{"gene":"EPB41L1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2009,"finding":"4.1N is required for activity-dependent GluR1 (GluA1) AMPA receptor insertion into the plasma membrane. PKC phosphorylation of GluR1 at S816 and S818 enhances 4.1N binding to GluR1 and facilitates GluR1 insertion. Palmitoylation of GluR1 C811 modulates PKC phosphorylation and GluR1 insertion. Disrupting 4.1N-dependent GluR1 insertion decreases surface GluR1 expression and impairs LTP expression.","method":"Live imaging of individual GluR1 insertion events, dominant-negative peptide disruption, co-immunoprecipitation, site-directed mutagenesis of GluR1 phosphorylation and palmitoylation sites, LTP electrophysiology","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, mutagenesis, Co-IP, electrophysiology) in one rigorous study with clear mechanistic dissection","pmids":["19503082"],"is_preprint":false},{"year":2000,"finding":"4.1N interacts with PIKE (a nuclear GTPase) and translocates to the nucleus upon NGF treatment, where overexpression of 4.1N abolishes PIKE-mediated enhancement of nuclear PI3K lipid kinase activity. NGF-stimulated nuclear translocation of 4.1N inhibits PIKE activation of nuclear PI3K.","method":"Yeast two-hybrid screen, co-immunoprecipitation, PI3K lipid kinase activity assay, dominant-negative overexpression, nuclear fractionation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic activity assay combined with Co-IP and overexpression in multiple orthogonal experiments in a high-rigor study","pmids":["11136977"],"is_preprint":false},{"year":2002,"finding":"4.1N interacts specifically with D2 and D3 dopamine receptors via the N-terminal segment of their third intracellular domain and the C-terminal domain of 4.1N. Expression of a 4.1N truncation fragment reduces plasma membrane localization of D2 and D3 receptors, indicating 4.1N is required for dopamine receptor surface expression.","method":"Yeast two-hybrid, pulldown, co-immunoprecipitation, deletion mapping, immunofluorescence in transfected HEK293 and Neuro2A cells","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP and pulldown with functional localization assay, single lab","pmids":["12181426"],"is_preprint":false},{"year":2002,"finding":"4.1N binds to the C-terminal cytoplasmic tail of IP3R1 (inositol 1,4,5-trisphosphate receptor type 1) and is required for translocation of IP3R1 to the basolateral membrane domain in polarized MDCK cells. The 4.1N-binding region of IP3R1 is necessary and sufficient for basolateral targeting, and a fragment of the IP3R1-binding region of 4.1N blocks co-expressed IP3R1 basolateral localization.","method":"Yeast two-hybrid, co-immunoprecipitation, dominant-negative fragment expression, immunofluorescence in polarized MDCK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, dominant-negative competition, and cell fractionation/imaging in polarized cells with functional consequence; replicated by independent groups","pmids":["12444087"],"is_preprint":false},{"year":1999,"finding":"4.1N interacts with the nuclear mitotic apparatus protein NuMA via its C-terminal domain. NGF treatment causes translocation of 4.1N to the nucleus and promotes 4.1N–NuMA association. Nuclear-targeted 4.1N arrests PC12 cells at G1 and produces aberrant nuclear morphology. Inhibition of 4.1N nuclear translocation prevents NGF-mediated cell division arrest, which is reversed by 4.1N overexpression.","method":"Co-immunoprecipitation, deletion mapping, targeted nuclear localization constructs, cell cycle analysis (G1 arrest), nuclear morphology imaging in PC12 cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with domain mapping, gain- and loss-of-function with defined cell-cycle phenotype, multiple orthogonal methods in one study","pmids":["10594058"],"is_preprint":false},{"year":2003,"finding":"4.1N binds specifically to the CTDDelta splice form of 4.1N via a 50-amino-acid fragment in the C-terminal tail of IP3R1. The 4.1N–IP3R1 complex is enriched in synaptic locations and can be immunoprecipitated from rat brain synaptosomes. A quaternary complex of IP3R1–4.1N–CASK–syndecan-2 can form in vitro.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation from rat brain synaptosomes, deletion mapping","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro binding plus synaptosome Co-IP, domain mapping, single lab","pmids":["12676536"],"is_preprint":false},{"year":2004,"finding":"4.1N acts as a linker between IP3R1 and actin filaments in neuronal dendrites, restricting lateral diffusion of IP3R1 on the ER membrane. Dominant-negative 4.1N or blockade of 4.1N binding to IP3R1 increased IP3R1 diffusion constant. Adding the 4.1N-binding sequence to IP3R3 (which normally lacks it) conferred actin-dependent restriction of its diffusion.","method":"FRAP (fluorescence recovery after photobleaching) of GFP-tagged IP3R1 in live hippocampal neurons, dominant-negative overexpression, actin depolymerization, domain swap experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell FRAP with multiple orthogonal manipulations (dominant-negative, domain swap, actin disruption) establishing mechanism in neurons","pmids":["15364918"],"is_preprint":false},{"year":2005,"finding":"4.1N interacts with nectin-like molecule 1 (NECL1) and NECL1 recruits 4.1N from the cytoplasm to the plasma membrane through its C-terminus, suggesting 4.1N participates in cell-cell junction organization in neurons.","method":"In vitro binding assay, co-immunoprecipitation, immunofluorescence localization in transfected cells","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and localization, single lab, no functional loss-of-function validation","pmids":["15893517"],"is_preprint":false},{"year":2006,"finding":"Both the C-terminal 14 amino acid segment (CTT14aa) and the middle segment (CTM1) of IP3R1 can bind 4.1N as peptide fragments, but the CTT14aa is the responsible binding site in the context of full-length tetrameric IP3R1.","method":"Immunoprecipitation with deletion constructs, FRAP in neuronal dendrites using competing peptides","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical binding mapped with deletion constructs and functionally tested by FRAP in neurons, single lab","pmids":["16487933"],"is_preprint":false},{"year":2011,"finding":"IP3R1 localization via 4.1N is necessary for Ca2+ wave formation, which in turn mediates neurite formation in NGF-differentiated PC12 cells. RNAi knockdown of 4.1N attenuated neurite formation and shifted IP3-evoked Ca2+ signaling from waves to homogeneous patterns.","method":"RNAi knockdown, dominant-negative binding-region overexpression, confocal