year":2017,"finding":"PSD-93 overexpression in APP/PS1 mice increases SSTR4 membrane levels (linked to reduced ubiquitination) and neprilysin expression, reduces amyloid plaque load and Aβ levels, and improves spatial memory; PSD-93 co-immunoprecipitates with SSTR4, indicating PSD-93 stabilizes SSTR4 at the membrane to promote Aβ catabolism.","method":"Lentivirus-mediated overexpression, Co-IP, Morris water maze, LTP recording, ELISA, immunohistochemistry","journal":"Journal of Alzheimer's disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus in vivo OE with behavioral and biochemical readout; single lab","pmids":["28697571"],"is_preprint":false},{"year":2018,"finding":"DLG2/PSD-93 has a regulatory role in cell division, migration, and tumorigenesis; DLG2-deficient osteosarcoma cell lines show increased cell proliferation and migration, and osteoblast-specific Dlg2 deletion in a mouse model accelerates osteosarcoma development, establishing DLG2 as a tumor suppressor.","method":"DLG2-deficient human and canine OS cell lines (functional assays: migration, proliferation, tumorigenesis), osteoblast-specific conditional KO mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — human and canine cell line loss-of-function plus in vivo conditional KO mouse model; cross-species validation","pmids":["30093633"],"is_preprint":false},{"year":2020,"finding":"PSD-93 directly interacts with SynGAP (binding region: 670-685 aa of SynGAP) and mediates SynGAP ubiquitination and proteasomal degradation following ischemia-reperfusion; in PSD-93 KO mice, NMDAR inhibition or proteasome inhibition did not further alter SynGAP levels, placing PSD-93 downstream of NMDAR activation and upstream of SynGAP ubiquitination; a fusion peptide Tat-SynGAP(670-685aa) inhibiting this interaction reduced ischemic brain damage.","method":"Co-IP, domain-mapping peptide competition, proteasome inhibitor (MG-132) rescue, PSD-93 KO mice, MCAO model, NMDAR inhibitor (MK801)","journal":"Translational stroke research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mapping plus KO epistasis; single lab","pmids":["32130656"],"is_preprint":false},{"year":2020,"finding":"Dlg2 KO mice (exon 14 deletion) show reduced excitatory synaptic input (decreased frequency of spontaneous EPSCs) in dorsolateral striatum without changes in inhibitory currents, establishing DLG2 as required for maintenance of excitatory synaptic transmission in the striatum.","method":"Dlg2 KO mouse, whole-cell patch-clamp electrophysiology in dorsolateral striatum, behavioral battery, in situ hybridization","journal":"Molecular autism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with specific electrophysiological phenotype, confirmed with behavioral analysis; replicated in later study (PMID:35966008)","pmids":["32164788"],"is_preprint":false},{"year":2020,"finding":"DLG2 restoration in neuroblastoma cells spontaneously drives differentiation; oncogenic ALK-ERK1/2-SP1 signaling represses DLG2 expression to maintain an undifferentiated state, placing DLG2 downstream of ALK-ERK-SP1 in the differentiation pathway.","method":"DLG2 re-expression in neuroblastoma cell lines, morphological and marker differentiation analysis, ALK inhibitor treatment, SP1 overexpression/knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via inhibitors and OE/KD with defined differentiation phenotype; single lab","pmids":["32966799"],"is_preprint":false},{"year":2020,"finding":"Knockdown of Dlg2 in MIN6 pancreatic beta cells impairs glucose-stimulated and non-glucose-stimulated insulin secretion, indicating DLG2 is functionally required for insulin secretion in beta cells.","method":"RNA interference knockdown in MIN6 cells, glucose-stimulated insulin secretion assay, in vivo congenic mouse mapping","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific functional readout; single lab","pmids":["32356104"],"is_preprint":false},{"year":2021,"finding":"PSD-93 interacts with CX3CL1 (binding sites: aa 420-535 of PSD-93 and aa 357-395 of CX3CL1) following ischemia-reperfusion; a peptide blocking this interaction (Tat-CX3CL1 357-395aa) inhibits pro-inflammatory cytokine expression (IL-1β, TNF-α) and reduces ischemic neuronal death, placing PSD-93 upstream of microglial activation via CX3CL1 in ischemic neuroinflammation.","method":"MCAO model, Co-IP, domain-mapping peptide competition, cytokine assay, infarct volume measurement","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus domain mapping plus peptide intervention in vivo; 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 upregulates LIN7A, reduces neuroblastoma cell proliferation and viability, and increases BAX/BCL2 ratio; the L27 domain-lacking isoform 2 does not bind LIN7A and its expression is not decreased in high-stage neuroblastoma, linking the L27-mediated LIN7A interaction to tumor-suppressive function.","method":"Co-IP/pulldown between DLG2 isoform 7 and LIN7A, isoform-specific expression in SKNAS cells, cell viability/proliferation assays, apoptosis marker analysis","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional OE assay; single lab","pmids":["33726762"],"is_preprint":false},{"year":2022,"finding":"Rho-kinase/ROCK directly phosphorylates PSD-93 at Thr612 downstream of NMDAR activation; NMDAR agonist stimulation increases this phosphorylation in striatal slices; phosphorylation at Thr612 increases PSD-93 binding to PSD-95 and NMDARs; chemical-LTP induction (glycine) increases PSD-93 Thr612 phosphorylation, spine size, and PSD-93/PSD-95 co-localization, all blocked by Rho-kinase inhibitor.","method":"In vitro kinase assay, phospho-specific antibody, LC-MS/MS interactome analysis, Co-IP, chemical-LTP in neurons, Rho-kinase inhibitor pharmacology","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in situ phosphorylation plus Co-IP and LTP; single lab with multiple methods","pmids":["36613848"],"is_preprint":false},{"year":2022,"finding":"Heterozygous Dlg2+/- rats show increased potassium channel function leading to decreased input resistance and impaired supra-linear dendritic integration, resulting in deficits in associative LTP; NMDA receptor-mediated currents are increased (not decreased); blockade of potassium channels or activation of muscarinic M1 receptors rescued the LTP impairment, placing DLG2 as a regulator of potassium channel activity that gates dendritic integration and synaptic plasticity.","method":"Heterozygous Dlg2+/- rat, patch-clamp electrophysiology, pharmacology (potassium channel blockers, M1 agonist 77-LH-28-1), computational modeling","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — patch-clamp with pharmacological rescue plus computational modeling; multiple orthogonal methods, novel mechanistic finding","pmids":["35115661"],"is_preprint":false},{"year":2022,"finding":"DLG2 KO in human embryonic stem cells impairs transcriptional programs of early cortical neurogenesis, resulting in deficits in neuronal migration, morphology, and action potential generation, establishing DLG2 as required for proper excitatory cortical neuronal differentiation and maturation.","method":"DLG2 KO hESC lines, cortical neuron differentiation, transcriptomics, neuronal migration assay, morphological analysis, electrophysiology (action potential recording)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO hESC with multiple orthogonal functional