{"gene":"DLG3","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":1996,"finding":"SAP102 (DLG3) directly interacts with NMDA receptor complex in vivo; all three PDZ domains of SAP102 bind the cytoplasmic tail of NR2B subunit in vitro, and anti-NMDA receptor antibodies co-immunoprecipitate SAP102 from rat brain synaptosomes.","method":"Co-immunoprecipitation from rat brain synaptosomes; recombinant protein pulldown; in vitro PDZ domain binding assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP and in vitro binding, replicated across two independent papers (PMID 8780649, PMID 8702950)","pmids":["8780649","8702950"],"is_preprint":false},{"year":1996,"finding":"SAP102 specifically binds the last 20 amino acids of the NR2 subunit C-terminal tail; no interaction was detected with the NR1a intracellular C-terminal tail or with AMPA receptor subunit GluR1.","method":"Hexahistidine fusion protein overlay assay; synthetic peptide binding; co-immunoprecipitation from cortical synaptic plasma membranes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal in vitro binding methods with domain specificity defined","pmids":["8702950"],"is_preprint":false},{"year":1997,"finding":"SAP102 can functionally substitute for Drosophila DlgA tumor suppressor: heterologous neuronal expression of SAP102 suppresses tumor formation and restores synaptic bouton structure in dlg-1 mutant flies, indicating conserved presynaptic scaffolding function.","method":"Heterologous expression in Drosophila dlg-1 mutants; morphological analysis of neuromuscular junctions","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 2 — genetic complementation with morphological readout in model organism","pmids":["9152008"],"is_preprint":false},{"year":1997,"finding":"NE-dlg/SAP102 interacts with the carboxyl-terminal region of the APC tumor suppressor protein, suggesting a role in regulating cell proliferation.","method":"Yeast two-hybrid screening; in vitro binding assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid confirmed by in vitro binding","pmids":["9188857"],"is_preprint":false},{"year":1999,"finding":"SAP102 interacts with calmodulin in a Ca2+-dependent manner via a basic alpha-helix region near the SH3 domain (Kd ~44 nM); Ca2+/calmodulin binding to SAP102 enables interaction with the GUK-like domain of PSD-95/SAP90, but does not alter SAP102 PDZ domain binding to NR2B.","method":"Surface plasmon resonance; yeast two-hybrid; pulldown assay; mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding quantified by SPR, confirmed by orthogonal pulldown and two-hybrid","pmids":["10026200"],"is_preprint":false},{"year":1999,"finding":"SAP102 interacts with nedasin (p51), a novel amidohydrolase-related protein predominantly expressed in neuronal cell bodies; nedasin competitively interferes with the SAP102–NR2B interaction in vitro, and may regulate receptor clustering during synaptogenesis.","method":"Yeast two-hybrid; co-immunoprecipitation; in vitro competition assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — two-hybrid confirmed by Co-IP and in vitro competition","pmids":["10542258"],"is_preprint":false},{"year":2000,"finding":"NE-dlg/SAP102 overexpression in proliferating cancer cells induces growth suppression, impairment of cell adhesion, and down-regulation of beta-catenin independent of APC mutation; the PDZ domains are essential for these effects.","method":"Overexpression in cancer cell lines; cell proliferation and adhesion assays; PDZ domain mutagenesis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — domain mutagenesis with defined cellular phenotypes","pmids":["10797259"],"is_preprint":false},{"year":2001,"finding":"SAP102 is detected at postsynaptic densities of asymmetric synapses on spines, as well as along presynaptic membranes, axonal cytoplasm, and dendritic shafts, suggesting dual roles in anchoring receptors at synapses and regulating receptor shuttling.","method":"Electron microscopic immunocytochemistry (EM-ICC) with quantitative analysis","journal":"Synapse (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — direct subcellular localization by EM with quantitative analysis","pmids":["11309840"],"is_preprint":false},{"year":2003,"finding":"The tyrosine kinase Pyk2 is recruited to the NMDA receptor complex via the SH3 domains of SAP102 and PSD-95; Pyk2 proline-rich regions bind SAP102 SH3 domain, and this binding is regulated by an intramolecular SH3–GK domain interaction in SAP102.","method":"Co-immunoprecipitation; pulldown assays; colocalization; deletion mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain-mapping by deletion mutants, functional intramolecular regulation defined","pmids":["12576483"],"is_preprint":false},{"year":2005,"finding":"mPins interacts with SAP102 and functions in formation of the NMDAR-MAGUK complex; mPins enhances trafficking of SAP102 and NMDARs to the plasma membrane, and siRNA knockdown of mPins decreases SAP102 in dendrites and reduces NMDAR surface expression.","method":"Co-immunoprecipitation; siRNA knockdown; dominant-negative constructs; immunofluorescence","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, loss-of-function siRNA, and dominant-negative with defined trafficking phenotype","pmids":["16299499"],"is_preprint":false},{"year":2008,"finding":"SAP102 mediates synaptic trafficking of both AMPA and NMDA receptors during synaptogenesis; after synaptogenesis, PSD-95 assumes these functions. In PSD-95/PSD-93 double-KO mice, the developmental NR2B-to-NR2A switch fails, and PSD-95 (not SAP102) rescues it.","method":"In utero electroporation; dual whole-cell electrophysiology; genetic knockout mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with electrophysiological readout in vivo and ex vivo","pmids":["19104036"],"is_preprint":false},{"year":2011,"finding":"SAP102 contains a novel NR2B-binding site in its N-terminal domain that is PDZ-independent and regulated by alternative splicing; the N-terminal insert splice variant promotes dendritic spine lengthening and synapse formation at long spines in an NMDA receptor activity-dependent manner.","method":"Co-immunoprecipitation; knockdown with shRNA; morphological analysis of dendritic spines; NMDA receptor blockade","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods: Co-IP, knockdown, pharmacological blockade with defined morphological phenotype","pmids":["21209193"],"is_preprint":false},{"year":2011,"finding":"Dlg3/SAP102 contributes to apical-basal polarity and epithelial tight junction formation; Dlg3 recruits E3 ubiquitin ligases Nedd4 and Nedd4-2 through its PPxY motifs, leading to Dlg3 monoubiquitination that is required for its apical membrane recruitment and tight junction consolidation.","method":"Complex purification by mass spectrometry; co-immunoprecipitation; mouse knockout; PPxY motif mutagenesis; ubiquitination assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 — mass spectrometry complex purification, mutagenesis, KO mouse with defined polarity phenotype","pmids":["21920314"],"is_preprint":false},{"year":2012,"finding":"SAP102 mediates synaptic clearance of GluN2B-containing NMDARs via a non-PDZ interaction; two critical residues on GluN2B are responsible for non-PDZ binding to SAP102, and mutation of these residues or SAP102 knockdown rescues defective surface and synaptic expression of PDZ-binding-deficient GluN2B.","method":"Site-directed mutagenesis of GluN2B; siRNA knockdown of SAP102; surface biotinylation; immunofluorescence","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of binding residues combined with knockdown, multiple readouts","pmids":["23103165"],"is_preprint":false},{"year":2012,"finding":"SAP102 binds to the C-terminal part of neurobeachin (containing DUF, PH, BEACH, and WD40 domains); a point mutation in the PH domain of neurobeachin that disrupts PH–BEACH interaction abolishes SAP102 binding.","method":"Mass spectrometry from mouse brain; Co-IP in heterologous cells; domain deletion and point mutagenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — MS identification confirmed by Co-IP with mutagenesis to define binding domain","pmids":["22745750"],"is_preprint":false},{"year":2013,"finding":"SAP102 regulates cortical synapse development through EphB and PAK signaling: SAP102 co-immunoprecipitates EphB2 and Kalirin-7 from neonatal cortex; SAP102 knockdown reduces EphB surface expression, prevents ephrinB-induced actin reorganization, synapse formation, and synaptic AMPAR trafficking, and downregulates PAK activity.","method":"Lentiviral shRNA knockdown; co-immunoprecipitation; surface receptor expression assay; immunofluorescence; PAK activity measurement","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for complex, loss-of-function with multiple pathway-specific phenotypic readouts","pmids":["23486974"],"is_preprint":false},{"year":2014,"finding":"SAP102 interacts with the A2A adenosine receptor C-terminus via