Affinage

DLG2

Disks large homolog 2 · UniProt Q15700

Length
870 aa
Mass
97.6 kDa
Annotated
2026-04-28
63 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    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

    PMID:8755482

    Open questions at the time
    • Stoichiometry and hierarchy of DLG2 versus PSD-95 within native complexes undefined
    • Functional consequence of clustering on channel/receptor gating not tested
  2. 2001 High

    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

    PMID:11309840 PMID:11312293

    Open questions at the time
    • Which synapse types require DLG2 remained unclear
    • Compensatory upregulation of other MAGUKs in KO not fully assessed
  3. 2003 High

    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

    PMID:13129934

    Open questions at the time
    • Functional consequence of Tyr-384 phosphorylation on synaptic receptor clustering not directly measured
    • Identity of phosphatase reversing this modification unknown
  4. 2003 High

    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

    PMID:14581127 PMID:15296832

    Open questions at the time
    • Whether disrupting DLG2-nNOS coupling spares physiological NMDAR signaling not tested
    • Antisense knockdown specificity not independently validated
  5. 2004 High

    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

    PMID:14724236 PMID:15304517

    Open questions at the time
    • Whether DLG2 regulates Kir2.1 surface expression in vivo not demonstrated
    • Mechanism by which DLG2 prevents nAChR cluster disassembly unknown
  6. 2008 High

    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

    PMID:18936077

    Open questions at the time
    • Molecular basis for why DLG2 favors LTP-promoting complexes not identified
    • Double-KO epistasis not tested
  7. 2011 High

    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

    PMID:21543610

    Open questions at the time
    • Signaling pathway linking DLG2 to scaling-up effectors unresolved
    • In vivo relevance of DLG2 in homeostatic plasticity not tested
  8. 2012 Medium

    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

    PMID:22618309

    Open questions at the time
    • Functional consequence of Ser-323 phosphorylation on DLG2 interactions or plasticity not determined
    • Not independently replicated
  9. 2013 High

    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

    PMID:23519667

    Open questions at the time
    • Full-length DLG2 structure or supramolecular arrangement within the PSD unknown
    • PDZ2/3 domain selectivity not structurally resolved
  10. 2014 High

    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

    PMID:24787897

    Open questions at the time
    • Whether DLG2 deletion is neuroprotective long-term after stroke not assessed
    • Contribution of DLG2-independent Fyn pathways unclear
  11. 2017 Medium

    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

    PMID:32341572

    Open questions at the time
    • Single family study; replication in independent cohorts needed
    • In vivo GnRH neuron-specific mechanism not demonstrated
  12. 2018 High

    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

    PMID:30093633

    Open questions at the time
    • Molecular mechanism of tumor suppression (which DLG2 interaction is critical) not defined
    • Relevance to human osteosarcoma patients not clinically validated
  13. 2020 High

    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

    PMID:32130656

    Open questions at the time
    • E3 ubiquitin ligase recruited by DLG2 for SynGAP ubiquitination not identified
    • Whether this mechanism operates in non-ischemic contexts unknown
  14. 2020 High

    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

    PMID:32164788 PMID:32356104

    Open questions at the time
    • Mechanism linking DLG2 to insulin granule exocytosis unknown
    • Which DLG2 isoform mediates striatal versus beta-cell function unresolved
  15. 2022 High

    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

    PMID:36613848

    Open questions at the time
    • Whether Thr-612 phosphorylation is necessary for LTP in vivo not demonstrated with phospho-dead knock-in
    • Phosphatase opposing ROCK at this site unknown
  16. 2022 High

    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

    PMID:35031607

    Open questions at the time
    • Whether developmental role requires PDZ-domain scaffolding or a transcriptional mechanism unclear
    • In vivo human relevance not validated
  17. 2022 High

    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

    PMID:35115661

    Open questions at the time
    • Identity of the specific potassium channel(s) dysregulated not determined
    • Whether M1 agonist rescue translates to behavioral improvement unknown
  18. 2022 Medium

    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

    PMID:35217496 PMID:35499706 PMID:35966008

    Open questions at the time
    • Whether DNA repair and inflammasome functions operate via scaffold activity or a distinct mechanism unknown
    • Non-neuronal roles not validated in vivo beyond overexpression
  19. 2026 High