readouts (migration, morphology, electrophysiology, transcriptomics); single lab but multiple methods","pmids":["35031607"],"is_preprint":false},{"year":2022,"finding":"A DLG2 deficiency causes compensatory increases of DLG4/PSD-95 and decreases in TrkA expression in the striatum; the density of postsynaptic densities and fraction of perforated synapses are significantly reduced in Dlg2 KO dorsolateral striatum, with reduced dendritic spine density in striatal SPNs but not in cortical pyramidal neurons, demonstrating a striatum-specific requirement for DLG2 in synapse formation.","method":"Transmission electron microscopy, miniature EPSC recording, dendritic spine analysis, Western blot, Dlg2 KO mouse","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — EM ultrastructure plus electrophysiology plus Western blot in KO mouse; multiple orthogonal methods single lab","pmids":["35966008"],"is_preprint":false},{"year":2022,"finding":"DLG2 overexpression in colon cancer cells increases expression of IL1B, IκBζ, and BAX (components of inflammasome formation), while DLG2 silencing increases IL-6 secretion leading to STAT3 phosphorylation in bystander cells; restoration of DLG2 reduces AKT and S6 signaling, linking DLG2 to inflammasome regulation and suppression of AKT/S6 signaling.","method":"DLG2 overexpression and siRNA knockdown in colon cancer cells, cytokine ELISA, Western blot (phospho-STAT3, phospho-AKT, phospho-S6), conditioned medium transfer assay","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — OE and KD with multiple downstream readouts; single lab","pmids":["35499706"],"is_preprint":false},{"year":2022,"finding":"DLG2 overexpression in neuroblastoma cells reduces DNA fragmentation after UVC irradiation, induces apoptosis in a p53 S46-dependent manner, causes CHK1 phosphorylation, and impairs expression of NHEJ genes PARP1 and FEN1; in Drosophila with UVC-induced breaks, DLG2 overexpression similarly reduces DNA fragmentation, supporting a role for DLG2 in DNA damage response and genome integrity maintenance.","method":"Comet assay, γH2AX immunofluorescence, qRT-PCR and Western blot, Drosophila UVC model, phospho-p53 and phospho-CHK1 Western blot","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in cell lines plus Drosophila model; single lab","pmids":["35217496"],"is_preprint":false},{"year":2026,"finding":"Src kinase phosphorylates PSD-93 at multiple tyrosine sites in vitro more robustly than PSD-95; phosphorylation differentially reduces PSD-93 affinity for postsynaptic client proteins and inhibits PSD-93 scaffolding activity (recruitment of clients into supercomplexes) while having opposite effects on PSD-95; phosphorylation of PSD-93 (but not PSD-95) affects biomolecular condensation, suggesting PSD-93 modulates condensate properties at higher protein concentrations.","method":"In vitro Src kinase assay, fluorescence polarization binding assay, small angle X-ray scattering, single-molecule FRET, supercomplex/scaffolding assay","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with multiple biophysical readouts; single lab, no in-cell validation","pmids":["41562278"],"is_preprint":false},{"year":2020,"finding":"The DLG2 F900V missense variant (associated with autosomal dominant delayed puberty) impairs the interaction between PSD-93 and Fyn kinase; this variant decreased GnRH expression in a GnRH neuronal cell line, suggesting that DLG2/PSD-93 regulates GnRH secretion through Fyn-dependent NMDA receptor signaling.","method":"Exome sequencing, Co-IP (interaction assay for F900V vs Fyn), GnRH expression assay in neuronal cell line","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP binding assay and cell-line functional assay; single lab, no in vivo mechanistic validation","pmids":["32341572"],"is_preprint":false}],"current_model":"DLG2/PSD-93 is a MAGUK scaffold protein that uses its PDZ domains to directly bind and cluster NMDA receptor subunits (preferentially GluN2B), Shaker-type K+ channels, Kir2.1, and nAChRs at postsynaptic densities; it is palmitoylated at its N-terminus for membrane anchoring and phosphorylated by Fyn (Tyr-384), Src (multiple tyrosines), ERK2 (Ser-323), and Rho-kinase/ROCK (Thr612), with phosphorylation regulating its affinity for client proteins, scaffolding activity, and condensate properties; it organizes distinct NMDA receptor signaling complexes from those formed by PSD-95, promotes NR2A localization to lipid rafts, is required for LTP and homeostatic scaling up in hippocampus, and for normal excitatory synaptic density in the dorsal striatum; it also couples NMDAR activity to Fyn-mediated NR2B phosphorylation and SynGAP ubiquitination, modulates neuronal-microglial crosstalk via CX3CL1, acts as a tumor suppressor by regulating cell division, DNA damage response, and Hippo/YAP signaling, and is required for insulin secretion in pancreatic beta cells."},"narrative":{"mechanistic_narrative":"DLG2 (PSD-93/Chapsyn-110) is a membrane-associated guanylate kinase (MAGUK) scaffold that organizes receptor and ion-channel signaling complexes at the postsynaptic density of excitatory synapses, where it localizes to asymmetric axo-spinous junctions and forms part of the PSD backbone scaffold [PMID:11309840, PMID:18392731]. Through its PDZ domains it directly binds and clusters NMDA receptor subunits and Shaker-type K+ channels, heteromultimerizing with PSD-95 into a multimeric scaffold [PMID:8755482]; its PDZ1/2 modules preferentially engage GluN2B over GluD2 C-terminal tails [PMID:23519667], and an alternatively spliced isoform clusters the inward-rectifier Kir2.1 while suppressing its internalization [PMID:15304517]. DLG2 also stabilizes neuronal nicotinic acetylcholine receptors at cholinergic synapses [PMID:14724236]. Its scaffolding output is gated by phosphorylation: Fyn phosphorylates DLG2 at Tyr-384 on a palmitoylation-anchored substrate, ERK2 at Ser-323, and Rho-kinase/ROCK at Thr612 to strengthen its binding to PSD-95 and NMDARs, while Src phosphorylation at multiple tyrosines reduces client affinity and modulates condensate behavior [PMID:13129934, PMID:22618309, PMID:36613848, PMID:41562278]. Functionally, DLG2 is required for hippocampal LTP and homeostatic scaling up and organizes NMDA receptor signaling complexes distinct from those of PSD-95, including coupling NMDAR activity to Fyn-mediated GluN2B phosphorylation and SynGAP ubiquitination in excitotoxic signaling [PMID:18936077, PMID:20554866, PMID:21543610, PMID:24787897, PMID:32130656]. DLG2 governs potassium-channel-dependent dendritic integration that gates associative plasticity [PMID:35115661], is required for striatum-specific excitatory synapse maintenance and for cortical neuronal differentiation [PMID:32164788, PMID:35031607, PMID:35966008], and acts as a tumor suppressor in osteosarcoma and neuroblastoma by controlling proliferation, differentiation, the DNA damage response, and apoptotic signaling [PMID:30093633, PMID:32966799, PMID:35217496]. A DLG2 F900V variant impairing the PSD-93–Fyn interaction is associated with autosomal dominant delayed puberty [PMID:32341572].","teleology":[{"year":1996,"claim":"Established DLG2 as a PDZ-domain MAGUK that physically clusters ionotropic receptors and channels, defining its core scaffolding identity at the synapse.","evidence":"Co-IP, yeast two-hybrid, and heterologous clustering of