live-cell Ca2+ imaging, neurite morphometry in PC12 cells","journal":"Neuro-Signals","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi and dominant-negative with defined Ca2+ signaling and morphological readouts, single lab","pmids":["21389686"],"is_preprint":false},{"year":2013,"finding":"4.1N interacts with GluK1 and GluK2 kainate receptor subunits through a membrane-proximal C-terminal domain region. This interaction is required for forward trafficking, plasma membrane distribution, and regulated endocytosis of GluK2a receptors. Palmitoylation of GluK2a promotes 4.1N association and surface expression, while PKC activation decreases 4.1N–GluK2/3 interaction in acute brain slices.","method":"Co-immunoprecipitation, surface expression assays, endocytosis assays, palmitoylation-deficient and PKC-activation experiments, acute brain slice biochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, surface biotinylation, endocytosis assays, mutagenesis, ex vivo brain slices) in single lab","pmids":["23400781"],"is_preprint":false},{"year":2013,"finding":"4.1N interacts with the α7 acetylcholine receptor. DCP-LA increases the association of α7 AChR with 4.1N in a PKC-dependent manner (without directly phosphorylating 4.1N). 4.1N knockdown suppresses α7 AChR membrane surface localization, and DCP-LA-enhanced membrane surface expression of α7 AChR is prevented by 4.1N knockdown.","method":"Yeast two-hybrid, co-immunoprecipitation from rat hippocampal slices, plasma membrane fractionation, α7 AChR surface fluorescence imaging in PC12 cells, siRNA knockdown","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP from native tissue plus knockdown with surface localization readout, single lab","pmids":["23256752"],"is_preprint":false},{"year":2016,"finding":"4.1N interacts with PP1 (protein phosphatase 1) via its FERM domain, and ectopic 4.1N expression inactivates the JNK–c-Jun signaling pathway by enhancing PP1 activity and PP1–p-JNK interaction, leading to suppression of downstream metastasis targets (ezrin, MMP9) and cell cycle targets (p53, p21, p19) in NSCLC cells.","method":"Co-immunoprecipitation, PP1 activity assay, FERM domain deletion mapping, siRNA knockdown and overexpression, xenograft mouse model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping, enzymatic activity assay, and in vivo xenograft; single lab","pmids":["26575790"],"is_preprint":false},{"year":2016,"finding":"4.1N directly interacts with flotillin-1 through its FERM and U2 domains in NSCLC cells. 4.1N suppresses cell proliferation and migration through a flotillin-1/β-catenin/Wnt signaling pathway.","method":"Co-immunoprecipitation, pulldown, domain deletion mapping, siRNA knockdown and overexpression, proliferation and migration assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/pulldown with domain mapping plus functional knockdown/overexpression experiments, single lab","pmids":["27448302"],"is_preprint":false},{"year":2018,"finding":"IP6K2 (inositol hexakisphosphate kinase 2) binds 4.1N with high affinity and specificity. Nuclear translocation of 4.1N is dependent on IP6K2. In cerebellar granule cells, the IP6K2–4.1N interaction regulates Purkinje cell morphology, cerebellar synapses, and locomotor function. Disruption of IP6K2–4.1N interactions impairs cell viability.","method":"Co-immunoprecipitation, IP6K2 knockout mice, cerebellar histology, synaptic morphology, locomotor behavioral assays, cell viability assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus knockout mouse with defined synaptic and behavioral phenotypes, single lab","pmids":["30006360"],"is_preprint":false},{"year":2018,"finding":"4.1N localizes to the lateral membrane of human bronchial epithelial cells, where it associates with E-cadherin, β-catenin, and βII spectrin. RNAi depletion of 4.1N reduces lateral membrane height; this is rescued by re-expression of mouse 4.1N. 4.1N is required for full lateral membrane assembly but not the initial phase of lateral membrane biogenesis.","method":"RNAi knockdown, rescue by re-expression, co-immunoprecipitation, confocal immunofluorescence, lateral membrane height measurement","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi with rescue and Co-IP, functional morphological readout, single lab","pmids":["29428502"],"is_preprint":false},{"year":2020,"finding":"4.1N directly binds 14-3-3 and promotes its degradation in suspension EOC cells, thereby inhibiting anoikis resistance and EMT. Loss of 4.1N leads to EMT in adherent EOC cells and increased anoikis resistance and entosis-based cell death resistance in suspension cells.","method":"Co-immunoprecipitation, ubiquitin-proteasome degradation assay, siRNA knockdown, overexpression, xenograft mouse model, in vitro anoikis/entosis assays","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with degradation assay and in vivo xenograft, multiple orthogonal functional assays, single lab","pmids":["32448967"],"is_preprint":false},{"year":2020,"finding":"4.1N knockout mice show defects in GnRH localization to hypothalamic axons (restricted to cell bodies only), decreased pituitary secretory granules, and gonadal atrophy with failed spermatogenesis and follicular development, indicating 4.1N is required for the hypothalamus-pituitary-reproductive axis.","method":"4.1N knockout mouse generation, histopathology, immunofluorescence of GnRH localization in hypothalamus, pituitary granule ultrastructure","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knockout mouse with defined neuroendocrine phenotype, but single lab and limited mechanistic dissection","pmids":["33046791"],"is_preprint":false},{"year":2023,"finding":"CaMKII phosphorylates 4.1N during TBS-induced LTP in rat hippocampal CA1 neurons, and this phosphorylation facilitates assembly of a p-CaMKII–4.1N–GluA1 complex that drives GluA1 trafficking to postsynaptic densities. Disrupting the 4.1N–GluA1 interaction (Tat-GluA1 MPR peptide) or inhibiting CaMKII (Myr-AIP) both attenuated LTP and reduced postsynaptic GluA1, but neither affected basal mEPSCs.","method":"Co-immunoprecipitation, immunoblotting for phospho-proteins, interfering peptides (Tat-GluA1 MPR), CaMKII inhibitor (Myr-AIP), LTP electrophysiology in acute hippocampal slices","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with phospho-specific antibodies and interfering peptides, electrophysiological LTP readout; single lab","pmids":["37993087"],"is_preprint":false},{"year":2023,"finding":"4.1N is required for GluA1 intracellular transport and exocytosis during both basal transmission and cLTP in neurons. SAP97 is essential for GluA1 intracellular transport