    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

    PMID:41562278

    Open questions at the time
    • In vivo relevance of Src-mediated DLG2 regulation at synapses not demonstrated
    • Which specific phosphosites are most functionally consequential not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005694 chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 8 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 1
Partners
CX3CL1DLG4FYNGRIN2BKCNJ2LIN7ANOS1SYNGAP1
Complex memberships
NMDAR-MAGUK postsynaptic complexPSD-93/PSD-95 heteromultimerPSD-93/SynGAP complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Heterologous cell clustering assay, co-immunoprecipitation, immunostaining in rat brain Neuron High 8755482
2001 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. Electron microscopic immunocytochemistry with quantitative immunogold labeling Synapse High 11309840
2001 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. Targeted gene disruption (knockout mouse), electrophysiology, immunohistochemistry, electron microscopy The Journal of neuroscience High 11312293
2003 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). In vitro kinase assay with recombinant proteins, phosphosite mutagenesis, Fyn-knockout mouse brain, co-immunoprecipitation, COS7 cell expression The Journal of biological chemistry High 13129934
2003 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. Intrathecal antisense oligodeoxynucleotide knockdown, behavioral pain testing (CFA and nerve injury models) Pain Medium 14581127
2003 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. PSD-93 knockout neurons, co-immunoprecipitation, cGMP measurement, cell death assay Experimental neurology High 15296832
2004 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. Co-immunoprecipitation, subcellular fractionation, immunostaining, PSD-93 knockout mouse denervation model The Journal of neuroscience High 14724236
2004 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. Yeast two-hybrid, in vitro PDZ-binding assay, co-immunoprecipitation from rat spinal cord, heterologous cell surface clustering The Journal of biological chemistry High 15304517
2008 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. Knockout mice, hippocampal CA1 electrophysiology, LTP/LTD induction protocols The Journal of physiology High 18936077
2008 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. Immunogold labeling and rotary shadow electron microscopy of isolated PSDs Brain cell biology Medium 18392731
2010 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). Tandem affinity purification from knock-in mice, lipid raft isolation, PSD-93 and PSD-95 knockout mice The Journal of neuroscience High 20554866
2011 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. shRNA knockdown and overexpression in neurons, mEPSC recording, PSD-93/95 mutant analysis The Journal of neuroscience High 21543610
2012 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. In vitro protein-protein interaction with purified proteins, in vitro kinase assay, co-immunoprecipitation from synaptosomal fractions Brain research Medium 22618309
2013 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. X-ray crystallography, fluorescence polarization spectroscopy Acta crystallographica. Section D High 23519667
2014 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. PSD-93 knockout mouse, MCAO model, Western blot for phospho-NR2B, pharmacological inhibitors (AP-5, PP2), co-immunoprecipitation Neurobiology of disease High 24787897
2018 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. DLG2-deficient human/canine cell lines (functional assays), osteoblast-specific Dlg2 conditional knockout mouse model, cross-species comparative genomics Oncogene High 30093633
2020 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. Co-immunoprecipitation, PSD-93 knockout mice, MCAO model, peptide competition (Tat-SynGAP), proteasome inhibitor MG-132, NMDAR inhibitor MK801, Western blot Translational stroke research High 32130656
2020 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. Dlg2 exon 14 knockout mouse, patch-clamp electrophysiology in striatal slices, behavioral battery, in situ hybridization Molecular autism High 32164788
2020 DLG2 knockdown in MIN6 pancreatic beta cells impairs glucose-stimulated and non-glucose-stimulated insulin secretion, establishing DLG2 as a regulator of insulin secretion. RNA interference (siRNA knockdown) in MIN6 cells, insulin secretion assay Diabetologia Medium 32356104
2021 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. Co-immunoprecipitation, peptide competition, MCAO model in mice, cytokine measurement Journal of neurochemistry Medium 33599284
2021 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. Co-immunoprecipitation/binding assay, isoform overexpression in neuroblastoma cells, cell viability/proliferation assays Cancer cell international Medium 33726762
2022 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. DLG2 overexpression and siRNA knockdown in colon cancer/THP1 cells, cytokine ELISA, Western blot for signaling proteins Journal of cancer research and clinical oncology Medium 35499706
2022 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. Comet assay, H2AX phosphorylation, UVC irradiation, Western blot, Drosophila model, neuroblastoma cell lines DNA repair Medium 35217496
2022 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. Heterozygous Dlg2+/- rat, ex vivo patch-clamp electrophysiology, pharmacology (K+ channel blockers, M1 agonist), computational modelling Neuropsychopharmacology High 35115661
2022 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. 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 International journal of molecular sciences High 36613848
2022 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. Dlg2 exon 14 KO mice, transmission electron microscopy, dendritic spine analysis, Western blot, patch-clamp (mEPSC) Frontiers in molecular neuroscience High 35966008
2022 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. DLG2 knockout hESCs, RNA-seq, neuronal differentiation assays (migration, morphology, electrophysiology) Nature communications High 35031607
2017 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. Exome sequencing, in vitro co-immunoprecipitation (F900V interaction with Fyn), GnRH expression assay in neuronal cell line Genetics in medicine Medium 32341572
2017 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. Co-immunoprecipitation, ubiquitination assay, lentivirus-mediated PSD-93 overexpression in APP/PS1 mice, behavioral and biochemical readouts Journal of Alzheimer's disease Medium 28697571
2026 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. In vitro kinase assay (Src kinase, multiple substrates), affinity measurements, supercomplex reconstitution, biomolecular condensation assay, SAXS, smFRET Protein science High 41562278