its SH3–GK domain fragment; SAP102 overexpression prevents agonist-induced confinement of A2A receptor to slow-mobility compartments, and a mutated A2A receptor (DVELL→RVRAA) is insensitive to SAP102 action.","method":"Co-immunoprecipitation; single-particle tracking; hidden Markov model analysis; C-terminal deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and live single-particle tracking with mutant validation","pmids":["24509856"],"is_preprint":false},{"year":2015,"finding":"Synaptic localization of SAP102 is regulated by C-terminal alternative splicing: the I2 splice variant (insert between SH3 and GK domains) is highly enriched at dendritic spines; knockdown of I2-containing SAP102 isoforms differentially affects NMDAR surface expression in a GluN2 subunit-specific manner.","method":"Alternative splicing analysis; shRNA knockdown; surface NMDAR expression by immunofluorescence; intramolecular SH3-GK interaction assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — isoform-specific knockdown with receptor trafficking readout","pmids":["25555912"],"is_preprint":false},{"year":2016,"finding":"SAP102 knockout in mice causes reduced thalamocortical axon innervation of somatosensory cortex and a transient acceleration of NMDA receptor kinetics during the critical period, without reducing GluN2B-mediated synaptic transmission; after the critical period, TC connectivity divergence is reduced.","method":"Dlg3 knockout mouse; electrophysiology; thalamocortical axon tracing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with electrophysiological and anatomical phenotypic readouts","pmids":["27466188"],"is_preprint":false},{"year":2017,"finding":"SAP102 synaptic targeting is regulated by phosphorylation of Ser632 (within the C-terminal alternatively spliced region) by casein kinase II (CK2); Ser632 phosphorylation increases synaptic enrichment and decreases SAP102 mobility, while elevated synaptic activity suppresses Ser632 phosphorylation and reduces synaptic SAP102.","method":"In vitro kinase assay; phospho-specific mutagenesis; FRAP; immunofluorescence in neurons","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay, mutagenesis, FRAP, and activity-dependent regulation all converge","pmids":["29282697"],"is_preprint":false},{"year":2018,"finding":"SAP102 regulates synaptic AMPAR function through a CNIH-2 (cornichon-2)-dependent mechanism; SAP102 rescues AMPAR eEPSCs following PSD-95 knockdown, increases AMPAR mEPSC decay time, and this rescue requires the auxiliary AMPAR subunit cornichon-2.","method":"Molecular replacement (cell-restricted shRNA + rescue expression); whole-cell electrophysiology; cornichon-2 knockdown","journal":"Journal of neurophysiology","confidence":"Medium","confidence_rationale":"Tier 2 — molecular replacement strategy with electrophysiology and auxiliary subunit epistasis","pmids":["30067114"],"is_preprint":false},{"year":2020,"finding":"MIAT lncRNA promotes methylation of CpG islands in the DLG3 promoter by binding DNMT1, DNMT3A, and DNMT3B; MIAT silencing upregulates DLG3, which then binds MST2 and regulates LATS1, preventing nuclear YAP translocation and activating the Hippo signaling pathway to suppress breast cancer progression.","method":"MS-PCR; RIP assay; co-immunoprecipitation (DLG3–MST2); in vitro and in vivo functional assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP and Co-IP with functional rescue; single lab","pmids":["32593652"],"is_preprint":false},{"year":2023,"finding":"COP1 E3 ubiquitin ligase binds DLG3 protein and promotes its ubiquitination; COP1 knockdown inhibits glioma cell proliferation, invasion, and migration, and DLG3 silencing reverses this inhibition, placing DLG3 downstream of COP1.","method":"Co-immunoprecipitation; ubiquitination assay with MG132; shRNA knockdown; functional rescue experiments","journal":"Neurological research","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP confirmed ubiquitination with epistasis rescue, single lab","pmids":["37356109"],"is_preprint":false},{"year":2023,"finding":"Sec8 preferentially binds PDZ2 of SAP102 (over PDZ1 and PDZ3) via its C-terminal ITTV motif; crystal structure of Sec8 C-terminus at 2.5 Å resolution reveals an unusually long helix with a 14-residue spacer bridging the ITTV motif to the Sec8 core, required for SAP102 binding.","method":"X-ray crystallography (2.5 Å); biochemical binding assays; deletion mutagenesis of spacer","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and biochemical validation","pmids":["37849738"],"is_preprint":false},{"year":2024,"finding":"JNK3 directly phosphorylates SAP102 and negatively regulates SAP102 dynamics at dendritic spines; SAP102 and JNK3 cooperate in trafficking kainate receptor subunit GluK2 to the cell membrane, and JNK inhibition reduces GluK2 surface expression in a SAP102-dependent manner.","method":"In vitro kinase assay; live-cell imaging; biochemical fractionation; pharmacological JNK inhibition; surface receptor expression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphorylation, live imaging, and loss-of-function with receptor trafficking readout","pmids":["38582451"],"is_preprint":false},{"year":2024,"finding":"SAP102 forms subsynaptic nanoclusters that are smaller and denser than PSD-95 nanoclusters; only a subset of SAP102 nanoclusters co-organize with PSD-95, defining distinct MAGUK nanodomains within single synapses that differ in their enrichment of presynaptic Munc13-1.","method":"DNA-PAINT super-resolution microscopy; nanocluster analysis in rat cultured neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct nanoscale localization by super-resolution imaging with functional correlate (Munc13-1 enrichment)","pmids":["38777601"],"is_preprint":false}],"current_model":"DLG3/SAP102 is a postsynaptic MAGUK scaffold protein that directly binds NMDA receptor GluN2B subunits through both PDZ-dependent and PDZ-independent mechanisms to cluster, traffic, and clear NMDARs at excitatory synapses; its synaptic targeting is regulated by CK2-mediated phosphorylation of Ser632 and by alternative splicing, it recruits Pyk2 via its SH3 domain to organize downstream signaling, mediates AMPAR trafficking through a cornichon-2-dependent pathway, organizes EphB/Kalirin-7/PAK signaling for cortical synapse development, and in epithelial cells recruits Nedd4/Nedd4-2 E3 ligases through PPxY motifs to undergo monoubiquitination required for apical membrane targeting and tight junction formation."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing that SAP102 is a direct physical link between the NMDA receptor complex and the postsynaptic scaffold answered the fundamental question of how NMDARs are anchored at synapses, revealing PDZ-domain-mediated binding to the NR2B C-terminal tail as the molecular basis.","evidence":"Co-immunoprecipitation from rat brain synaptosomes, recombinant PDZ domain binding assays, and overlay assays with synthetic peptides","pmids":["8780649","8702950"],"confidence":"High","gaps":["Stoichiometry of SAP102–NMDAR complex unknown","In vivo functional consequence of disrupting this interaction not tested","Whether other MAGUK family members are redundant at this stage was unclear"]},{"year":1997,"claim":"Demonstrating that SAP102 functionally substitutes for the Drosophila Dlg tumor suppressor and interacts with APC established that its scaffolding function is evolutionarily conserved and extends beyond receptor anchoring to growth regulation.","evidence":"Genetic complementation of Drosophila dlg-1 mutants; yeast two-hybrid and in vitro binding with APC","pmids":["9152008","9188857"],"confidence":"Medium","gaps":["APC interaction not validated endogenously in mammalian neurons","Relevance of tumor suppression to normal neuronal SAP102 function unclear"]},{"year":1999,"claim":"Identification of Ca²⁺/calmodulin binding (Kd ~44 nM) near the SH3 domain and the competitive regulator nedasin revealed that SAP102 scaffolding is subject to calcium-dependent conformational regulation and competitive interference during synaptogenesis.","evidence":"Surface plasmon resonance, yeast two-hybrid, and in vitro competition assays","pmids":["10026200","10542258"],"confidence":"High","gaps":["Physiological consequences of calmodulin binding on SAP102 scaffolding in neurons not shown","Nedasin's in vivo role in regulating SAP102–NMDAR not confirmed"]},{"year":2003,"claim":"Showing that Pyk2 binds the SAP102 SH3 domain—regulated by intramolecular SH3–GK interaction—answered how tyrosine kinase signaling is recruited to the NMDAR complex and revealed an autoinhibitory conformational switch in SAP102.","evidence":"Reciprocal co-immunoprecipitation, pulldown with deletion mutants","pmids":["12576483"],"confidence":"High","gaps":["Functional consequence of Pyk2 recruitment through SAP102 on NMDAR signaling not directly measured","Structural basis of intramolecular SH3–GK regulation not resolved"]},{"year":2005,"claim":"Discovery