under basal conditions, while 4.1N controls exocytosis basally and both transport and exocytosis during cLTP. Deletion of the GluA1 C-terminal domain fully suppresses intracellular transport.","method":"siRNA knockdown of 4.1N and SAP97, live-cell single-molecule imaging of GluA1 trafficking and exocytosis, cLTP induction, total internal reflection fluorescence microscopy","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — single-molecule live imaging with siRNA knockdown, orthogonal trafficking and exocytosis assays, rigorous dissection of basal vs. plasticity conditions","pmids":["37079350"],"is_preprint":false},{"year":2023,"finding":"4.1N plays a cell type-specific role in hippocampal glutamatergic synapses: knockdown in dentate gyrus (DG) granule neurons reduces glutamatergic synapse number and function, whereas knockdown in CA1 pyramidal neurons has no effect on basal transmission. The FERM domain of 4.1N (not the CTD) is essential for supporting synaptic AMPAR function in DG granule neurons.","method":"In vivo/ex vivo stereotaxic viral knockdown of 4.1N, electrophysiology (mEPSC recording), domain-specific rescue (FERM vs. CTD deletion constructs), immunofluorescence synapse counting","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific knockdown with electrophysiological readout, domain-specific rescue, multiple orthogonal approaches; single lab but rigorous","pmids":["37845032"],"is_preprint":false},{"year":2025,"finding":"A GluA1 C80 peptide that disrupts GluA1–4.1N binding impairs LTP and short-term spatial memory (but not long-term spatial memory) when expressed bilaterally in hippocampal CA1, demonstrating that the 4.1N–GluA1 interaction is required for synaptic plasticity and short-term memory in vivo.","method":"Viral expression of interfering GluA1 C80 peptide in dorsal hippocampus CA1, LTP electrophysiology, spatial memory behavioral testing (Morris water maze variants)","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — interfering peptide in vivo with behavioral and electrophysiological readouts; single lab, single method per endpoint","pmids":["41417164"],"is_preprint":false}],"current_model":"EPB41L1/4.1N is a neuron-enriched FERM-domain scaffolding protein that links transmembrane receptors (AMPA receptors GluA1/GluA4, kainate receptors GluK1/2, IP3R1, D2/D3 dopamine receptors, α7 AChR) to the spectrin-actin cytoskeleton; it controls receptor surface expression, lateral membrane diffusion, and synaptic delivery by acting as a regulated scaffold whose interactions are tuned by PKC phosphorylation and palmitoylation of the bound receptor, and by CaMKII phosphorylation of 4.1N itself during LTP; it also translocates to the nucleus upon NGF stimulation where it inhibits PIKE-mediated nuclear PI3K activation and associates with NuMA to mediate G1 arrest, and in non-neural contexts suppresses tumor progression by recruiting PP1 to inactivate the JNK–c-Jun pathway and by directly binding and promoting degradation of 14-3-3 to inhibit EMT and anoikis resistance."},"narrative":{"mechanistic_narrative":"EPB41L1 (4.1N) is a neuron-enriched FERM-domain scaffolding protein that couples transmembrane receptors to the spectrin–actin cytoskeleton and thereby governs receptor surface delivery, lateral membrane diffusion, and synaptic plasticity [PMID:19503082, PMID:15364918]. At excitatory synapses it binds the C-terminal domain of the AMPA receptor subunit GluA1 to drive activity-dependent receptor exocytosis and insertion into the plasma membrane, a step required for LTP expression; this interaction is gated by PKC phosphorylation and palmitoylation of GluA1 and by CaMKII phosphorylation of 4.1N itself, which nucleates a p-CaMKII–4.1N–GluA1 complex during LTP [PMID:19503082, PMID:37993087, PMID:37079350]. The 4.1N–GluA1 interaction is required for LTP and short-term spatial memory in vivo, and its synaptic role is cell-type-specific, depending on the FERM domain in dentate gyrus granule neurons [PMID:37845032, PMID:41417164]. Beyond AMPA receptors, 4.1N scaffolds kainate receptors GluK1/GluK2 (controlling forward trafficking and regulated endocytosis), the α7 acetylcholine receptor, D2/D3 dopamine receptors, and IP3R1, where it tethers the receptor to actin to restrict ER-membrane lateral diffusion, organize basolateral targeting in polarized cells, and shape Ca2+ wave signaling that supports neurite formation [PMID:12181426, PMID:12444087, PMID:15364918, PMID:23400781, PMID:23256752, PMID:21389686]. Independently of its membrane scaffolding function, 4.1N undergoes NGF-induced, IP6K2-dependent nuclear translocation, where it inhibits PIKE-mediated nuclear PI3K activation and associates with NuMA to impose G1 arrest [PMID:11136977, PMID:10594058, PMID:30006360]. In epithelial and tumor contexts it suppresses progression by recruiting PP1 through its FERM domain to inactivate JNK–c-Jun signaling and by directly binding 14-3-3 to promote its degradation, thereby restraining EMT and anoikis resistance [PMID:26575790, PMID:32448967]. 4.1N is also required for lateral membrane assembly in epithelial cells and for the hypothalamus–pituitary–reproductive axis in vivo [PMID:29428502, PMID:33046791].","teleology":[{"year":1999,"claim":"Established that 4.1N is not solely a membrane scaffold but can act in the nucleus, linking NGF signaling to cell-cycle control.","evidence":"Co-IP, domain mapping, and nuclear-targeting constructs with G1 arrest readout in PC12 cells","pmids":["10594058"],"confidence":"High","gaps":["How NGF triggers nuclear import was not defined","Whether NuMA binding is the direct effector of G1 arrest unresolved"]},{"year":2000,"claim":"Defined a nuclear signaling function in which 4.1N restrains nuclear PI3K activity, connecting it to the PIKE GTPase pathway.","evidence":"Yeast two-hybrid, Co-IP, and PI3K lipid kinase activity assays with nuclear fractionation","pmids":["11136977"],"confidence":"High","gaps":["Physiological consequence of PIKE inhibition not established in neurons","Mechanism of inhibition (sequestration vs. catalytic) unknown"]},{"year":2002,"claim":"Showed 4.1N is a general receptor-surface-expression scaffold by mapping direct binding to D2/D3 dopamine receptors and IP3R1 with functional trafficking consequences.","evidence":"Yeast two-hybrid, pulldown, Co-IP, deletion mapping, and immunofluorescence in transfected and polarized cells","pmids":["12181426","12444087"],"confidence":"High","gaps":["Whether endogenous receptor trafficking depends on 4.1N not tested","Binding stoichiometry and regulation unexamined"]},{"year":2004,"claim":"Provided the mechanistic principle of 4.1N action — tethering a receptor to actin to restrict its lateral membrane diffusion — using IP3R1 as a model.","evidence":"FRAP of GFP-IP3R1 in live hippocampal neurons with dominant-negative, domain-swap, and actin-depolymerization manipulations","pmids":["15364918"],"confidence":"High","gaps":["Did not address whether diffusion restriction applies to other 4.1N receptor partners","Quantitative spectrin contribution not dissected"]},{"year":2009,"claim":"Established 4.1N as a required effector of activity-dependent AMPA receptor insertion, tying its scaffold function to synaptic plasticity and identifying PKC/palmitoylation as upstream regulators.","evidence":"Live imaging of GluA1 insertion events, dominant-negative peptide, GluA1 phospho/palmitoylation mutants, and LTP electrophysiology","pmids":["19503082"],"confidence":"High","gaps":["How 4.1N couples GluA1 to exocytic machinery left open","In vivo behavioral relevance not addressed in this study"]},{"year":2013,"claim":"Extended the scaffolding role to kainate and nicotinic receptors, showing a common palmitoylation/PKC-regulated binding logic across receptor families.","evidence":"Co-IP, surface biotinylation, endocytosis and palmitoylation-mutant assays, and acute brain slice biochemistry for GluK2/GluK1 and α7 AChR","pmids":["23400781","23256752"],"confidence":"Medium","gaps":["Receptor-specific differences in regulation not reconciled","Endogenous knockout validation limited"]},{"year":2016,"claim":"Defined a tumor-suppressive mechanism in which 4.1N recruits PP1 via its FERM domain to inactivate JNK–c-Jun signaling.","evidence":"Co-IP, PP1 activity assay, FERM-deletion mapping, knockdown/overexpression, and xenograft model in NSCLC","pmids":["26575790"],"confidence":"Medium","gaps":["Single lab without reciprocal validation across cancer types","Direct PP1 dephosphorylation of JNK not biochemically reconstituted"]},{"year":2018,"claim":"Identified IP6K2 as the determinant of 4.1N nuclear translocation and linked the interaction to cerebellar synapse and locomotor phenotypes in vivo.","evidence":"Co-IP, IP6K2 knockout mice, cerebellar histology, synaptic morphology, and behavioral assays","pmids":["30006360"],"confidence":"Medium","gaps":["Whether IP6K2 acts catalytically or structurally in nuclear import unknown","Connection to PIKE/NuMA nuclear functions not integrated"]},{"year":2020,"claim":"Revealed an additional anti-tumor mechanism — direct binding and proteasomal degradation of 14-3-3 to block EMT and anoikis resistance — and an in vivo neuroendocrine requirement.","evidence":"Co-IP, ubiquitin-proteasome degradation assays, xenografts in EOC cells, and 4.1N knockout mouse neuroendocrine phenotyping","pmids":["32448967","33046791"],"confidence":"Medium","gaps":["Mechanism linking 4.1N to the 14-3-3 degradation machinery undefined","Molecular basis of GnRH axonal trafficking defect not resolved"]},{"year":2023,"claim":"Resolved the trafficking step controlled by 4.1N (exocytosis basally; both transport and exocytosis during plasticity), showed CaMKII phosphorylation builds the plasticity complex, and uncovered cell-type-specific synaptic dependence.","evidence":"Single-molecule live imaging with siRNA knockdown, phospho-specific Co-IP, interfering peptides, LTP electrophysiology, and cell-type-specific viral knockdown with domain rescue","pmids":["37079350","37993087","37845032"],"confidence":"High","gaps":["Why DG vs CA1 neurons differ in 4.1N dependence mechanistically unexplained","Functional partition between 4.1N and SAP97 not fully delineated"]},{"year":2025,"claim":"Demonstrated behavioral relevance, showing the 4.1N–GluA1 interaction is required for LTP and short-term spatial memory in vivo.","evidence":"Viral interfering GluA1 C80 peptide in CA1, LTP electrophysiology, and spatial memory testing","pmids":["41417164"],"confidence":"Medium","gaps":["Single interfering-peptide approach without genetic confirmation","Selective effect on short- but not long-term memory mechanistically unexplained"]},{"year":null,"claim":"How 4.1N's distinct functional modes — membrane receptor scaffolding, nuclear cell-cycle/PI3K regulation, and tumor-suppressive PP1/14-3-3 signaling — are partitioned and switched within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating cytoplasmic, synaptic, and nuclear pools","Structural basis for FERM-domain selection among diverse partners undefined","Regulation of subcellular partitioning beyond NGF/IP6K2 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,6,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,12,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10,11,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,18,19,20]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,10,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,12,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,13,16]}],"complexes":["p-CaMKII–4.1N–GluA1 complex","IP3R1–4.1N–CASK–syndecan-2 complex"],"partners":["GRIA1","ITPR1","GRIK2","NUMA1","PP1","YWHA (14-3-3)","IP6K2","FLOT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H4G0","full_name":"Band 4.1-like protein 1","aliases":["Erythrocyte membrane protein band 4.1-like 1","Neuronal protein 4.1","4.1N"],"length_aa":881,"mass_kda":98.5,"function":"May function to confer stability and plasticity to neuronal membrane via multiple interactions, including the spectrin-actin-based cytoskeleton, integral membrane channels and membrane-associated guanylate kinases","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9H4G0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPB41L1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLNS1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPB41L1","total_profiled":1310},"omim":[{"mim_id":"614257","title":"CHROMOSOME 20q11-q12 DELETION SYNDROME","url":"https://www.omim.org/entry/614257"},{"mim_id":"612406","title":"DYSTONIA 17, TORSION, AUTOSOMAL RECESSIVE; DYT17","url":"https://www.omim.org/entry/612406"},{"mim_id":"602879","title":"ERYTHROCYTE MEMBRANE PROTEIN BAND 4.1-LIKE 1; EPB41L1","url":"https://www.omim.org/entry/602879"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EPB41L1"},"hgnc":{"alias_symbol":["KIAA0338","4.1N"],"prev_symbol":[]},"alphafold":{"accession":"Q9H4G0","domains":[{"cath_id":"3.10.20.90","chopping":"97-174","consensus_level":"high","plddt":95.4859,"start":97,"end":174},{"cath_id":"1.20.80.10","chopping":"181-279","consensus_level":"high","plddt":95.5609,"start":181,"end":279},{"cath_id":"2.30.29.30","chopping":"287-382_391-409","consensus_level":"high","plddt":90.8379,"start":287,"end":409}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4G0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4G0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4G0-F1-predicted_aligned_error_v6.png","plddt_mean":61.