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Heteromultimerization and NMDA receptor-clustering activity of Chapsyn-110, a member of the PSD-95 family of proteins. Neuron 491 8755482
2008 Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity. The Journal of physiology 132 18936077
2011 PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down. The Journal of neuroscience : the official journal of the Society for Neuroscience 110 21543610
2001 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. Synapse (New York, N.Y.) 108 11309840
2004 PSD93 regulates synaptic stability at neuronal cholinergic synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 93 14724236
2001 PSD-93 knock-out mice reveal that neuronal MAGUKs are not required for development or function of parallel fiber synapses in cerebellum. The Journal of neuroscience : the official journal of the Society for Neuroscience 89 11312293
2010 In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93. The Journal of neuroscience : the official journal of the Society for Neuroscience 74 20554866
2018 Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma. Oncogene 63 30093633
2003 Effect of knock down of spinal cord PSD-93/chapsin-110 on persistent pain induced by complete Freund's adjuvant and peripheral nerve injury. Pain 54 14581127
2008 Distribution of the scaffolding proteins PSD-95, PSD-93, and SAP97 in isolated PSDs. Brain cell biology 49 18392731
2003 Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. The Journal of biological chemistry 45 13129934
2017 Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93. Behavioural brain research 40 28189758
2020 Circ0106714 inhibits tumorigenesis of colorectal cancer by sponging miR-942-5p and releasing DLG2 via Hippo-YAP signaling. Molecular carcinogenesis 36 33128289
1995 A gene (DLG2) located at 17q12-q21 encodes a new homologue of the Drosophila tumor suppressor dIg-A. Genomics 34 7590743
2020 11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma. Cell reports 33 32966799
2019 MicroRNA-23a depletion promotes apoptosis of ovarian cancer stem cell and inhibits cell migration by targeting DLG2. Cancer biology & therapy 31 30862230
2020 A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum. Molecular autism 30 32164788
2017 PSD-93 Attenuates Amyloid-β-Mediated Cognitive Dysfunction by Promoting the Catabolism of Amyloid-β. Journal of Alzheimer's disease : JAD 30 28697571
2004 An alternatively spliced isoform of PSD-93/chapsyn 110 binds to the inwardly rectifying potassium channel, Kir2.1. The Journal of biological chemistry 29 15304517
2022 Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2. Molecular psychiatry 28 35246634
2019 MicroRNA-152-3p protects neurons from oxygen-glucose-deprivation/reoxygenation-induced injury through upregulation of Nrf2/ARE antioxidant signaling by targeting PSD-93. Biochemical and biophysical research communications 27 31326116
2017 Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability. Genome medicine 27 28724449
2020 PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice. Translational stroke research 26 32130656
2014 PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia. Neurobiology of disease 26 24787897
2010 Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26. Journal of Cancer 26 20842219
2003 Neonatal hypoxia-ischemia differentially upregulates MAGUKs and associated proteins in PSD-93-deficient mouse brain. Stroke 26 14605317
2022 Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants. Nature communications 24 35031607
2023 Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway. International journal of biological sciences 23 37416779
2004 Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons. Experimental neurology 21 15296832
2017 DLG2, but not TMEM229B, GPNMB, and ITGA8 polymorphism, is associated with Parkinson's disease in a Taiwanese population. Neurobiology of aging 19 29290481
2022 Inflammation suppresses DLG2 expression decreasing inflammasome formation. Journal of cancer research and clinical oncology 18 35499706
2022 Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 17 35115661
2012 Interactions and phosphorylation of postsynaptic density 93 (PSD-93) by extracellular signal-regulated kinase (ERK). Brain research 16 22618309
2020 SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population. Journal of cellular and molecular medicine 15 32652860