NMDA receptors and Shaker K+ channels, with heteromultimerization to PSD-95","pmids":["8755482"],"confidence":"High","gaps":["Did not establish in vivo synaptic requirement","Affinity and subunit selectivity among receptor partners not quantified"]},{"year":2001,"claim":"Localized DLG2 ultrastructurally to postsynaptic densities of asymmetric synapses and showed a single-MAGUK synapse type tolerates its loss, framing both a synaptic anchoring role and functional redundancy.","evidence":"EM immunogold mapping in visual cortex; knockout mouse analysis of cerebellar parallel-fiber synapses","pmids":["11309840","11312293"],"confidence":"High","gaps":["Did not resolve which synapse types strictly require DLG2","Presynaptic and cytoplasmic pools not functionally assigned"]},{"year":2003,"claim":"Identified DLG2 as a tyrosine kinase substrate, linking its membrane anchoring and phosphorylation by Fyn (Tyr-384) to NMDA receptor signaling regulation.","evidence":"In vitro kinase assay, mutagenesis, Fyn-KO brain comparison, and Csk Co-IP; antisense knockdown in spinal pain models; KO of NMDAR-nNOS complex assembly","pmids":["13129934","14581127","15296832"],"confidence":"Medium","gaps":["Functional consequence of Tyr-384 phosphorylation in vivo not isolated","nNOS coupling tested in single contexts"]},{"year":2004,"claim":"Broadened the DLG2 client repertoire beyond NMDARs to nAChRs and Kir2.1 channels, showing it stabilizes diverse postsynaptic surface receptors via isoform-specific PDZ interactions.","evidence":"Co-IP and KO denervation phenotype for nAChRs; yeast two-hybrid, in vitro binding, and surface clustering for Kir2.1 (PSD-93delta)","pmids":["14724236","15304517"],"confidence":"High","gaps":["Isoform-specific expression patterns across neuron types not mapped","Mechanism of internalization suppression unresolved"]},{"year":2008,"claim":"Demonstrated that DLG2 and PSD-95 have divergent, non-interchangeable roles in plasticity and that DLG2 organizes distinct NMDA receptor signaling complexes.","evidence":"KO mouse electrophysiology showing LTP deficits without LTD changes; quantitative EM immunogold mapping of isolated PSDs","pmids":["18936077","18392731"],"confidence":"High","gaps":["Molecular basis of opposing PSD-93 vs PSD-95 LTP roles not defined","Complex composition differences not biochemically resolved"]},{"year":2010,"claim":"Distinguished DLG2 from PSD-95 in membrane microdomain organization, showing PSD-95 (not DLG2) targets NR2A complexes to lipid rafts.","evidence":"TAP-tag knockin mice, lipid raft fractionation, and PSD-93/PSD-95 KO comparison","pmids":["20554866"],"confidence":"High","gaps":["Which subunit complexes DLG2 selectively organizes left open","Raft-independent DLG2 functions not characterized"]},{"year":2011,"claim":"Showed DLG2 is functionally required for homeostatic scaling up through interactions distinct from those PSD-95 uses for scaling down, despite not being activity-regulated itself.","evidence":"Lentiviral knockdown/overexpression in cortical neurons with mEPSC recording","pmids":["21543610"],"confidence":"Medium","gaps":["The specific scaling-up interactions not molecularly identified","Age dependence mechanism unexplained"]},{"year":2012,"claim":"Added ERK2 as a second kinase regulating DLG2, mapping phosphorylation to Ser-323 and embedding DLG2 in synaptic signaling cascades.","evidence":"In vitro protein interaction and kinase assays, mutagenesis, and striatal synaptosomal Co-IP","pmids":["22618309"],"confidence":"Medium","gaps":["Functional consequence of Ser-323 phosphorylation untested","Single-lab in vitro identification"]},{"year":2013,"claim":"Resolved structurally that DLG2 PDZ1/2 preferentially bind GluN2B over GluD2, providing atomic-level basis for receptor selectivity.","evidence":"X-ray crystallography of PDZ1-GluD2 peptide complex and fluorescence polarization binding measurements","pmids":["23519667"],"confidence":"High","gaps":["Selectivity not validated in cells","Full-length scaffold avidity effects not addressed"]},{"year":2014,"claim":"Placed DLG2 upstream of Fyn-mediated GluN2B Tyr1472 phosphorylation in excitotoxic signaling, defining a mechanistic link between scaffolding and ischemic injury.","evidence":"KO mouse MCAO model, phospho-Western, Co-IP, and PP2 pharmacological epistasis","pmids":["24787897"],"confidence":"High","gaps":["Therapeutic targeting feasibility not addressed here","Whether effect is purely scaffold-dependent unresolved"]},{"year":2020,"claim":"Extended DLG2 mechanism to ubiquitin-dependent degradation of SynGAP downstream of NMDAR activation, with a defined interaction interface and a protective interfering peptide.","evidence":"Co-IP, domain mapping (SynGAP 670-685), proteasome inhibitor rescue, KO epistasis, and MCAO peptide intervention","pmids":["32130656"],"confidence":"Medium","gaps":["E3 ligase mediating ubiquitination not identified","Direct DLG2 catalytic involvement vs adaptor role unclear"]},{"year":2020,"claim":"Established region-specific in vivo synaptic requirements for DLG2 in the striatum and revealed non-neuronal roles in beta-cell insulin secretion and a disease-associated Fyn-binding variant.","evidence":"Dlg2 KO mouse striatal patch-clamp; MIN6 knockdown insulin secretion assay; exome sequencing and Co-IP of F900V variant","pmids":["32164788","32356104","32341572"],"confidence":"High","gaps":["Mechanism of insulin-secretion role uncharacterized","F900V causality not validated in vivo"]},{"year":2020,"claim":"Defined DLG2 as a tumor suppressor controlling proliferation and differentiation, downstream of oncogenic ALK-ERK-SP1 repression in neuroblastoma and through L27-mediated LIN7A binding.","evidence":"DLG2-deficient osteosarcoma cell lines and conditional KO mice (2018); neuroblastoma re-expression with ALK-inhibitor/SP1 epistasis; isoform-specific LIN7A Co-IP","pmids":["30093633","32966799","33726762"],"confidence":"High","gaps":["Molecular mechanism coupling DLG2 to cell-cycle control incomplete","Isoform-dependent tumor-suppressive interactions not fully mapped"]},{"year":2022,"claim":"Identified ROCK/Thr612 phosphorylation as a positive regulator of DLG2 scaffolding and discovered that DLG2 regulates potassium-channel-dependent dendritic integration gating associative plasticity.","evidence":"In vitro kinase assay, phospho-antibody, LC-MS/MS interactome, chemical-LTP (Thr612); Dlg2+/- rat patch-clamp with K+-channel and M1 pharmacological rescue and modeling","pmids":["36613848","35115661"],"confidence":"High","gaps":["Which K+ channels DLG2 regulates not molecularly identified","Link between phosphorylation and dendritic integration not integrated"]},{"year":2022,"claim":"Showed DLG2 is required for cortical neuronal differentiation and striatum-specific synapse formation, and extended its tumor-suppressor mechanism to the DNA damage response and inflammasome/AKT-S6 signaling.","evidence":"DLG2 KO hESC cortical differentiation with transcriptomics and electrophysiology; Dlg2 KO striatal EM/mEPSC; comet/gammaH2AX assays with Drosophila model; colon cancer OE/KD cytokine and signaling readouts","pmids":["35031607","35966008","35217496","35499706"],"confidence":"High","gaps":["Transcriptional mechanism in neurogenesis not defined","Connection between synaptic scaffold and DNA-damage roles unexplained"]},{"year":2026,"claim":"Provided biophysical