that mPins promotes SAP102 and NMDAR trafficking to the plasma membrane, with mPins knockdown reducing dendritic SAP102 and surface NMDARs, established a dedicated trafficking pathway for the SAP102–NMDAR complex.","evidence":"Co-immunoprecipitation, siRNA knockdown, and dominant-negative constructs in neurons","pmids":["16299499"],"confidence":"High","gaps":["Mechanism by which mPins drives vesicular transport of SAP102 undefined","Whether mPins acts on SAP102 independently of other MAGUKs not determined"]},{"year":2008,"claim":"Genetic epistasis in PSD-95/PSD-93 double-knockout mice demonstrated that SAP102 is the predominant MAGUK mediating both AMPAR and NMDAR trafficking during synaptogenesis, with PSD-95 assuming these roles after synapses mature.","evidence":"In utero electroporation, dual whole-cell electrophysiology, and knockout mice","pmids":["19104036"],"confidence":"High","gaps":["Molecular basis of the developmental handoff from SAP102 to PSD-95 unknown","Whether SAP102 retains any unique function at mature synapses not fully resolved"]},{"year":2011,"claim":"Two breakthroughs redefined SAP102 function: discovery of a PDZ-independent N-terminal NR2B-binding site regulated by alternative splicing, and demonstration that DLG3 monoubiquitination by Nedd4/Nedd4-2 via PPxY motifs drives apical membrane targeting and tight junction formation in epithelia.","evidence":"Co-IP with shRNA knockdown and spine morphology in neurons; mass spectrometry complex purification, PPxY mutagenesis, and KO mouse for epithelial phenotype","pmids":["21209193","21920314"],"confidence":"High","gaps":["How the N-terminal and PDZ-mediated interactions with NR2B are coordinated at a single synapse is unknown","Whether monoubiquitination similarly regulates SAP102 in neurons not tested"]},{"year":2012,"claim":"Identification of specific GluN2B residues required for non-PDZ binding to SAP102 established that SAP102 mediates synaptic clearance of GluN2B-NMDARs through this second binding mode, explaining why PDZ-binding-deficient receptors are still regulated.","evidence":"Site-directed mutagenesis of GluN2B, SAP102 siRNA, surface biotinylation","pmids":["23103165"],"confidence":"High","gaps":["Whether clearance occurs via endocytosis or lateral diffusion not resolved","Structural basis of non-PDZ interaction not determined"]},{"year":2013,"claim":"Demonstration that SAP102 scaffolds an EphB2/Kalirin-7/PAK signaling complex in neonatal cortex, with SAP102 loss blocking ephrinB-induced actin reorganization and synapse formation, identified a specific developmental signaling axis organized by SAP102.","evidence":"Lentiviral shRNA knockdown, co-immunoprecipitation, PAK activity measurement in cortical neurons","pmids":["23486974"],"confidence":"High","gaps":["Whether EphB signaling through SAP102 is independent of its NMDAR scaffolding role unclear","Downstream PAK substrates mediating synaptogenesis not identified"]},{"year":2017,"claim":"Identifying CK2-mediated phosphorylation of Ser632 as a regulator of SAP102 synaptic enrichment and mobility established that activity-dependent kinase signaling tunes SAP102 residence time at synapses.","evidence":"In vitro kinase assay, phosphomutant analysis, FRAP in cultured neurons","pmids":["29282697"],"confidence":"High","gaps":["In vivo relevance of Ser632 phosphorylation to synaptic plasticity not tested","Other kinases that may co-regulate SAP102 localization not surveyed"]},{"year":2023,"claim":"A 2.5 Å crystal structure of Sec8 C-terminus bound to SAP102 PDZ2 revealed how the exocyst complex interfaces with the MAGUK scaffold, providing the first structural view of an SAP102 PDZ domain interaction and defining a 14-residue spacer required for binding.","evidence":"X-ray crystallography, biochemical binding assays, deletion mutagenesis","pmids":["37849738"],"confidence":"High","gaps":["Functional consequence of Sec8–SAP102 interaction for receptor exocytosis not demonstrated","No full-length SAP102 structure available"]},{"year":2024,"claim":"JNK3 was identified as a direct SAP102 kinase that regulates dendritic spine dynamics and cooperates with SAP102 to traffic kainate receptor GluK2 to the surface, extending SAP102's scaffolding role beyond NMDA and AMPA receptors to a third ionotropic glutamate receptor class.","evidence":"In vitro kinase assay, live-cell imaging, pharmacological JNK inhibition with surface GluK2 measurement","pmids":["38582451"],"confidence":"High","gaps":["JNK3 phosphorylation site(s) on SAP102 not mapped","Whether GluK2 trafficking by SAP102 is PDZ-dependent or uses the N-terminal binding mode unknown"]},{"year":2024,"claim":"Super-resolution imaging revealed that SAP102 forms subsynaptic nanoclusters distinct from PSD-95 nanodomains, with differential presynaptic Munc13-1 alignment, establishing that MAGUKs create heterogeneous signaling subcompartments within single synapses.","evidence":"DNA-PAINT super-resolution microscopy with nanocluster analysis in rat neurons","pmids":["38777601"],"confidence":"Medium","gaps":["Functional significance of SAP102-specific nanodomains for receptor signaling not tested","Whether nanocluster composition changes with development or plasticity unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of full-length SAP102 autoinhibition and how multiple binding modes (PDZ, N-terminal, SH3) are simultaneously coordinated; the precise phosphorylation sites targeted by JNK3; and whether SAP102's epithelial polarity function involves the same molecular interactions as its synaptic scaffolding role.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structural model of SAP102","Relationship between neuronal and epithelial functions mechanistically undefined","In vivo consequences of SAP102 nanocluster organization for synaptic transmission not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,9,11,15,23]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,7,25]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,9,12,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,10,11,13,15,19,20,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,15,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,15,18]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9,12,13,24]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[12]}],"complexes":["NMDAR-MAGUK postsynaptic complex","EphB2/Kalirin-7/PAK complex"],"partners":["GRIN2B","PTK2B","CNIH2","EPHB2","KALRN","NEDD4","EXOC5","GPSM2"],"other_free_text":[]},"mechanistic_narrative":"DLG3 (SAP102) is a MAGUK-family postsynaptic scaffold protein that organizes glutamate receptor trafficking, clustering, and downstream signaling at excitatory synapses, with additional roles in epithelial polarity and growth suppression. SAP102 binds NMDA receptor GluN2B subunits through both PDZ-dependent and PDZ-independent N-terminal interactions, mediating synaptic delivery of NMDARs during early synaptogenesis and activity-dependent clearance of GluN2B-containing receptors, while also regulating AMPAR trafficking through a cornichon-2-dependent pathway [PMID:8780649, PMID:21209193, PMID:23103165, PMID:19104036, PMID:30067114]. Its synaptic residence is dynamically controlled by CK2 phosphorylation of Ser632 and JNK3 phosphorylation, and it recruits signaling effectors including Pyk2 (via SH3 domain), EphB2/Kalirin-7/PAK, and the exocyst subunit Sec8 (via PDZ2) to coordinate actin remodeling and synapse formation [PMID:29282697, PMID:38582451, PMID:12576483, PMID:23486974, PMID:37849738]. In epithelial cells, DLG3 recruits Nedd4/Nedd4-2 E3 ligases through PPxY motifs, undergoes monoubiquitination required for apical membrane targeting and tight junction formation, and can suppress cell proliferation through PDZ-domain-dependent downregulation of β-catenin [PMID:21920314, PMID:10797259]."},"prefetch_data":{"uniprot":{"accession":"Q92796","full_name":"Disks large homolog 3","aliases":["Neuroendocrine-DLG","Synapse-associated protein 102","SAP-102","SAP102","XLMR"],"length_aa":817,"mass_kda":90.3,"function":"Required for learning most likely through its role in synaptic plasticity following NMDA receptor signaling","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q92796/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLG3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DLG3","total_profiled":1310},"omim":[{"mim_id":"612808","title":"LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 2; LRFN2","url":"https://www.omim.org/entry/612808"},{"mim_id":"609743","title":"CELL ADHESION MOLECULE 3; CADM3","url":"https://www.omim.org/entry/609743"},{"mim_id":"609425","title":"CHROMOSOME 3q29 DELETION SYNDROME","url":"https://www.omim.org/entry/609425"},{"mim_id":"605022","title":"p21 PROTEIN-ACTIVATED KINASE 2; PAK2","url":"https://www.omim.org/entry/605022"},{"mim_id":"601114","title":"MEMBRANE PROTEIN, PALMITOYLATED 3; MPP3","url":"https://www.omim.org/entry/601114"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DLG3"},"hgnc":{"alias_symbol":["NE-Dlg","SAP102","SAP-102","NEDLG","KIAA1232","MRX90","PPP1R82"],"prev_symbol":[]},"alphafold":{"accession":"Q92796","domains":[{"cath_id":"2.30.42.10","chopping":"126-216","consensus_level":"high","plddt":90.9374,"start":126,"end":216},{"cath_id":"2.30.42.10","chopping":"222-310","consensus_level":"high","plddt":90.4233,"start":222,"end":310},{"cath_id":"2.30.42.10","chopping":"384-479","consensus_level":"high","plddt":89.7944,"start":384,"end":479},{"cath_id":"2.30.30.40","chopping":"503-574","consensus_level":"high","plddt":88.7474,"start":503,"end":574},{"cath_id":"3.40.50.300","chopping":"624-811","consensus_level":"medium","plddt":93.9584,"start":624,"end":811}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92796","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92796-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92796-F1-predicted_aligned_error_v6.png","plddt_mean":73.