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPB41L1","jax_strain_url":"https://www.jax.org/strain/search?query=EPB41L1"},"sequence":{"accession":"Q9H4G0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H4G0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H4G0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4G0"}},"corpus_meta":[{"pmid":"19503082","id":"PMC_19503082","title":"Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation.","date":"2009","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19503082","citation_count":289,"is_preprint":false},{"pmid":"11136977","id":"PMC_11136977","title":"Pike. 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PKC phosphorylation of GluR1 at S816 and S818 enhances 4.1N binding to GluR1 and facilitates GluR1 insertion. Palmitoylation of GluR1 C811 modulates PKC phosphorylation and GluR1 insertion. Disrupting 4.1N-dependent GluR1 insertion decreases surface GluR1 expression and impairs LTP expression.\",\n      \"method\": \"Live imaging of individual GluR1 insertion events, dominant-negative peptide disruption, co-immunoprecipitation, site-directed mutagenesis of GluR1 phosphorylation and palmitoylation sites, LTP electrophysiology\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, mutagenesis, Co-IP, electrophysiology) in one rigorous study with clear mechanistic dissection\",\n      \"pmids\": [\"19503082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"4.1N interacts with PIKE (a nuclear GTPase) and translocates to the nucleus upon NGF treatment, where overexpression of 4.1N abolishes PIKE-mediated enhancement of nuclear PI3K lipid kinase activity. NGF-stimulated nuclear translocation of 4.1N inhibits PIKE activation of nuclear PI3K.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, PI3K lipid kinase activity assay, dominant-negative overexpression, nuclear fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic activity assay combined with Co-IP and overexpression in multiple orthogonal experiments in a high-rigor study\",\n      \"pmids\": [\"11136977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"4.1N interacts specifically with D2 and D3 dopamine receptors via the N-terminal segment of their third intracellular domain and the C-terminal domain of 4.1N. Expression of a 4.1N truncation fragment reduces plasma membrane localization of D2 and D3 receptors, indicating 4.1N is required for dopamine receptor surface expression.\",\n      \"method\": \"Yeast two-hybrid, pulldown, co-immunoprecipitation, deletion mapping, immunofluorescence in transfected HEK293 and Neuro2A cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP and pulldown with functional localization assay, single lab\",\n      \"pmids\": [\"12181426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"4.1N binds to the C-terminal cytoplasmic tail of IP3R1 (inositol 1,4,5-trisphosphate receptor type 1) and is required for translocation of IP3R1 to the basolateral membrane domain in polarized MDCK cells. The 4.1N-binding region of IP3R1 is necessary and sufficient for basolateral targeting, and a fragment of the IP3R1-binding region of 4.1N blocks co-expressed IP3R1 basolateral localization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, dominant-negative fragment expression, immunofluorescence in polarized MDCK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, dominant-negative competition, and cell fractionation/imaging in polarized cells with functional consequence; replicated by independent groups\",\n      \"pmids\": [\"12444087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"4.1N interacts with the nuclear mitotic apparatus protein NuMA via its C-terminal domain. NGF treatment causes translocation of 4.1N to the nucleus and promotes 4.1N–NuMA association. Nuclear-targeted 4.1N arrests PC12 cells at G1 and produces aberrant nuclear morphology. Inhibition of 4.1N nuclear translocation prevents NGF-mediated cell division arrest, which is reversed by 4.1N overexpression.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, targeted nuclear localization constructs, cell cycle analysis (G1 arrest), nuclear morphology imaging in PC12 cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with domain mapping, gain- and loss-of-function with defined cell-cycle phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10594058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"4.1N binds specifically to the CTDDelta splice form of 4.1N via a 50-amino-acid fragment in the C-terminal tail of IP3R1. The 4.1N–IP3R1 complex is enriched in synaptic locations and can be immunoprecipitated from rat brain synaptosomes. A quaternary complex of IP3R1–4.1N–CASK–syndecan-2 can form in vitro.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation from rat brain synaptosomes, deletion mapping\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro binding plus synaptosome Co-IP, domain mapping, single lab\",\n      \"pmids\": [\"12676536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"4.1N acts as a linker between IP3R1 and actin filaments in neuronal dendrites, restricting lateral diffusion of IP3R1 on the ER membrane. Dominant-negative 4.1N or blockade of 4.1N binding to IP3R1 increased IP3R1 diffusion constant. Adding the 4.1N-binding sequence to IP3R3 (which normally lacks it) conferred actin-dependent restriction of its diffusion.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching) of GFP-tagged IP3R1 in live hippocampal neurons, dominant-negative overexpression, actin depolymerization, domain swap experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell FRAP with multiple orthogonal manipulations (dominant-negative, domain swap, actin disruption) establishing mechanism in neurons\",\n      \"pmids\": [\"15364918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"4.1N interacts with nectin-like molecule 1 (NECL1) and NECL1 recruits 4.1N from the cytoplasm to the plasma membrane through its C-terminus, suggesting 4.1N participates in cell-cell junction organization in neurons.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, immunofluorescence localization in transfected cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and localization, single lab, no functional loss-of-function validation\",\n      \"pmids\": [\"15893517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Both the C-terminal 14 amino acid segment (CTT14aa) and the middle segment (CTM1) of IP3R1 can bind 4.1N as peptide fragments, but the CTT14aa is the responsible binding site in the context of full-length tetrameric IP3R1.