mechanism distinguishing DLG2 from PSD-95: Src tyrosine phosphorylation reduces DLG2 client affinity, inhibits supercomplex formation, and uniquely alters its biomolecular condensation.","evidence":"In vitro Src kinase assay, fluorescence polarization, SAXS, single-molecule FRET, and scaffolding/condensation assays","pmids":["41562278"],"confidence":"Medium","gaps":["No in-cell validation of condensate effects","Physiological phospho-site occupancy unknown"]},{"year":null,"claim":"How DLG2's synaptic scaffolding mechanism mechanistically connects to its tumor-suppressor and DNA-damage roles, and what E3 ligase and signaling intermediates execute these non-synaptic functions, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified mechanism linking synaptic scaffold and proliferation control","SynGAP-degrading E3 ligase unidentified","Cross-tissue mechanistic basis (beta cell, tumor) uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,14,30]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,18,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,13]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,9,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,15,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,20,29]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[29]}],"complexes":["postsynaptic density"],"partners":["PSD-95","FYN","CSK","ERK2","SYNGAP","KIR2.1","CX3CL1","LIN7A"],"other_free_text":[]}},"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. 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\"Co-immunoprecipitation, heterologous cell clustering assay, yeast two-hybrid, subcellular fractionation\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, heterologous clustering assay, and fractionation; foundational paper replicated by subsequent work\",\n      \"pmids\": [\"8755482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Electron microscopic immunocytochemistry demonstrated that PSD-93/DLG2 localizes to postsynaptic densities of asymmetric axo-spinous synapses in rat visual cortex, as well as along presynaptic membranes and in axonal/dendritic cytoplasm, suggesting dual roles in maintaining receptors at synapses and regulating receptor shuttling.\",\n      \"method\": \"Electron microscopic immunocytochemistry with quantitative immunogold labeling\",\n      \"journal\": \"Synapse\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct EM-ICC localization with quantitative mapping, systematic survey across multiple MAGUKs\",\n      \"pmids\": [\"11309840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PSD-93 knockout mice show no structural or functional abnormality in cerebellar parallel fiber synapses despite PSD-93 being the only MAGUK expressed in Purkinje neurons, indicating PSD-93 is not essential for development of certain central synapses but may participate in specialized synaptic signaling.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), light and electron microscopy, electrophysiology, behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and behavioral phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"11312293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PSD-93/DLG2 is a substrate for the Src family tyrosine kinase Fyn; Fyn phosphorylates PSD-93 in vitro and in vivo at Tyr-384, an N-terminal palmitoylation signal is required for membrane anchoring where Fyn is localized, and tyrosine-phosphorylated PSD-93 binds Csk (a negative regulator of Src family kinases).\",\n      \"method\": \"Immunopurification of NMDA receptor complex, microsequencing, in vitro kinase assay with recombinant proteins, site-directed mutagenesis, Fyn-deficient mouse brain comparison, Co-IP from brain lysate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis identifying Tyr-384, validated in Fyn-KO mice and brain lysate Co-IP\",\n      \"pmids\": [\"13129934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Knockdown of spinal cord PSD-93/DLG2 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 mechanisms downstream of NMDAR activation.\",\n      \"method\": \"Intrathecal antisense oligodeoxynucleotide knockdown in rat, behavioral pain assays (paw withdrawal thresholds), Western blot confirmation of knockdown\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with specific behavioral readout, single lab, antisense approach\",\n      \"pmids\": [\"14581127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In neonatal hypoxia-ischemia, PSD-93 deletion does not provide neuroprotection; PSD-95 compensates by still interacting with NR2B and nNOS in PSD-93 KO mice, and PSD-95 expression is upregulated after HI in KO pups, demonstrating functional redundancy between MAGUKs at baseline.\",\n      \"method\": \"PSD-93 KO mouse model, neonatal HI model, Western blot, co-immunoprecipitation, brain injury scoring\",\n      \"journal\": \"Stroke\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined phenotypic readout and Co-IP validation; single lab\",\n      \"pmids\": [\"14605317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PSD-93/DLG2 colocalizes and co-immunoprecipitates with NMDA receptors and neuronal nitric oxide synthase in cultured cortical neurons; PSD-93 gene disruption prevents NMDA receptor-nNOS complex formation, attenuates PAF-induced cGMP elevation, and significantly reduces PAF-triggered NMDA receptor-nitric oxide signaling-dependent neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation, targeted gene disruption (KO neurons), cGMP measurement, neurotoxicity assay\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KO functional readout, single lab\",\n      \"pmids\": [\"15296832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Novel splice forms of PSD-93/DLG2 are expressed in mouse superior cervical ganglion (SCG); PSD-93 co-localizes with and co-immunoprecipitates neuronal nicotinic acetylcholine receptors (nAChRs) at cholinergic synapses, and PSD-93 KO mice show accelerated disassembly of nAChR synaptic clusters after denervation, establishing PSD-93 as a stabilizing scaffold at neuronal cholinergic postsynaptic densities.\",\n      \"method\": \"Immunostaining, subcellular fractionation, co-immunoprecipitation, PSD-93 KO mouse denervation model\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vivo KO with defined synaptic stability phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"14724236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"An alternatively spliced isoform of PSD-93 (PSD-93δ) directly interacts with the inwardly rectifying K+ channel Kir2.1 via a type I PDZ recognition motif at the Kir2.1 C-terminus; co-expression of Kir2.1 and PSD-93δ causes cell surface clustering of Kir2.1 and suppresses channel internalization without affecting channel kinetics.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro binding assay, co-immunoprecipitation from rat spinal cord, heterologous cell expression with surface clustering assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — yeast two-hybrid, in vitro binding, Co-IP from native tissue, and functional cell surface assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15304517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSD-93 KO mice exhibit normal AMPA and NMDA receptor-mediated synaptic transmission but show deficits in LTP induction without affecting LTD, demonstrating that PSD-93 and PSD-95 have opposing roles in LTP in hippocampal CA1 and likely organize distinct NMDA receptor signaling complexes.