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLG3","jax_strain_url":"https://www.jax.org/strain/search?query=DLG3"},"sequence":{"accession":"Q92796","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92796.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92796/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92796"}},"corpus_meta":[{"pmid":"8780649","id":"PMC_8780649","title":"SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo.","date":"1996","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8780649","citation_count":373,"is_preprint":false},{"pmid":"19104036","id":"PMC_19104036","title":"Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19104036","citation_count":184,"is_preprint":false},{"pmid":"8702950","id":"PMC_8702950","title":"Interaction of the N-methyl-D-aspartate receptor complex with a novel synapse-associated protein, SAP102.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702950","citation_count":160,"is_preprint":false},{"pmid":"15185169","id":"PMC_15185169","title":"Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15185169","citation_count":135,"is_preprint":false},{"pmid":"17113057","id":"PMC_17113057","title":"Decreased NR1, NR2A, and SAP102 transcript expression in the hippocampus in bipolar disorder.","date":"2006","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/17113057","citation_count":124,"is_preprint":false},{"pmid":"11309840","id":"PMC_11309840","title":"Electron microscopic immunocytochemical detection of PSD-95, PSD-93, SAP-102, and SAP-97 at postsynaptic, presynaptic, and nonsynaptic sites of adult and neonatal rat visual cortex.","date":"2001","source":"Synapse (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11309840","citation_count":108,"is_preprint":false},{"pmid":"16299499","id":"PMC_16299499","title":"mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16299499","citation_count":99,"is_preprint":false},{"pmid":"9152008","id":"PMC_9152008","title":"Functional expression of rat synapse-associated proteins SAP97 and SAP102 in Drosophila dlg-1 mutants: effects on tumor suppression and synaptic bouton structure.","date":"1997","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/9152008","citation_count":86,"is_preprint":false},{"pmid":"20634587","id":"PMC_20634587","title":"Reduction in post-synaptic scaffolding PSD-95 and SAP-102 protein levels in the Alzheimer inferior temporal cortex is correlated with disease pathology.","date":"2010","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/20634587","citation_count":83,"is_preprint":false},{"pmid":"10026200","id":"PMC_10026200","title":"Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10026200","citation_count":79,"is_preprint":false},{"pmid":"23103165","id":"PMC_23103165","title":"SAP102 mediates synaptic clearance of NMDA receptors.","date":"2012","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23103165","citation_count":69,"is_preprint":false},{"pmid":"12576483","id":"PMC_12576483","title":"Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12576483","citation_count":61,"is_preprint":false},{"pmid":"9188857","id":"PMC_9188857","title":"Cloning and characterization of NE-dlg: a novel human homolog of the Drosophila discs large (dlg) tumor suppressor protein interacts with the APC protein.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9188857","citation_count":53,"is_preprint":false},{"pmid":"21209193","id":"PMC_21209193","title":"NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21209193","citation_count":49,"is_preprint":false},{"pmid":"23486974","id":"PMC_23486974","title":"Postsynaptic density scaffold SAP102 regulates cortical synapse development through EphB and PAK signaling pathway.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23486974","citation_count":48,"is_preprint":false},{"pmid":"21920314","id":"PMC_21920314","title":"Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/21920314","citation_count":46,"is_preprint":false},{"pmid":"19795139","id":"PMC_19795139","title":"A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation.","date":"2009","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19795139","citation_count":43,"is_preprint":false},{"pmid":"32593652","id":"PMC_32593652","title":"Silence of lncRNA MIAT-mediated inhibition of DLG3 promoter methylation suppresses breast cancer progression via the Hippo signaling pathway.","date":"2020","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/32593652","citation_count":35,"is_preprint":false},{"pmid":"24739954","id":"PMC_24739954","title":"Parallel mRNA and microRNA profiling of HEV71-infected human neuroblastoma cells reveal the up-regulation of miR-1246 in association with DLG3 repression.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24739954","citation_count":32,"is_preprint":false},{"pmid":"8824795","id":"PMC_8824795","title":"Isolation of a gene (DLG3) encoding a second member of the discs-large family on chromosome 17q12-q21.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8824795","citation_count":31,"is_preprint":false},{"pmid":"30168311","id":"PMC_30168311","title":"Tetrahedral DNA Nanomaterial Regulates the Biological Behaviors of Adipose-Derived Stem Cells via DNA Methylation on Dlg3.","date":"2018","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/30168311","citation_count":25,"is_preprint":false},{"pmid":"9674560","id":"PMC_9674560","title":"Immunocytochemical localization of the synapse-associated protein SAP102 in the rat retina.","date":"1998","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/9674560","citation_count":25,"is_preprint":false},{"pmid":"22745750","id":"PMC_22745750","title":"Synapse associated protein 102 (SAP102) binds the C-terminal part of the scaffolding protein neurobeachin.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22745750","citation_count":25,"is_preprint":false},{"pmid":"10797259","id":"PMC_10797259","title":"NE-dlg, a mammalian homolog of Drosophila dlg tumor suppressor, induces growth suppression and impairment of cell adhesion: possible involvement of down-regulation of beta-catenin by NE-dlg expression.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10797259","citation_count":23,"is_preprint":false},{"pmid":"10542258","id":"PMC_10542258","title":"A novel NE-dlg/SAP102-associated protein, p51-nedasin, related to the amidohydrolase superfamily, interferes with the association between NE-dlg/SAP102 and N-methyl-D-aspartate receptor.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10542258","citation_count":21,"is_preprint":false},{"pmid":"25555912","id":"PMC_25555912","title":"Subunit-specific regulation of N-methyl-D-aspartate (NMDA) receptor trafficking by SAP102 protein splice variants.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25555912","citation_count":19,"is_preprint":false},{"pmid":"33117688","id":"PMC_33117688","title":"LINC01315 Impairs microRNA-211-Dependent DLG3 Downregulation to Inhibit the Development of Oral Squamous Cell Carcinoma.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33117688","citation_count":17,"is_preprint":false},{"pmid":"24509856","id":"PMC_24509856","title":"A two-state model for the diffusion of the A2A adenosine receptor in hippocampal neurons: agonist-induced switch to slow mobility is modified by synapse-associated protein 102 (SAP102).","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24509856","citation_count":17,"is_preprint":false},{"pmid":"31271664","id":"PMC_31271664","title":"High expression of DLG3 is associated with decreased survival from breast cancer.","date":"2019","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31271664","citation_count":16,"is_preprint":false},{"pmid":"38805774","id":"PMC_38805774","title":"The prediction of pCR and chemosensitivity for breast cancer patients using DLG3, RADL and Pathomics signatures based on machine learning and deep learning.