\",\n      \"method\": \"Immunoprecipitation with deletion constructs, FRAP in neuronal dendrites using competing peptides\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical binding mapped with deletion constructs and functionally tested by FRAP in neurons, single lab\",\n      \"pmids\": [\"16487933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IP3R1 localization via 4.1N is necessary for Ca2+ wave formation, which in turn mediates neurite formation in NGF-differentiated PC12 cells. RNAi knockdown of 4.1N attenuated neurite formation and shifted IP3-evoked Ca2+ signaling from waves to homogeneous patterns.\",\n      \"method\": \"RNAi knockdown, dominant-negative binding-region overexpression, confocal live-cell Ca2+ imaging, neurite morphometry in PC12 cells\",\n      \"journal\": \"Neuro-Signals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi and dominant-negative with defined Ca2+ signaling and morphological readouts, single lab\",\n      \"pmids\": [\"21389686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"4.1N interacts with GluK1 and GluK2 kainate receptor subunits through a membrane-proximal C-terminal domain region. This interaction is required for forward trafficking, plasma membrane distribution, and regulated endocytosis of GluK2a receptors. Palmitoylation of GluK2a promotes 4.1N association and surface expression, while PKC activation decreases 4.1N–GluK2/3 interaction in acute brain slices.\",\n      \"method\": \"Co-immunoprecipitation, surface expression assays, endocytosis assays, palmitoylation-deficient and PKC-activation experiments, acute brain slice biochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, surface biotinylation, endocytosis assays, mutagenesis, ex vivo brain slices) in single lab\",\n      \"pmids\": [\"23400781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"4.1N interacts with the α7 acetylcholine receptor. DCP-LA increases the association of α7 AChR with 4.1N in a PKC-dependent manner (without directly phosphorylating 4.1N). 4.1N knockdown suppresses α7 AChR membrane surface localization, and DCP-LA-enhanced membrane surface expression of α7 AChR is prevented by 4.1N knockdown.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from rat hippocampal slices, plasma membrane fractionation, α7 AChR surface fluorescence imaging in PC12 cells, siRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP from native tissue plus knockdown with surface localization readout, single lab\",\n      \"pmids\": [\"23256752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"4.1N interacts with PP1 (protein phosphatase 1) via its FERM domain, and ectopic 4.1N expression inactivates the JNK–c-Jun signaling pathway by enhancing PP1 activity and PP1–p-JNK interaction, leading to suppression of downstream metastasis targets (ezrin, MMP9) and cell cycle targets (p53, p21, p19) in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, PP1 activity assay, FERM domain deletion mapping, siRNA knockdown and overexpression, xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping, enzymatic activity assay, and in vivo xenograft; single lab\",\n      \"pmids\": [\"26575790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"4.1N directly interacts with flotillin-1 through its FERM and U2 domains in NSCLC cells. 4.1N suppresses cell proliferation and migration through a flotillin-1/β-catenin/Wnt signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, domain deletion mapping, siRNA knockdown and overexpression, proliferation and migration assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/pulldown with domain mapping plus functional knockdown/overexpression experiments, single lab\",\n      \"pmids\": [\"27448302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IP6K2 (inositol hexakisphosphate kinase 2) binds 4.1N with high affinity and specificity. Nuclear translocation of 4.1N is dependent on IP6K2. In cerebellar granule cells, the IP6K2–4.1N interaction regulates Purkinje cell morphology, cerebellar synapses, and locomotor function. Disruption of IP6K2–4.1N interactions impairs cell viability.\",\n      \"method\": \"Co-immunoprecipitation, IP6K2 knockout mice, cerebellar histology, synaptic morphology, locomotor behavioral assays, cell viability assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus knockout mouse with defined synaptic and behavioral phenotypes, single lab\",\n      \"pmids\": [\"30006360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"4.1N localizes to the lateral membrane of human bronchial epithelial cells, where it associates with E-cadherin, β-catenin, and βII spectrin. RNAi depletion of 4.1N reduces lateral membrane height; this is rescued by re-expression of mouse 4.1N. 4.1N is required for full lateral membrane assembly but not the initial phase of lateral membrane biogenesis.\",\n      \"method\": \"RNAi knockdown, rescue by re-expression, co-immunoprecipitation, confocal immunofluorescence, lateral membrane height measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi with rescue and Co-IP, functional morphological readout, single lab\",\n      \"pmids\": [\"29428502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"4.1N directly binds 14-3-3 and promotes its degradation in suspension EOC cells, thereby inhibiting anoikis resistance and EMT. Loss of 4.1N leads to EMT in adherent EOC cells and increased anoikis resistance and entosis-based cell death resistance in suspension cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin-proteasome degradation assay, siRNA knockdown, overexpression, xenograft mouse model, in vitro anoikis/entosis assays\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with degradation assay and in vivo xenograft, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"32448967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"4.1N knockout mice show defects in GnRH localization to hypothalamic axons (restricted to cell bodies only), decreased pituitary secretory granules, and gonadal atrophy with failed spermatogenesis and follicular development, indicating 4.1N is required for the hypothalamus-pituitary-reproductive axis.