\",\n      \"method\": \"PSD-93 KO and PSD-95 KO mouse electrophysiology, field recordings in hippocampal slices, multiple LTP/LTD induction protocols\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined synaptic plasticity phenotype using multiple induction protocols, replicated across two mutant lines\",\n      \"pmids\": [\"18936077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PSD-93 is homogeneously distributed throughout isolated postsynaptic densities (similar distribution to PSD-95), consistent with PSD-93 forming part of a backbone scaffold that stabilizes binding partners within the PSD.\",\n      \"method\": \"EM immunogold labeling and quantitative mapping of isolated PSDs on glass coverslips\",\n      \"journal\": \"Brain cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct EM immunogold quantitative mapping, single lab, no functional manipulation\",\n      \"pmids\": [\"18392731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In vivo, PSD-95 (not PSD-93) is the critical scaffold for localizing NR2A-containing NMDA receptor complexes to lipid rafts; PSD-93 KO does not alter NR2A raft localization, while PSD-95 KO reduces NR2A association with rafts, indicating differential roles in organizing NMDA receptor signaling complexes across membrane microdomains.\",\n      \"method\": \"Tandem affinity purification (TAP-tag knockin mice), lipid raft isolation, PSD-95 and PSD-93 KO mice, immunoblot\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetically encoded TAP tags, KO mouse comparison, fractionation; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"20554866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PSD-93 is required for scaling up of synaptic strength (homeostatic synaptic potentiation) in a manner that depends on neuronal age and can substitute for PSD-95 in this process; synaptic PSD-93 abundance is not bidirectionally regulated by activity (unlike PSD-95 and SAP102), yet it is functionally necessary for scaling up via distinct protein-protein interactions from those used by PSD-95 in scaling down.\",\n      \"method\": \"Lentiviral shRNA knockdown, overexpression in cortical neurons, mEPSC recording, immunofluorescence quantification\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD/OE with specific electrophysiological phenotype, single lab\",\n      \"pmids\": [\"21543610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PSD-93 is a direct substrate of ERK2; purified ERK2 physically interacts with an N-terminal region of PSD-93 and phosphorylates it at Ser-323 in vitro; native ERK co-associates with PSD-93 in striatal synaptosomal fractions and immunoprecipitated PSD-93 shows basal ERK-sensitive phosphorylation in vivo.\",\n      \"method\": \"In vitro protein-protein interaction assay with purified proteins, in vitro kinase assay, site-directed mutagenesis, synaptosomal co-immunoprecipitation\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with phosphosite identification, Co-IP from native tissue; single lab\",\n      \"pmids\": [\"22618309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure and fluorescence polarization spectroscopy of PSD-93 PDZ1 with a GluD2 C-terminal peptide (GTSI) revealed two different binding modes of weak affinity; the two N-terminal PDZ domains of PSD-93 show no appreciable binding to a GluD2-derived octapeptide but micromolar affinity for a GluN2B-derived C-terminal octapeptide, indicating PDZ1/2 of PSD-93 preferentially engage GluN2B over GluD2.\",\n      \"method\": \"X-ray crystallography, fluorescence polarization spectroscopy (in vitro binding assay)\",\n      \"journal\": \"Acta crystallographica Section D\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus quantitative binding measurements; single lab with two orthogonal methods\",\n      \"pmids\": [\"23519667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSD-93 deletion reduces ischemic infarct volume and neurological deficits in adult mice after MCAO; PSD-93 KO decreased Fyn-mediated phosphorylation of NR2B at Tyr1472 and reduced NR2B-Fyn interaction after ischemia, and prevented induction of ischemic LTP; Src family inhibitor PP2 phenocopied the KO effect, placing PSD-93 upstream of Fyn-NR2B phosphorylation in excitotoxic signaling.\",\n      \"method\": \"PSD-93 KO mouse MCAO model, electrophysiology (ischemic LTP), phospho-Western blot, Co-IP, pharmacological inhibition with AP-5 and PP2\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined phenotype, epistasis via pharmacological inhibitors, phospho-specific Western blot; multiple orthogonal methods single lab\",\n      \"pmids\": [\"24787897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSD-93 overexpression in APP/PS1 mice increases SSTR4 membrane levels (linked to reduced ubiquitination) and neprilysin expression, reduces amyloid plaque load and Aβ levels, and improves spatial memory; PSD-93 co-immunoprecipitates with SSTR4, indicating PSD-93 stabilizes SSTR4 at the membrane to promote Aβ catabolism.\",\n      \"method\": \"Lentivirus-mediated overexpression, Co-IP, Morris water maze, LTP recording, ELISA, immunohistochemistry\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus in vivo OE with behavioral and biochemical readout; single lab\",\n      \"pmids\": [\"28697571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DLG2/PSD-93 has a regulatory role in cell division, migration, and tumorigenesis; DLG2-deficient osteosarcoma cell lines show increased cell proliferation and migration, and osteoblast-specific Dlg2 deletion in a mouse model accelerates osteosarcoma development, establishing DLG2 as a tumor suppressor.\",\n      \"method\": \"DLG2-deficient human and canine OS cell lines (functional assays: migration, proliferation, tumorigenesis), osteoblast-specific conditional KO mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human and canine cell line loss-of-function plus in vivo conditional KO mouse model; cross-species validation\",\n      \"pmids\": [\"30093633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PSD-93 directly interacts with SynGAP (binding region: 670-685 aa of SynGAP) and mediates SynGAP ubiquitination and proteasomal degradation following ischemia-reperfusion; in PSD-93 KO mice, NMDAR inhibition or proteasome inhibition did not further alter SynGAP levels, placing PSD-93 downstream of NMDAR activation and upstream of SynGAP ubiquitination; a fusion peptide Tat-SynGAP(670-685aa) inhibiting this interaction reduced ischemic brain damage.\",\n      \"method\": \"Co-IP, domain-mapping peptide competition, proteasome inhibitor (MG-132) rescue, PSD-93 KO mice, MCAO model, NMDAR inhibitor (MK801)\",\n      \"journal\": \"Translational stroke research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mapping plus KO epistasis; single lab\",\n      \"pmids\": [\"32130656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dlg2 KO mice (exon 14 deletion) show reduced excitatory synaptic input (decreased frequency of spontaneous EPSCs) in dorsolateral striatum without changes in inhibitory currents, establishing DLG2 as required for maintenance of excitatory synaptic transmission in the striatum.