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38805774","citation_count":16,"is_preprint":false},{"pmid":"38249294","id":"PMC_38249294","title":"DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation.","date":"2024","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38249294","citation_count":13,"is_preprint":false},{"pmid":"28777483","id":"PMC_28777483","title":"Skewed X-inactivation in a family with DLG3-associated X-linked intellectual disability.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28777483","citation_count":13,"is_preprint":false},{"pmid":"21384559","id":"PMC_21384559","title":"Fine mapping of Xq11.1-q21.33 and mutation screening of RPS6KA6, ZNF711, ACSL4, DLG3, and IL1RAPL2 for autism spectrum disorders (ASD).","date":"2011","source":"Autism research : official journal of the International Society for Autism Research","url":"https://pubmed.ncbi.nlm.nih.gov/21384559","citation_count":13,"is_preprint":false},{"pmid":"38777601","id":"PMC_38777601","title":"Distinct SAP102 and PSD-95 Nano-organization Defines Multiple Types of Synaptic Scaffold Protein Domains at Single Synapses.","date":"2024","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38777601","citation_count":12,"is_preprint":false},{"pmid":"29282697","id":"PMC_29282697","title":"Regulation of SAP102 Synaptic Targeting by Phosphorylation.","date":"2017","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29282697","citation_count":12,"is_preprint":false},{"pmid":"27466188","id":"PMC_27466188","title":"Altered thalamocortical development in the SAP102 knockout model of intellectual disability.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27466188","citation_count":11,"is_preprint":false},{"pmid":"21509195","id":"PMC_21509195","title":"Differential localization of SAP102 and PSD-95 is revealed in hippocampal spines using super-resolution light microscopy.","date":"2011","source":"Communicative & integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/21509195","citation_count":11,"is_preprint":false},{"pmid":"9598320","id":"PMC_9598320","title":"DLG3, the gene encoding human neuroendocrine Dlg (NE-Dlg), is located within the 1.8-Mb dystonia-parkinsonism region at Xq13.1.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9598320","citation_count":11,"is_preprint":false},{"pmid":"29574717","id":"PMC_29574717","title":"Dynamic SAP102 expression in the hippocampal subregions of rats and APP/PS1 mice of various ages.","date":"2018","source":"Journal of anatomy","url":"https://pubmed.ncbi.nlm.nih.gov/29574717","citation_count":10,"is_preprint":false},{"pmid":"27222290","id":"PMC_27222290","title":"A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability.","date":"2016","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/27222290","citation_count":10,"is_preprint":false},{"pmid":"30067114","id":"PMC_30067114","title":"SAP102 regulates synaptic AMPAR function through a CNIH-2-dependent mechanism.","date":"2018","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/30067114","citation_count":10,"is_preprint":false},{"pmid":"32021600","id":"PMC_32021600","title":"A Novel DLG3 Mutation Expanding the Phenotype of X-Linked Intellectual Disability Caused by DLG3 Nonsense Variants.","date":"2019","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/32021600","citation_count":9,"is_preprint":false},{"pmid":"10446262","id":"PMC_10446262","title":"A recessive mutation leading to vertebral ankylosis in zebrafish is associated with amino acid alterations in the homologue of the human membrane-associated guanylate kinase DLG3.","date":"1999","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/10446262","citation_count":9,"is_preprint":false},{"pmid":"23178474","id":"PMC_23178474","title":"Ligand binding of PDZ domains has various roles in the synaptic clustering of SAP102 and PSD-95.","date":"2012","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/23178474","citation_count":9,"is_preprint":false},{"pmid":"32246869","id":"PMC_32246869","title":"Triple diagnosis of Wiedemann-Steiner, Waardenburg and DLG3-related intellectual disability association found by WES: A case report.","date":"2020","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32246869","citation_count":8,"is_preprint":false},{"pmid":"34765009","id":"PMC_34765009","title":"Hypermethylation of DLG3 Promoter Upregulates RAC1 and Activates the PI3K/AKT Signaling Pathway to Promote Breast Cancer Progression.","date":"2021","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/34765009","citation_count":7,"is_preprint":false},{"pmid":"37745494","id":"PMC_37745494","title":"Distinct SAP102 and PSD-95 nano-organization defines multiple types of synaptic scaffold protein domains at single synapses.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37745494","citation_count":3,"is_preprint":false},{"pmid":"38273165","id":"PMC_38273165","title":"Identification of a DLG3 stop mutation in the MRX20 family.","date":"2024","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/38273165","citation_count":3,"is_preprint":false},{"pmid":"37356109","id":"PMC_37356109","title":"COP1 facilitates the proliferation, invasion, and migration of glioma cells by ubiquitination of DLG3 protein.","date":"2023","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/37356109","citation_count":2,"is_preprint":false},{"pmid":"18618587","id":"PMC_18618587","title":"Cloning and characterization of E-dlg, a novel splice variant of mouse homologue of the Drosophila discs large tumor suppressor binds preferentially to SAP102.","date":"2008","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/18618587","citation_count":2,"is_preprint":false},{"pmid":"21369957","id":"PMC_21369957","title":"Polymorphisms in the DLG3 gene is not associated with non-syndromic mental retardation in the Chinese Han population of Qin-Ba mountain.","date":"2011","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/21369957","citation_count":2,"is_preprint":false},{"pmid":"39638232","id":"PMC_39638232","title":"Multifaceted roles of DLG3/SAP102 in neurophysiology, neurological disorders and tumorigenesis.","date":"2024","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39638232","citation_count":1,"is_preprint":false},{"pmid":"40983642","id":"PMC_40983642","title":"Further phenotypical delineation of DLG3-related neurodevelopmental disorders.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/40983642","citation_count":1,"is_preprint":false},{"pmid":"37849738","id":"PMC_37849738","title":"Sec8 specifically interacts with the PDZ2 domain of synapse associated protein 102 (SAP102).","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/37849738","citation_count":1,"is_preprint":false},{"pmid":"38582451","id":"PMC_38582451","title":"JNK activity modulates postsynaptic scaffold protein SAP102 and kainate receptor dynamics in dendritic spines.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38582451","citation_count":1,"is_preprint":false},{"pmid":"31682872","id":"PMC_31682872","title":"SAP102 contributes to hyperalgesia formation in the cancer induced bone pain rat model by anchoring NMDA receptors.","date":"2019","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/31682872","citation_count":1,"is_preprint":false},{"pmid":"40881055","id":"PMC_40881055","title":"A New Family with X-Linked Intellectual Disability 90: A Case Report of a Novel DLG3 Variant and Literature Review.","date":"2025","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/40881055","citation_count":1,"is_preprint":false},{"pmid":"39026977","id":"PMC_39026977","title":"Retraction: LINC01315 impairs microRNA-211-dependent DLG3 downregulation to inhibit the development of oral squamous cell carcinoma.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39026977","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.24.671450","title":"Paralog-specific intrabodies for PSD-93 and SAP102 expand the molecular toolkit to resolve excitatory synapse organization","date":"2025-08-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.24.671450","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.24.634803","title":"Synaptome architecture shapes regional dynamics in the mouse brain","date":"2025-01-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.24.634803","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.23.607324","title":"Input-specific localization of NMDA receptor GluN2 subunits in thalamocortical neurons","date":"2024-08-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.23.607324","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29910,"output_tokens":5657,"usd":0.087292},"stage2":{"model":"claude-opus-4-6","input_tokens":9301,"output_tokens":3561,"usd":0.203295},"total_usd":0.290587,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"SAP102 (DLG3) directly interacts with NMDA receptor complex in vivo; all three PDZ domains of SAP102 bind the cytoplasmic tail of NR2B subunit in vitro, and anti-NMDA receptor antibodies co-immunoprecipitate SAP102 from rat brain synaptosomes.