\",\n      \"method\": \"4.1N knockout mouse generation, histopathology, immunofluorescence of GnRH localization in hypothalamus, pituitary granule ultrastructure\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knockout mouse with defined neuroendocrine phenotype, but single lab and limited mechanistic dissection\",\n      \"pmids\": [\"33046791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CaMKII phosphorylates 4.1N during TBS-induced LTP in rat hippocampal CA1 neurons, and this phosphorylation facilitates assembly of a p-CaMKII–4.1N–GluA1 complex that drives GluA1 trafficking to postsynaptic densities. Disrupting the 4.1N–GluA1 interaction (Tat-GluA1 MPR peptide) or inhibiting CaMKII (Myr-AIP) both attenuated LTP and reduced postsynaptic GluA1, but neither affected basal mEPSCs.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting for phospho-proteins, interfering peptides (Tat-GluA1 MPR), CaMKII inhibitor (Myr-AIP), LTP electrophysiology in acute hippocampal slices\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with phospho-specific antibodies and interfering peptides, electrophysiological LTP readout; single lab\",\n      \"pmids\": [\"37993087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"4.1N is required for GluA1 intracellular transport and exocytosis during both basal transmission and cLTP in neurons. SAP97 is essential for GluA1 intracellular transport under basal conditions, while 4.1N controls exocytosis basally and both transport and exocytosis during cLTP. Deletion of the GluA1 C-terminal domain fully suppresses intracellular transport.\",\n      \"method\": \"siRNA knockdown of 4.1N and SAP97, live-cell single-molecule imaging of GluA1 trafficking and exocytosis, cLTP induction, total internal reflection fluorescence microscopy\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — single-molecule live imaging with siRNA knockdown, orthogonal trafficking and exocytosis assays, rigorous dissection of basal vs. plasticity conditions\",\n      \"pmids\": [\"37079350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"4.1N plays a cell type-specific role in hippocampal glutamatergic synapses: knockdown in dentate gyrus (DG) granule neurons reduces glutamatergic synapse number and function, whereas knockdown in CA1 pyramidal neurons has no effect on basal transmission. The FERM domain of 4.1N (not the CTD) is essential for supporting synaptic AMPAR function in DG granule neurons.\",\n      \"method\": \"In vivo/ex vivo stereotaxic viral knockdown of 4.1N, electrophysiology (mEPSC recording), domain-specific rescue (FERM vs. CTD deletion constructs), immunofluorescence synapse counting\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific knockdown with electrophysiological readout, domain-specific rescue, multiple orthogonal approaches; single lab but rigorous\",\n      \"pmids\": [\"37845032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A GluA1 C80 peptide that disrupts GluA1–4.1N binding impairs LTP and short-term spatial memory (but not long-term spatial memory) when expressed bilaterally in hippocampal CA1, demonstrating that the 4.1N–GluA1 interaction is required for synaptic plasticity and short-term memory in vivo.\",\n      \"method\": \"Viral expression of interfering GluA1 C80 peptide in dorsal hippocampus CA1, LTP electrophysiology, spatial memory behavioral testing (Morris water maze variants)\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — interfering peptide in vivo with behavioral and electrophysiological readouts; single lab, single method per endpoint\",\n      \"pmids\": [\"41417164\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPB41L1/4.1N is a neuron-enriched FERM-domain scaffolding protein that links transmembrane receptors (AMPA receptors GluA1/GluA4, kainate receptors GluK1/2, IP3R1, D2/D3 dopamine receptors, α7 AChR) to the spectrin-actin cytoskeleton; it controls receptor surface expression, lateral membrane diffusion, and synaptic delivery by acting as a regulated scaffold whose interactions are tuned by PKC phosphorylation and palmitoylation of the bound receptor, and by CaMKII phosphorylation of 4.1N itself during LTP; it also translocates to the nucleus upon NGF stimulation where it inhibits PIKE-mediated nuclear PI3K activation and associates with NuMA to mediate G1 arrest, and in non-neural contexts suppresses tumor progression by recruiting PP1 to inactivate the JNK–c-Jun pathway and by directly binding and promoting degradation of 14-3-3 to inhibit EMT and anoikis resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPB41L1 (4.1N) is a neuron-enriched FERM-domain scaffolding protein that couples transmembrane receptors to the spectrin–actin cytoskeleton and thereby governs receptor surface delivery, lateral membrane diffusion, and synaptic plasticity [#0, #6]. At excitatory synapses it binds the C-terminal domain of the AMPA receptor subunit GluA1 to drive activity-dependent receptor exocytosis and insertion into the plasma membrane, a step required for LTP expression; this interaction is gated by PKC phosphorylation and palmitoylation of GluA1 and by CaMKII phosphorylation of 4.1N itself, which nucleates a p-CaMKII–4.1N–GluA1 complex during LTP [#0, #18, #19]. The 4.1N–GluA1 interaction is required for LTP and short-term spatial memory in vivo, and its synaptic role is cell-type-specific, depending on the FERM domain in dentate gyrus granule neurons [#20, #21]. Beyond AMPA receptors, 4.1N scaffolds kainate receptors GluK1/GluK2 (controlling forward trafficking and regulated endocytosis), the α7 acetylcholine receptor, D2/D3 dopamine receptors, and IP3R1, where it tethers the receptor to actin to restrict ER-membrane lateral diffusion, organize basolateral targeting in polarized cells, and shape Ca2+ wave signaling that supports neurite formation [#2, #3, #6, #10, #11, #9]. Independently of its membrane scaffolding function, 4.1N undergoes NGF-induced, IP6K2-dependent nuclear translocation, where it inhibits PIKE-mediated nuclear PI3K activation and associates with NuMA to impose G1 arrest [#1, #4, #14]. In epithelial and tumor contexts it suppresses progression by recruiting PP1 through its FERM domain to inactivate JNK–c-Jun signaling and by directly binding 14-3-3 to promote its degradation, thereby restraining EMT and anoikis resistance [#12, #16]. 4.1N is also required for lateral membrane assembly in epithelial cells and for the hypothalamus–pituitary–reproductive axis in vivo [#15, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that 4.1N is not solely a membrane scaffold but can act in the nucleus, linking NGF signaling to cell-cycle control.\",\n      \"evidence\": \"Co-IP, domain mapping, and nuclear-targeting constructs with G1 arrest readout in PC12 cells\",\n      \"pmids\": [\"10594058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NGF triggers nuclear import was not defined\", \"Whether NuMA binding is the direct effector of G1 arrest unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined a nuclear signaling function in which 4.1N restrains nuclear PI3K activity, connecting it to the PIKE GTPase pathway.