\",\n      \"method\": \"Dlg2 KO mouse, whole-cell patch-clamp electrophysiology in dorsolateral striatum, behavioral battery, in situ hybridization\",\n      \"journal\": \"Molecular autism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with specific electrophysiological phenotype, confirmed with behavioral analysis; replicated in later study (PMID:35966008)\",\n      \"pmids\": [\"32164788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DLG2 restoration in neuroblastoma cells spontaneously drives differentiation; oncogenic ALK-ERK1/2-SP1 signaling represses DLG2 expression to maintain an undifferentiated state, placing DLG2 downstream of ALK-ERK-SP1 in the differentiation pathway.\",\n      \"method\": \"DLG2 re-expression in neuroblastoma cell lines, morphological and marker differentiation analysis, ALK inhibitor treatment, SP1 overexpression/knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via inhibitors and OE/KD with defined differentiation phenotype; single lab\",\n      \"pmids\": [\"32966799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of Dlg2 in MIN6 pancreatic beta cells impairs glucose-stimulated and non-glucose-stimulated insulin secretion, indicating DLG2 is functionally required for insulin secretion in beta cells.\",\n      \"method\": \"RNA interference knockdown in MIN6 cells, glucose-stimulated insulin secretion assay, in vivo congenic mouse mapping\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific functional readout; single lab\",\n      \"pmids\": [\"32356104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSD-93 interacts with CX3CL1 (binding sites: aa 420-535 of PSD-93 and aa 357-395 of CX3CL1) following ischemia-reperfusion; a peptide blocking this interaction (Tat-CX3CL1 357-395aa) inhibits pro-inflammatory cytokine expression (IL-1β, TNF-α) and reduces ischemic neuronal death, placing PSD-93 upstream of microglial activation via CX3CL1 in ischemic neuroinflammation.\",\n      \"method\": \"MCAO model, Co-IP, domain-mapping peptide competition, cytokine assay, infarct volume measurement\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus domain mapping plus peptide intervention in vivo; 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 upregulates LIN7A, reduces neuroblastoma cell proliferation and viability, and increases BAX/BCL2 ratio; the L27 domain-lacking isoform 2 does not bind LIN7A and its expression is not decreased in high-stage neuroblastoma, linking the L27-mediated LIN7A interaction to tumor-suppressive function.\",\n      \"method\": \"Co-IP/pulldown between DLG2 isoform 7 and LIN7A, isoform-specific expression in SKNAS cells, cell viability/proliferation assays, apoptosis marker analysis\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional OE assay; single lab\",\n      \"pmids\": [\"33726762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rho-kinase/ROCK directly phosphorylates PSD-93 at Thr612 downstream of NMDAR activation; NMDAR agonist stimulation increases this phosphorylation in striatal slices; phosphorylation at Thr612 increases PSD-93 binding to PSD-95 and NMDARs; chemical-LTP induction (glycine) increases PSD-93 Thr612 phosphorylation, spine size, and PSD-93/PSD-95 co-localization, all blocked by Rho-kinase inhibitor.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, LC-MS/MS interactome analysis, Co-IP, chemical-LTP in neurons, Rho-kinase inhibitor pharmacology\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in situ phosphorylation plus Co-IP and LTP; single lab with multiple methods\",\n      \"pmids\": [\"36613848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Heterozygous Dlg2+/- rats show increased potassium channel function leading to decreased input resistance and impaired supra-linear dendritic integration, resulting in deficits in associative LTP; NMDA receptor-mediated currents are increased (not decreased); blockade of potassium channels or activation of muscarinic M1 receptors rescued the LTP impairment, placing DLG2 as a regulator of potassium channel activity that gates dendritic integration and synaptic plasticity.\",\n      \"method\": \"Heterozygous Dlg2+/- rat, patch-clamp electrophysiology, pharmacology (potassium channel blockers, M1 agonist 77-LH-28-1), computational modeling\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — patch-clamp with pharmacological rescue plus computational modeling; multiple orthogonal methods, novel mechanistic finding\",\n      \"pmids\": [\"35115661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 KO in human embryonic stem cells impairs transcriptional programs of early cortical neurogenesis, resulting in deficits in neuronal migration, morphology, and action potential generation, establishing DLG2 as required for proper excitatory cortical neuronal differentiation and maturation.\",\n      \"method\": \"DLG2 KO hESC lines, cortical neuron differentiation, transcriptomics, neuronal migration assay, morphological analysis, electrophysiology (action potential recording)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO hESC with multiple orthogonal functional readouts (migration, morphology, electrophysiology, transcriptomics); single lab but multiple methods\",\n      \"pmids\": [\"35031607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A DLG2 deficiency causes compensatory increases of DLG4/PSD-95 and decreases in TrkA expression in the striatum; the density of postsynaptic densities and fraction of perforated synapses are significantly reduced in Dlg2 KO dorsolateral striatum, with reduced dendritic spine density in striatal SPNs but not in cortical pyramidal neurons, demonstrating a striatum-specific requirement for DLG2 in synapse formation.\",\n      \"method\": \"Transmission electron microscopy, miniature EPSC recording, dendritic spine analysis, Western blot, Dlg2 KO mouse\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EM ultrastructure plus electrophysiology plus Western blot in KO mouse; multiple orthogonal methods single lab\",\n      \"pmids\": [\"35966008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 overexpression in colon cancer cells increases expression of IL1B, IκBζ, and BAX (components of inflammasome formation), while DLG2 silencing increases IL-6 secretion leading to STAT3 phosphorylation in bystander cells; restoration of DLG2 reduces AKT and S6 signaling, linking DLG2 to inflammasome regulation and suppression of AKT/S6 signaling.\",\n      \"method\": \"DLG2 overexpression and siRNA knockdown in colon cancer cells, cytokine ELISA, Western blot (phospho-STAT3, phospho-AKT, phospho-S6), conditioned medium transfer assay\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — OE and KD with multiple downstream readouts; single lab\",\n      \"pmids\": [\"35499706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DLG2 overexpression in neuroblastoma cells reduces DNA fragmentation after UVC irradiation, induces apoptosis in a p53 S46-dependent manner, causes CHK1 phosphorylation, and impairs expression of NHEJ genes PARP1 and FEN1; in Drosophila with UVC-induced breaks, DLG2 overexpression similarly reduces DNA fragmentation, supporting a role for DLG2 in DNA damage response and genome integrity maintenance.