\",\n      \"method\": \"Co-immunoprecipitation from rat brain synaptosomes; recombinant protein pulldown; in vitro PDZ domain binding assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP and in vitro binding, replicated across two independent papers (PMID 8780649, PMID 8702950)\",\n      \"pmids\": [\"8780649\", \"8702950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SAP102 specifically binds the last 20 amino acids of the NR2 subunit C-terminal tail; no interaction was detected with the NR1a intracellular C-terminal tail or with AMPA receptor subunit GluR1.\",\n      \"method\": \"Hexahistidine fusion protein overlay assay; synthetic peptide binding; co-immunoprecipitation from cortical synaptic plasma membranes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal in vitro binding methods with domain specificity defined\",\n      \"pmids\": [\"8702950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SAP102 can functionally substitute for Drosophila DlgA tumor suppressor: heterologous neuronal expression of SAP102 suppresses tumor formation and restores synaptic bouton structure in dlg-1 mutant flies, indicating conserved presynaptic scaffolding function.\",\n      \"method\": \"Heterologous expression in Drosophila dlg-1 mutants; morphological analysis of neuromuscular junctions\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic complementation with morphological readout in model organism\",\n      \"pmids\": [\"9152008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NE-dlg/SAP102 interacts with the carboxyl-terminal region of the APC tumor suppressor protein, suggesting a role in regulating cell proliferation.\",\n      \"method\": \"Yeast two-hybrid screening; in vitro binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid confirmed by in vitro binding\",\n      \"pmids\": [\"9188857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SAP102 interacts with calmodulin in a Ca2+-dependent manner via a basic alpha-helix region near the SH3 domain (Kd ~44 nM); Ca2+/calmodulin binding to SAP102 enables interaction with the GUK-like domain of PSD-95/SAP90, but does not alter SAP102 PDZ domain binding to NR2B.\",\n      \"method\": \"Surface plasmon resonance; yeast two-hybrid; pulldown assay; mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding quantified by SPR, confirmed by orthogonal pulldown and two-hybrid\",\n      \"pmids\": [\"10026200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SAP102 interacts with nedasin (p51), a novel amidohydrolase-related protein predominantly expressed in neuronal cell bodies; nedasin competitively interferes with the SAP102–NR2B interaction in vitro, and may regulate receptor clustering during synaptogenesis.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; in vitro competition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — two-hybrid confirmed by Co-IP and in vitro competition\",\n      \"pmids\": [\"10542258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NE-dlg/SAP102 overexpression in proliferating cancer cells induces growth suppression, impairment of cell adhesion, and down-regulation of beta-catenin independent of APC mutation; the PDZ domains are essential for these effects.\",\n      \"method\": \"Overexpression in cancer cell lines; cell proliferation and adhesion assays; PDZ domain mutagenesis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — domain mutagenesis with defined cellular phenotypes\",\n      \"pmids\": [\"10797259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SAP102 is detected at postsynaptic densities of asymmetric synapses on spines, as well as along presynaptic membranes, axonal cytoplasm, and dendritic shafts, suggesting dual roles in anchoring receptors at synapses and regulating receptor shuttling.\",\n      \"method\": \"Electron microscopic immunocytochemistry (EM-ICC) with quantitative analysis\",\n      \"journal\": \"Synapse (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by EM with quantitative analysis\",\n      \"pmids\": [\"11309840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The tyrosine kinase Pyk2 is recruited to the NMDA receptor complex via the SH3 domains of SAP102 and PSD-95; Pyk2 proline-rich regions bind SAP102 SH3 domain, and this binding is regulated by an intramolecular SH3–GK domain interaction in SAP102.\",\n      \"method\": \"Co-immunoprecipitation; pulldown assays; colocalization; deletion mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain-mapping by deletion mutants, functional intramolecular regulation defined\",\n      \"pmids\": [\"12576483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"mPins interacts with SAP102 and functions in formation of the NMDAR-MAGUK complex; mPins enhances trafficking of SAP102 and NMDARs to the plasma membrane, and siRNA knockdown of mPins decreases SAP102 in dendrites and reduces NMDAR surface expression.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; dominant-negative constructs; immunofluorescence\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, loss-of-function siRNA, and dominant-negative with defined trafficking phenotype\",\n      \"pmids\": [\"16299499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SAP102 mediates synaptic trafficking of both AMPA and NMDA receptors during synaptogenesis; after synaptogenesis, PSD-95 assumes these functions. In PSD-95/PSD-93 double-KO mice, the developmental NR2B-to-NR2A switch fails, and PSD-95 (not SAP102) rescues it.\",\n      \"method\": \"In utero electroporation; dual whole-cell electrophysiology; genetic knockout mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with electrophysiological readout in vivo and ex vivo\",\n      \"pmids\": [\"19104036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SAP102 contains a novel NR2B-binding site in its N-terminal domain that is PDZ-independent and regulated by alternative splicing; the N-terminal insert splice variant promotes dendritic spine lengthening and synapse formation at long spines in an NMDA receptor activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation; knockdown with shRNA; morphological analysis of dendritic spines; NMDA receptor blockade\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods: Co-IP, knockdown, pharmacological blockade with defined morphological phenotype\",\n      \"pmids\": [\"21209193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dlg3/SAP102 contributes to apical-basal polarity and epithelial tight junction formation; Dlg3 recruits E3 ubiquitin ligases Nedd4 and Nedd4-2 through its PPxY motifs, leading to Dlg3 monoubiquitination that is required for its apical membrane recruitment and tight junction consolidation.\",\n      \"method\": \"Complex purification by mass spectrometry; co-immunoprecipitation; mouse knockout; PPxY motif mutagenesis; ubiquitination assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mass spectrometry complex purification, mutagenesis, KO mouse with defined polarity phenotype\",\n      \"pmids\": [\"21920314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SAP102 mediates synaptic clearance of GluN2B-containing NMDARs via a non-PDZ interaction; two critical residues on GluN2B are responsible for non-PDZ binding to SAP102, and mutation of these residues or SAP102 knockdown rescues defective surface and synaptic expression of PDZ-binding-deficient GluN2B.\",\n      \"method\": \"Site-directed mutagenesis of GluN2B; siRNA knockdown of SAP102; surface biotinylation; immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of binding residues combined with knockdown, multiple readouts\",\n      \"pmids\": [\"23103165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SAP102 binds to the C-terminal part of neurobeachin (containing DUF, PH, BEACH, and WD40 domains); a point mutation in the PH domain of neurobeachin that disrupts PH–BEACH interaction abolishes SAP102 binding.\",\n      \"method\": \"Mass spectrometry from mouse brain; Co-IP in heterologous cells; domain deletion and point mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS identification confirmed by Co-IP with mutagenesis to define binding domain\",\n      \"pmids\": [\"22745750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SAP102 regulates cortical synapse development through EphB and PAK signaling: SAP102 co-immunoprecipitates EphB2 and Kalirin-7 from neonatal cortex; SAP102 knockdown reduces EphB surface expression, prevents ephrinB-induced actin reorganization, synapse formation, and synaptic AMPAR trafficking, and downregulates PAK activity.\",\n      \"method\": \"Lentiviral shRNA knockdown; co-immunoprecipitation; surface receptor expression assay; immunofluorescence; PAK activity measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for complex, loss-of-function with multiple pathway-specific phenotypic readouts\",\n      \"pmids\": [\"23486974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SAP102 interacts with the A2A adenosine receptor C-terminus via its SH3–GK domain fragment; SAP102 overexpression prevents agonist-induced confinement of A2A receptor to slow-mobility compartments, and a mutated A2A receptor (DVELL→RVRAA) is insensitive to SAP102 action.