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and PI3K lipid kinase activity assays with nuclear fractionation\",\n      \"pmids\": [\"11136977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of PIKE inhibition not established in neurons\", \"Mechanism of inhibition (sequestration vs. catalytic) unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed 4.1N is a general receptor-surface-expression scaffold by mapping direct binding to D2/D3 dopamine receptors and IP3R1 with functional trafficking consequences.\",\n      \"evidence\": \"Yeast two-hybrid, pulldown, Co-IP, deletion mapping, and immunofluorescence in transfected and polarized cells\",\n      \"pmids\": [\"12181426\", \"12444087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous receptor trafficking depends on 4.1N not tested\", \"Binding stoichiometry and regulation unexamined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the mechanistic principle of 4.1N action — tethering a receptor to actin to restrict its lateral membrane diffusion — using IP3R1 as a model.\",\n      \"evidence\": \"FRAP of GFP-IP3R1 in live hippocampal neurons with dominant-negative, domain-swap, and actin-depolymerization manipulations\",\n      \"pmids\": [\"15364918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether diffusion restriction applies to other 4.1N receptor partners\", \"Quantitative spectrin contribution not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established 4.1N as a required effector of activity-dependent AMPA receptor insertion, tying its scaffold function to synaptic plasticity and identifying PKC/palmitoylation as upstream regulators.\",\n      \"evidence\": \"Live imaging of GluA1 insertion events, dominant-negative peptide, GluA1 phospho/palmitoylation mutants, and LTP electrophysiology\",\n      \"pmids\": [\"19503082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How 4.1N couples GluA1 to exocytic machinery left open\", \"In vivo behavioral relevance not addressed in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the scaffolding role to kainate and nicotinic receptors, showing a common palmitoylation/PKC-regulated binding logic across receptor families.\",\n      \"evidence\": \"Co-IP, surface biotinylation, endocytosis and palmitoylation-mutant assays, and acute brain slice biochemistry for GluK2/GluK1 and α7 AChR\",\n      \"pmids\": [\"23400781\", \"23256752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-specific differences in regulation not reconciled\", \"Endogenous knockout validation limited\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a tumor-suppressive mechanism in which 4.1N recruits PP1 via its FERM domain to inactivate JNK–c-Jun signaling.\",\n      \"evidence\": \"Co-IP, PP1 activity assay, FERM-deletion mapping, knockdown/overexpression, and xenograft model in NSCLC\",\n      \"pmids\": [\"26575790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal validation across cancer types\", \"Direct PP1 dephosphorylation of JNK not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified IP6K2 as the determinant of 4.1N nuclear translocation and linked the interaction to cerebellar synapse and locomotor phenotypes in vivo.\",\n      \"evidence\": \"Co-IP, IP6K2 knockout mice, cerebellar histology, synaptic morphology, and behavioral assays\",\n      \"pmids\": [\"30006360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IP6K2 acts catalytically or structurally in nuclear import unknown\", \"Connection to PIKE/NuMA nuclear functions not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed an additional anti-tumor mechanism — direct binding and proteasomal degradation of 14-3-3 to block EMT and anoikis resistance — and an in vivo neuroendocrine requirement.\",\n      \"evidence\": \"Co-IP, ubiquitin-proteasome degradation assays, xenografts in EOC cells, and 4.1N knockout mouse neuroendocrine phenotyping\",\n      \"pmids\": [\"32448967\", \"33046791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking 4.1N to the 14-3-3 degradation machinery undefined\", \"Molecular basis of GnRH axonal trafficking defect not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the trafficking step controlled by 4.1N (exocytosis basally; both transport and exocytosis during plasticity), showed CaMKII phosphorylation builds the plasticity complex, and uncovered cell-type-specific synaptic dependence.\",\n      \"evidence\": \"Single-molecule live imaging with siRNA knockdown, phospho-specific Co-IP, interfering peptides, LTP electrophysiology, and cell-type-specific viral knockdown with domain rescue\",\n      \"pmids\": [\"37079350\", \"37993087\", \"37845032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why DG vs CA1 neurons differ in 4.1N dependence mechanistically unexplained\", \"Functional partition between 4.1N and SAP97 not fully delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated behavioral relevance, showing the 4.1N–GluA1 interaction is required for LTP and short-term spatial memory in vivo.\",\n      \"evidence\": \"Viral interfering GluA1 C80 peptide in CA1, LTP electrophysiology, and spatial memory testing\",\n      \"pmids\": [\"41417164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single interfering-peptide approach without genetic confirmation\", \"Selective effect on short- but not long-term memory mechanistically unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How 4.1N's distinct functional modes — membrane receptor scaffolding, nuclear cell-cycle/PI3K regulation, and tumor-suppressive PP1/14-3-3 signaling — are partitioned and switched within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating cytoplasmic, synaptic, and nuclear pools\", \"Structural basis for FERM-domain selection among diverse partners undefined\", \"Regulation of subcellular partitioning beyond NGF/IP6K2 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 6, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10, 11, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 18, 19, 20]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 10, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 12, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 13, 16]}\n    ],\n    \"complexes\": [\n      \"p-CaMKII–4.1N–GluA1 complex\",\n      \"IP3R1–4.1N–CASK–syndecan-2 complex\"\n    ],\n    \"partners\": [\n      \"GRIA1\",\n      \"ITPR1\",\n      \"GRIK2\",\n      \"NUMA1\",\n      \"PP1\",\n      \"YWHA (14-3-3)\",\n      \"IP6K2\",\n      \"FLOT1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}