\",\n      \"method\": \"Comet assay, γH2AX immunofluorescence, qRT-PCR and Western blot, Drosophila UVC model, phospho-p53 and phospho-CHK1 Western blot\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in cell lines plus Drosophila model; single lab\",\n      \"pmids\": [\"35217496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Src kinase phosphorylates PSD-93 at multiple tyrosine sites in vitro more robustly than PSD-95; phosphorylation differentially reduces PSD-93 affinity for postsynaptic client proteins and inhibits PSD-93 scaffolding activity (recruitment of clients into supercomplexes) while having opposite effects on PSD-95; phosphorylation of PSD-93 (but not PSD-95) affects biomolecular condensation, suggesting PSD-93 modulates condensate properties at higher protein concentrations.\",\n      \"method\": \"In vitro Src kinase assay, fluorescence polarization binding assay, small angle X-ray scattering, single-molecule FRET, supercomplex/scaffolding assay\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with multiple biophysical readouts; single lab, no in-cell validation\",\n      \"pmids\": [\"41562278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The DLG2 F900V missense variant (associated with autosomal dominant delayed puberty) impairs the interaction between PSD-93 and Fyn kinase; this variant decreased GnRH expression in a GnRH neuronal cell line, suggesting that DLG2/PSD-93 regulates GnRH secretion through Fyn-dependent NMDA receptor signaling.\",\n      \"method\": \"Exome sequencing, Co-IP (interaction assay for F900V vs Fyn), GnRH expression assay in neuronal cell line\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP binding assay and cell-line functional assay; single lab, no in vivo mechanistic validation\",\n      \"pmids\": [\"32341572\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLG2/PSD-93 is a MAGUK scaffold protein that uses its PDZ domains to directly bind and cluster NMDA receptor subunits (preferentially GluN2B), Shaker-type K+ channels, Kir2.1, and nAChRs at postsynaptic densities; it is palmitoylated at its N-terminus for membrane anchoring and phosphorylated by Fyn (Tyr-384), Src (multiple tyrosines), ERK2 (Ser-323), and Rho-kinase/ROCK (Thr612), with phosphorylation regulating its affinity for client proteins, scaffolding activity, and condensate properties; it organizes distinct NMDA receptor signaling complexes from those formed by PSD-95, promotes NR2A localization to lipid rafts, is required for LTP and homeostatic scaling up in hippocampus, and for normal excitatory synaptic density in the dorsal striatum; it also couples NMDAR activity to Fyn-mediated NR2B phosphorylation and SynGAP ubiquitination, modulates neuronal-microglial crosstalk via CX3CL1, acts as a tumor suppressor by regulating cell division, DNA damage response, and Hippo/YAP signaling, and is required for insulin secretion in pancreatic beta cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DLG2 (PSD-93/Chapsyn-110) is a membrane-associated guanylate kinase (MAGUK) scaffold that organizes receptor and ion-channel signaling complexes at the postsynaptic density of excitatory synapses, where it localizes to asymmetric axo-spinous junctions and forms part of the PSD backbone scaffold [#1, #10]. Through its PDZ domains it directly binds and clusters NMDA receptor subunits and Shaker-type K+ channels, heteromultimerizing with PSD-95 into a multimeric scaffold [#0]; its PDZ1/2 modules preferentially engage GluN2B over GluD2 C-terminal tails [#14], and an alternatively spliced isoform clusters the inward-rectifier Kir2.1 while suppressing its internalization [#8]. DLG2 also stabilizes neuronal nicotinic acetylcholine receptors at cholinergic synapses [#7]. Its scaffolding output is gated by phosphorylation: Fyn phosphorylates DLG2 at Tyr-384 on a palmitoylation-anchored substrate, ERK2 at Ser-323, and Rho-kinase/ROCK at Thr612 to strengthen its binding to PSD-95 and NMDARs, while Src phosphorylation at multiple tyrosines reduces client affinity and modulates condensate behavior [#3, #13, #24, #30]. Functionally, DLG2 is required for hippocampal LTP and homeostatic scaling up and organizes NMDA receptor signaling complexes distinct from those of PSD-95, including coupling NMDAR activity to Fyn-mediated GluN2B phosphorylation and SynGAP ubiquitination in excitotoxic signaling [#9, #11, #12, #15, #18]. DLG2 governs potassium-channel-dependent dendritic integration that gates associative plasticity [#25], is required for striatum-specific excitatory synapse maintenance and for cortical neuronal differentiation [#19, #26, #27], and acts as a tumor suppressor in osteosarcoma and neuroblastoma by controlling proliferation, differentiation, the DNA damage response, and apoptotic signaling [#17, #20, #29]. A DLG2 F900V variant impairing the PSD-93–Fyn interaction is associated with autosomal dominant delayed puberty [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established DLG2 as a PDZ-domain MAGUK that physically clusters ionotropic receptors and channels, defining its core scaffolding identity at the synapse.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, and heterologous clustering of NMDA receptors and Shaker K+ channels, with heteromultimerization to PSD-95\",\n      \"pmids\": [\"8755482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo synaptic requirement\", \"Affinity and subunit selectivity among receptor partners not quantified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localized DLG2 ultrastructurally to postsynaptic densities of asymmetric synapses and showed a single-MAGUK synapse type tolerates its loss, framing both a synaptic anchoring role and functional redundancy.\",\n      \"evidence\": \"EM immunogold mapping in visual cortex; knockout mouse analysis of cerebellar parallel-fiber synapses\",\n      \"pmids\": [\"11309840\", \"11312293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which synapse types strictly require DLG2\", \"Presynaptic and cytoplasmic pools not functionally assigned\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified DLG2 as a tyrosine kinase substrate, linking its membrane anchoring and phosphorylation by Fyn (Tyr-384) to NMDA receptor signaling regulation.\",\n      \"evidence\": \"In vitro kinase assay, mutagenesis, Fyn-KO brain comparison, and Csk Co-IP; antisense knockdown in spinal pain models; KO of NMDAR-nNOS complex assembly\",\n      \"pmids\": [\"13129934\", \"14581127\", \"15296832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Tyr-384 phosphorylation in vivo not isolated\", \"nNOS coupling tested in single contexts\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened the DLG2 client repertoire beyond NMDARs to nAChRs and Kir2.1 channels, showing it stabilizes diverse postsynaptic surface receptors via isoform-specific PDZ interactions.\",\n      \"evidence\": \"Co-IP and KO denervation phenotype for nAChRs; yeast two-hybrid, in vitro binding, and surface clustering for Kir2.1 (PSD-93delta)\",\n      \"pmids\": [\"14724236\", \"15304517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific expression patterns across neuron types not mapped\", \"Mechanism of internalization suppression unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that DLG2 and PSD-95 have divergent, non-interchangeable roles in plasticity and that DLG2 organizes distinct NMDA receptor signaling complexes.