\",\n      \"method\": \"Co-immunoprecipitation; single-particle tracking; hidden Markov model analysis; C-terminal deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and live single-particle tracking with mutant validation\",\n      \"pmids\": [\"24509856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Synaptic localization of SAP102 is regulated by C-terminal alternative splicing: the I2 splice variant (insert between SH3 and GK domains) is highly enriched at dendritic spines; knockdown of I2-containing SAP102 isoforms differentially affects NMDAR surface expression in a GluN2 subunit-specific manner.\",\n      \"method\": \"Alternative splicing analysis; shRNA knockdown; surface NMDAR expression by immunofluorescence; intramolecular SH3-GK interaction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — isoform-specific knockdown with receptor trafficking readout\",\n      \"pmids\": [\"25555912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SAP102 knockout in mice causes reduced thalamocortical axon innervation of somatosensory cortex and a transient acceleration of NMDA receptor kinetics during the critical period, without reducing GluN2B-mediated synaptic transmission; after the critical period, TC connectivity divergence is reduced.\",\n      \"method\": \"Dlg3 knockout mouse; electrophysiology; thalamocortical axon tracing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with electrophysiological and anatomical phenotypic readouts\",\n      \"pmids\": [\"27466188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SAP102 synaptic targeting is regulated by phosphorylation of Ser632 (within the C-terminal alternatively spliced region) by casein kinase II (CK2); Ser632 phosphorylation increases synaptic enrichment and decreases SAP102 mobility, while elevated synaptic activity suppresses Ser632 phosphorylation and reduces synaptic SAP102.\",\n      \"method\": \"In vitro kinase assay; phospho-specific mutagenesis; FRAP; immunofluorescence in neurons\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay, mutagenesis, FRAP, and activity-dependent regulation all converge\",\n      \"pmids\": [\"29282697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAP102 regulates synaptic AMPAR function through a CNIH-2 (cornichon-2)-dependent mechanism; SAP102 rescues AMPAR eEPSCs following PSD-95 knockdown, increases AMPAR mEPSC decay time, and this rescue requires the auxiliary AMPAR subunit cornichon-2.\",\n      \"method\": \"Molecular replacement (cell-restricted shRNA + rescue expression); whole-cell electrophysiology; cornichon-2 knockdown\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular replacement strategy with electrophysiology and auxiliary subunit epistasis\",\n      \"pmids\": [\"30067114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MIAT lncRNA promotes methylation of CpG islands in the DLG3 promoter by binding DNMT1, DNMT3A, and DNMT3B; MIAT silencing upregulates DLG3, which then binds MST2 and regulates LATS1, preventing nuclear YAP translocation and activating the Hippo signaling pathway to suppress breast cancer progression.\",\n      \"method\": \"MS-PCR; RIP assay; co-immunoprecipitation (DLG3–MST2); in vitro and in vivo functional assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP and Co-IP with functional rescue; single lab\",\n      \"pmids\": [\"32593652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"COP1 E3 ubiquitin ligase binds DLG3 protein and promotes its ubiquitination; COP1 knockdown inhibits glioma cell proliferation, invasion, and migration, and DLG3 silencing reverses this inhibition, placing DLG3 downstream of COP1.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay with MG132; shRNA knockdown; functional rescue experiments\",\n      \"journal\": \"Neurological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP confirmed ubiquitination with epistasis rescue, single lab\",\n      \"pmids\": [\"37356109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sec8 preferentially binds PDZ2 of SAP102 (over PDZ1 and PDZ3) via its C-terminal ITTV motif; crystal structure of Sec8 C-terminus at 2.5 Å resolution reveals an unusually long helix with a 14-residue spacer bridging the ITTV motif to the Sec8 core, required for SAP102 binding.\",\n      \"method\": \"X-ray crystallography (2.5 Å); biochemical binding assays; deletion mutagenesis of spacer\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and biochemical validation\",\n      \"pmids\": [\"37849738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"JNK3 directly phosphorylates SAP102 and negatively regulates SAP102 dynamics at dendritic spines; SAP102 and JNK3 cooperate in trafficking kainate receptor subunit GluK2 to the cell membrane, and JNK inhibition reduces GluK2 surface expression in a SAP102-dependent manner.\",\n      \"method\": \"In vitro kinase assay; live-cell imaging; biochemical fractionation; pharmacological JNK inhibition; surface receptor expression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphorylation, live imaging, and loss-of-function with receptor trafficking readout\",\n      \"pmids\": [\"38582451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SAP102 forms subsynaptic nanoclusters that are smaller and denser than PSD-95 nanoclusters; only a subset of SAP102 nanoclusters co-organize with PSD-95, defining distinct MAGUK nanodomains within single synapses that differ in their enrichment of presynaptic Munc13-1.\",\n      \"method\": \"DNA-PAINT super-resolution microscopy; nanocluster analysis in rat cultured neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct nanoscale localization by super-resolution imaging with functional correlate (Munc13-1 enrichment)\",\n      \"pmids\": [\"38777601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLG3/SAP102 is a postsynaptic MAGUK scaffold protein that directly binds NMDA receptor GluN2B subunits through both PDZ-dependent and PDZ-independent mechanisms to cluster, traffic, and clear NMDARs at excitatory synapses; its synaptic targeting is regulated by CK2-mediated phosphorylation of Ser632 and by alternative splicing, it recruits Pyk2 via its SH3 domain to organize downstream signaling, mediates AMPAR trafficking through a cornichon-2-dependent pathway, organizes EphB/Kalirin-7/PAK signaling for cortical synapse development, and in epithelial cells recruits Nedd4/Nedd4-2 E3 ligases through PPxY motifs to undergo monoubiquitination required for apical membrane targeting and tight junction formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DLG3 (SAP102) is a MAGUK-family postsynaptic scaffold protein that organizes glutamate receptor trafficking, clustering, and downstream signaling at excitatory synapses, with additional roles in epithelial polarity and growth suppression. SAP102 binds NMDA receptor GluN2B subunits through both PDZ-dependent and PDZ-independent N-terminal interactions, mediating synaptic delivery of NMDARs during early synaptogenesis and activity-dependent clearance of GluN2B-containing receptors, while also regulating AMPAR trafficking through a cornichon-2-dependent pathway [PMID:8780649, PMID:21209193, PMID:23103165, PMID:19104036, PMID:30067114]. Its synaptic residence is dynamically controlled by CK2 phosphorylation of Ser632 and JNK3 phosphorylation, and it recruits signaling effectors including Pyk2 (via SH3 domain), EphB2/Kalirin-7/PAK, and the exocyst subunit Sec8 (via PDZ2) to coordinate actin remodeling and synapse formation [PMID:29282697, PMID:38582451, PMID:12576483, PMID:23486974, PMID:37849738]. In epithelial cells, DLG3 recruits Nedd4/Nedd4-2 E3 ligases through PPxY motifs, undergoes monoubiquitination required for apical membrane targeting and tight junction formation, and can suppress cell proliferation through PDZ-domain-dependent downregulation of β-catenin [PMID:21920314, PMID:10797259].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that SAP102 is a direct physical link between the NMDA receptor complex and the postsynaptic scaffold answered the fundamental question of how NMDARs are anchored at synapses, revealing PDZ-domain-mediated binding to the NR2B C-terminal tail as the molecular basis.\",\n      \"evidence\": \"Co-immunoprecipitation from rat brain synaptosomes, recombinant PDZ domain binding assays, and overlay assays with synthetic peptides\",\n      \"pmids\": [\"8780649\", \"8702950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of SAP102–NMDAR complex unknown\", \"In vivo functional consequence of disrupting this interaction not tested\", \"Whether other MAGUK family members are redundant at this stage was unclear\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that SAP102 functionally substitutes for the Drosophila Dlg tumor suppressor and interacts with APC established that its scaffolding function is evolutionarily conserved and extends beyond receptor anchoring to growth regulation.