2020 E2f8 and Dlg2 genes have independent effects on impaired insulin secretion associated with hyperglycaemia. Diabetologia 14 32356104
2006 Differential expression of a new isoform of DLG2 in renal oncocytoma. BMC cancer 14 16640776
2022 Selective behavioural impairments in mice heterozygous for the cross disorder psychiatric risk gene DLG2. Genes, brain, and behavior 12 35118804
2024 Glioma stem cell-derived exosomes induce the transformation of astrocytes via the miR-3065-5p/DLG2 signaling axis. Glia 11 38234042
2022 Rho-Kinase/ROCK Phosphorylates PSD-93 Downstream of NMDARs to Orchestrate Synaptic Plasticity. International journal of molecular sciences 11 36613848
2021 PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1. Journal of neurochemistry 11 33599284
2020 LncRNA DLG2-AS1 as a Novel Biomarker in Lung Adenocarcinoma. Cancers 11 32731343
2010 Effect of PSD-95/SAP90 and/or PSD-93/chapsyn-110 deficiency on the minimum alveolar anesthetic concentration of halothane in mice. Anesthesiology 11 20460989
2022 DLG2 impairs dsDNA break repair and maintains genome integrity in neuroblastoma. DNA repair 10 35217496
2020 All-trans Retinoic Acid-induced Abnormal Hippocampal Expression of Synaptic Genes SynDIG1 and DLG2 is Correlated with Anxiety or Depression-Like Behavior in Mice. International journal of molecular sciences 10 32290523
2015 Proteomic analysis of PSD-93 knockout mice following the induction of ischemic cerebral injury. Neurotoxicology 10 26680505
2013 Decrease in neuronal nicotinic acetylcholine receptor subunit and PSD-93 transcript levels in the male mouse MPG after cavernous nerve injury or explant culture. American journal of physiology. Renal physiology 9 24049141
2020 DLG2 variants in patients with pubertal disorders. Genetics in medicine : official journal of the American College of Medical Genetics 8 32341572
2018 Identification of a novel Dlg2 isoform differentially expressed in IFNβ-producing plasmacytoid dendritic cells. BMC genomics 8 29703139
2009 Evaluation of DLG2 as a positional candidate for disposition index in African-Americans from the IRAS Family Study. Diabetes research and clinical practice 8 19931931
2022 Enhancing DLG2 Implications in Neuropsychiatric Disorders: Analysis of a Cohort of Eight Patients with 11q14.1 Imbalances. Genes 7 35627244
2021 The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma. Cancer cell international 7 33726762
2015 The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury. Cell biochemistry and biophysics 7 27259312
2023 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. Genes, brain, and behavior 6 37705179
2022 Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder. Genes, brain, and behavior 5 35075790
2022 A Deficiency of the Psychiatric Risk Gene DLG2/PSD-93 Causes Excitatory Synaptic Deficits in the Dorsolateral Striatum. Frontiers in molecular neuroscience 5 35966008
2013 Interaction partners of PSD-93 studied by X-ray crystallography and fluorescence polarization spectroscopy. Acta crystallographica. Section D, Biological crystallography 5 23519667
2022 Silencing of AKIP1 Suppresses the Proliferation, Migration, and Epithelial-Mesenchymal Transition Process of Glioma Cells by Upregulating DLG2. BioMed research international 4 35111846
2025 METTL3-dependent DLG2 inhibits the malignant progression of cervical cancer by inactivating the Hippo/YAP signaling. Hereditas 3 39856747
2021 DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism. Hormone research in paediatrics 2 34695822
2023 DLG2 intragenic exonic deletions reinforce the link to neurodevelopmental disorders and suggest a potential association with congenital anomalies and dysmorphism. Genetics in medicine : official journal of the American College of Medical Genetics 1 37860969
2023 Impaired reversal learning in the Dlg2+/- rat model of genetic risk for psychiatric disorder: Important questions regarding the neuro-behavioral mechanisms of reversal learning. Genes, brain, and behavior 1 38123893
2026 Differences in Src phosphorylation of PSD-93 and PSD-95 drive differences in scaffolding activity. Protein science : a publication of the Protein Society 0 41562278
2025 DLG2 rs11607886 polymorphism associated with schizophrenia and precuneus functional changes. Schizophrenia research 0 40220608