\",\n      \"evidence\": \"KO mouse electrophysiology showing LTP deficits without LTD changes; quantitative EM immunogold mapping of isolated PSDs\",\n      \"pmids\": [\"18936077\", \"18392731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of opposing PSD-93 vs PSD-95 LTP roles not defined\", \"Complex composition differences not biochemically resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Distinguished DLG2 from PSD-95 in membrane microdomain organization, showing PSD-95 (not DLG2) targets NR2A complexes to lipid rafts.\",\n      \"evidence\": \"TAP-tag knockin mice, lipid raft fractionation, and PSD-93/PSD-95 KO comparison\",\n      \"pmids\": [\"20554866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which subunit complexes DLG2 selectively organizes left open\", \"Raft-independent DLG2 functions not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed DLG2 is functionally required for homeostatic scaling up through interactions distinct from those PSD-95 uses for scaling down, despite not being activity-regulated itself.\",\n      \"evidence\": \"Lentiviral knockdown/overexpression in cortical neurons with mEPSC recording\",\n      \"pmids\": [\"21543610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific scaling-up interactions not molecularly identified\", \"Age dependence mechanism unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Added ERK2 as a second kinase regulating DLG2, mapping phosphorylation to Ser-323 and embedding DLG2 in synaptic signaling cascades.\",\n      \"evidence\": \"In vitro protein interaction and kinase assays, mutagenesis, and striatal synaptosomal Co-IP\",\n      \"pmids\": [\"22618309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Ser-323 phosphorylation untested\", \"Single-lab in vitro identification\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved structurally that DLG2 PDZ1/2 preferentially bind GluN2B over GluD2, providing atomic-level basis for receptor selectivity.\",\n      \"evidence\": \"X-ray crystallography of PDZ1-GluD2 peptide complex and fluorescence polarization binding measurements\",\n      \"pmids\": [\"23519667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity not validated in cells\", \"Full-length scaffold avidity effects not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed DLG2 upstream of Fyn-mediated GluN2B Tyr1472 phosphorylation in excitotoxic signaling, defining a mechanistic link between scaffolding and ischemic injury.\",\n      \"evidence\": \"KO mouse MCAO model, phospho-Western, Co-IP, and PP2 pharmacological epistasis\",\n      \"pmids\": [\"24787897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic targeting feasibility not addressed here\", \"Whether effect is purely scaffold-dependent unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended DLG2 mechanism to ubiquitin-dependent degradation of SynGAP downstream of NMDAR activation, with a defined interaction interface and a protective interfering peptide.\",\n      \"evidence\": \"Co-IP, domain mapping (SynGAP 670-685), proteasome inhibitor rescue, KO epistasis, and MCAO peptide intervention\",\n      \"pmids\": [\"32130656\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating ubiquitination not identified\", \"Direct DLG2 catalytic involvement vs adaptor role unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established region-specific in vivo synaptic requirements for DLG2 in the striatum and revealed non-neuronal roles in beta-cell insulin secretion and a disease-associated Fyn-binding variant.\",\n      \"evidence\": \"Dlg2 KO mouse striatal patch-clamp; MIN6 knockdown insulin secretion assay; exome sequencing and Co-IP of F900V variant\",\n      \"pmids\": [\"32164788\", \"32356104\", \"32341572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of insulin-secretion role uncharacterized\", \"F900V causality not validated in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined DLG2 as a tumor suppressor controlling proliferation and differentiation, downstream of oncogenic ALK-ERK-SP1 repression in neuroblastoma and through L27-mediated LIN7A binding.\",\n      \"evidence\": \"DLG2-deficient osteosarcoma cell lines and conditional KO mice (2018); neuroblastoma re-expression with ALK-inhibitor/SP1 epistasis; isoform-specific LIN7A Co-IP\",\n      \"pmids\": [\"30093633\", \"32966799\", \"33726762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism coupling DLG2 to cell-cycle control incomplete\", \"Isoform-dependent tumor-suppressive interactions not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ROCK/Thr612 phosphorylation as a positive regulator of DLG2 scaffolding and discovered that DLG2 regulates potassium-channel-dependent dendritic integration gating associative plasticity.\",\n      \"evidence\": \"In vitro kinase assay, phospho-antibody, LC-MS/MS interactome, chemical-LTP (Thr612); Dlg2+/- rat patch-clamp with K+-channel and M1 pharmacological rescue and modeling\",\n      \"pmids\": [\"36613848\", \"35115661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which K+ channels DLG2 regulates not molecularly identified\", \"Link between phosphorylation and dendritic integration not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed DLG2 is required for cortical neuronal differentiation and striatum-specific synapse formation, and extended its tumor-suppressor mechanism to the DNA damage response and inflammasome/AKT-S6 signaling.\",\n      \"evidence\": \"DLG2 KO hESC cortical differentiation with transcriptomics and electrophysiology; Dlg2 KO striatal EM/mEPSC; comet/gammaH2AX assays with Drosophila model; colon cancer OE/KD cytokine and signaling readouts\",\n      \"pmids\": [\"35031607\", \"35966008\", \"35217496\", \"35499706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism in neurogenesis not defined\", \"Connection between synaptic scaffold and DNA-damage roles unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided biophysical mechanism distinguishing DLG2 from PSD-95: Src tyrosine phosphorylation reduces DLG2 client affinity, inhibits supercomplex formation, and uniquely alters its biomolecular condensation.\",\n      \"evidence\": \"In vitro Src kinase assay, fluorescence polarization, SAXS, single-molecule FRET, and scaffolding/condensation assays\",\n      \"pmids\": [\"41562278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in-cell validation of condensate effects\", \"Physiological phospho-site occupancy unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DLG2's synaptic scaffolding mechanism mechanistically connects to its tumor-suppressor and DNA-damage roles, and what E3 ligase and signaling intermediates execute these non-synaptic functions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified mechanism linking synaptic scaffold and proliferation control\", \"SynGAP-degrading E3 ligase unidentified\", \"Cross-tissue mechanistic basis (beta cell, tumor) uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 14, 30]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 18, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 9, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 15, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 20, 29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"complexes\": [\n      \"postsynaptic density\"\n    ],\n    \"partners\": [\n      \"PSD-95\",\n      \"Fyn\",\n      \"Csk\",\n      \"ERK2\",\n      \"SynGAP\",\n      \"Kir2.1\",\n      \"CX3CL1\",\n      \"LIN7A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}