\",\n      \"evidence\": \"Genetic complementation of Drosophila dlg-1 mutants; yeast two-hybrid and in vitro binding with APC\",\n      \"pmids\": [\"9152008\", \"9188857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"APC interaction not validated endogenously in mammalian neurons\", \"Relevance of tumor suppression to normal neuronal SAP102 function unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of Ca²⁺/calmodulin binding (Kd ~44 nM) near the SH3 domain and the competitive regulator nedasin revealed that SAP102 scaffolding is subject to calcium-dependent conformational regulation and competitive interference during synaptogenesis.\",\n      \"evidence\": \"Surface plasmon resonance, yeast two-hybrid, and in vitro competition assays\",\n      \"pmids\": [\"10026200\", \"10542258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of calmodulin binding on SAP102 scaffolding in neurons not shown\", \"Nedasin's in vivo role in regulating SAP102–NMDAR not confirmed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that Pyk2 binds the SAP102 SH3 domain—regulated by intramolecular SH3–GK interaction—answered how tyrosine kinase signaling is recruited to the NMDAR complex and revealed an autoinhibitory conformational switch in SAP102.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, pulldown with deletion mutants\",\n      \"pmids\": [\"12576483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Pyk2 recruitment through SAP102 on NMDAR signaling not directly measured\", \"Structural basis of intramolecular SH3–GK regulation not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that mPins promotes SAP102 and NMDAR trafficking to the plasma membrane, with mPins knockdown reducing dendritic SAP102 and surface NMDARs, established a dedicated trafficking pathway for the SAP102–NMDAR complex.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and dominant-negative constructs in neurons\",\n      \"pmids\": [\"16299499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which mPins drives vesicular transport of SAP102 undefined\", \"Whether mPins acts on SAP102 independently of other MAGUKs not determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic epistasis in PSD-95/PSD-93 double-knockout mice demonstrated that SAP102 is the predominant MAGUK mediating both AMPAR and NMDAR trafficking during synaptogenesis, with PSD-95 assuming these roles after synapses mature.\",\n      \"evidence\": \"In utero electroporation, dual whole-cell electrophysiology, and knockout mice\",\n      \"pmids\": [\"19104036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the developmental handoff from SAP102 to PSD-95 unknown\", \"Whether SAP102 retains any unique function at mature synapses not fully resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two breakthroughs redefined SAP102 function: discovery of a PDZ-independent N-terminal NR2B-binding site regulated by alternative splicing, and demonstration that DLG3 monoubiquitination by Nedd4/Nedd4-2 via PPxY motifs drives apical membrane targeting and tight junction formation in epithelia.\",\n      \"evidence\": \"Co-IP with shRNA knockdown and spine morphology in neurons; mass spectrometry complex purification, PPxY mutagenesis, and KO mouse for epithelial phenotype\",\n      \"pmids\": [\"21209193\", \"21920314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the N-terminal and PDZ-mediated interactions with NR2B are coordinated at a single synapse is unknown\", \"Whether monoubiquitination similarly regulates SAP102 in neurons not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of specific GluN2B residues required for non-PDZ binding to SAP102 established that SAP102 mediates synaptic clearance of GluN2B-NMDARs through this second binding mode, explaining why PDZ-binding-deficient receptors are still regulated.\",\n      \"evidence\": \"Site-directed mutagenesis of GluN2B, SAP102 siRNA, surface biotinylation\",\n      \"pmids\": [\"23103165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether clearance occurs via endocytosis or lateral diffusion not resolved\", \"Structural basis of non-PDZ interaction not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstration that SAP102 scaffolds an EphB2/Kalirin-7/PAK signaling complex in neonatal cortex, with SAP102 loss blocking ephrinB-induced actin reorganization and synapse formation, identified a specific developmental signaling axis organized by SAP102.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, co-immunoprecipitation, PAK activity measurement in cortical neurons\",\n      \"pmids\": [\"23486974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EphB signaling through SAP102 is independent of its NMDAR scaffolding role unclear\", \"Downstream PAK substrates mediating synaptogenesis not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying CK2-mediated phosphorylation of Ser632 as a regulator of SAP102 synaptic enrichment and mobility established that activity-dependent kinase signaling tunes SAP102 residence time at synapses.\",\n      \"evidence\": \"In vitro kinase assay, phosphomutant analysis, FRAP in cultured neurons\",\n      \"pmids\": [\"29282697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Ser632 phosphorylation to synaptic plasticity not tested\", \"Other kinases that may co-regulate SAP102 localization not surveyed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A 2.5 Å crystal structure of Sec8 C-terminus bound to SAP102 PDZ2 revealed how the exocyst complex interfaces with the MAGUK scaffold, providing the first structural view of an SAP102 PDZ domain interaction and defining a 14-residue spacer required for binding.\",\n      \"evidence\": \"X-ray crystallography, biochemical binding assays, deletion mutagenesis\",\n      \"pmids\": [\"37849738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Sec8–SAP102 interaction for receptor exocytosis not demonstrated\", \"No full-length SAP102 structure available\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"JNK3 was identified as a direct SAP102 kinase that regulates dendritic spine dynamics and cooperates with SAP102 to traffic kainate receptor GluK2 to the surface, extending SAP102's scaffolding role beyond NMDA and AMPA receptors to a third ionotropic glutamate receptor class.\",\n      \"evidence\": \"In vitro kinase assay, live-cell imaging, pharmacological JNK inhibition with surface GluK2 measurement\",\n      \"pmids\": [\"38582451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"JNK3 phosphorylation site(s) on SAP102 not mapped\", \"Whether GluK2 trafficking by SAP102 is PDZ-dependent or uses the N-terminal binding mode unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Super-resolution imaging revealed that SAP102 forms subsynaptic nanoclusters distinct from PSD-95 nanodomains, with differential presynaptic Munc13-1 alignment, establishing that MAGUKs create heterogeneous signaling subcompartments within single synapses.\",\n      \"evidence\": \"DNA-PAINT super-resolution microscopy with nanocluster analysis in rat neurons\",\n      \"pmids\": [\"38777601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of SAP102-specific nanodomains for receptor signaling not tested\", \"Whether nanocluster composition changes with development or plasticity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of full-length SAP102 autoinhibition and how multiple binding modes (PDZ, N-terminal, SH3) are simultaneously coordinated; the precise phosphorylation sites targeted by JNK3; and whether SAP102's epithelial polarity function involves the same molecular interactions as its synaptic scaffolding role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structural model of SAP102\", \"Relationship between neuronal and epithelial functions mechanistically undefined\", \"In vivo consequences of SAP102 nanocluster organization for synaptic transmission not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 9, 11, 15, 23]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 7, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 9, 12, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 10, 11, 13, 15, 19, 20, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 15, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 15, 18]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9, 12, 13, 24]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"NMDAR-MAGUK postsynaptic complex\",\n      \"EphB2/Kalirin-7/PAK complex\"\n    ],\n    \"partners\": [\n      \"GRIN2B\",\n      \"PTK2B\",\n      \"CNIH2\",\n      \"EPHB2\",\n      \"KALRN\",\n      \"NEDD4\",\n      \"EXOC5\",\n      \"GPSM2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}