{"gene":"LRP8","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2005,"finding":"ApoER2 (LRP8) is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors; Reelin signaling through ApoER2 enhances LTP through an alternatively spliced intracellular exon (exon 19) that is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits","method":"Co-immunoprecipitation, alternative splicing analysis, LTP electrophysiology, knock-in mice lacking the exon, behavioral testing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (biochemistry, electrophysiology, genetics, behavior) in a single rigorous study","pmids":["16102539"],"is_preprint":false},{"year":2000,"finding":"ApoER2 (but not VLDLR) binds JNK-interacting proteins JIP-1 and JIP-2 through its intracellular domain, assembling a multiprotein complex at the neuronal cell surface that may participate in ApoER2-specific Reelin signaling","method":"Co-immunoprecipitation, yeast two-hybrid, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal pulldowns with domain mapping, single lab","pmids":["10827199"],"is_preprint":false},{"year":2003,"finding":"Purified Reelin binds ApoER2 more readily than VLDLR and induces tyrosine phosphorylation of Dab1 through both receptors; ApoER2 and VLDLR are jointly essential for Reelin-induced Dab1 phosphorylation with no compensatory receptor","method":"Purified Reelin binding assays, cortical neuron cultures from single/double receptor knockout mice, Dab1 phosphorylation immunoblotting, layer-specific marker analysis","journal":"Brain research. Molecular brain research","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted binding with purified protein, genetic knockouts with multiple readouts, replicated across receptor combinations","pmids":["12670700"],"is_preprint":false},{"year":2007,"finding":"PCSK9 binds to ApoER2 (as well as LDLR and VLDLR) and induces its lysosomal degradation either by cellular co-expression or re-internalization of secreted PCSK9; membrane-bound PCSK9 chimeras greatly enhance receptor targeting to late endosomes/lysosomes; catalytic activity of PCSK9 is not required for degradation","method":"Co-expression experiments, secreted PCSK9 re-internalization assay, membrane-bound PCSK9 chimera constructs, lysosomal inhibitor studies, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple mechanistic dissections (catalytic mutants, chimeras, re-internalization) in a single study with strong controls","pmids":["18039658"],"is_preprint":false},{"year":2007,"finding":"ApoER2 in Sertoli cells is a selenoprotein P (Sepp1) receptor that mediates receptor-dependent uptake of selenium into the testis; co-immunoprecipitation confirmed ApoER2-Sepp1 interaction; ApoER2 knockout mice have sharply reduced testis selenium and identical sperm defects as Sepp1 knockout mice","method":"Sepp1 affinity chromatography + mass spectrometry, co-immunoprecipitation, in situ hybridization, selenium measurement in ApoER2-/- mice, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — affinity chromatography/MS identification confirmed by Co-IP, validated in vivo with knockout mice showing matching phenotypes","pmids":["17314095"],"is_preprint":false},{"year":2010,"finding":"The E3 ubiquitin ligase IDOL induces ubiquitination of ApoER2 (and VLDLR) on their cytoplasmic tails, leading to their lysosomal degradation; LXR activation increases IDOL expression and decreases ApoER2/VLDLR levels; reduced IDOL-dependent ApoER2 levels decrease Reelin-induced Dab1 phosphorylation","method":"Ubiquitination assays, immunoblotting, siRNA knockdown, pharmacological LXR activation in mice, Dab1 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct ubiquitination demonstrated biochemically, confirmed in vivo; functional consequence on Reelin signaling shown","pmids":["20427281"],"is_preprint":false},{"year":2012,"finding":"ApoE-secreted by melanoma cells suppresses metastatic endothelial recruitment by engaging endothelial cell LRP8 receptors; miR-1908, miR-199a-5p, and miR-199a-3p convergently target ApoE, and their inhibition suppresses LRP8-mediated angiogenesis","method":"In vivo selection, locked nucleic acid (LNA) inhibition, cancer cell-endothelial co-culture assays, receptor-specific functional studies","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo validation with LNA treatment and functional receptor engagement, single lab","pmids":["23142051"],"is_preprint":false},{"year":2008,"finding":"Activated protein C (APC) binds directly to ApoER2 (LRP8) with ~30 nM affinity (surface plasmon resonance) and signals via Dab1 Tyr-220 phosphorylation, followed by PI3K/Akt activation and GSK3β Ser-9 phosphorylation; siRNA knockdown of ApoER2 ablates APC-induced Dab1 phosphorylation","method":"Surface plasmon resonance, siRNA knockdown, phospho-specific immunoblotting, kinase inhibitors, receptor-associated protein (RAP) competition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding measured by SPR, mechanistic pathway confirmed by siRNA and pharmacological inhibitors with multiple readouts","pmids":["19116273"],"is_preprint":false},{"year":2010,"finding":"In antiphospholipid syndrome, aPL antibodies bind β2GPI which dimerizes and engages ApoER2 on endothelial cells; this activates PP2A which dephosphorylates eNOS at Ser1179, suppressing NO production; ApoER2-/- mice are protected from aPL-induced thrombosis and leukocyte-endothelial adhesion","method":"Endothelial cell culture, RAP competition, ApoER2 knockout mice, eNOS phosphorylation immunoblotting, PP2A activity assays, intravital microscopy","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection in cells and validated in ApoER2-/- mice with multiple functional readouts","pmids":["21123944"],"is_preprint":false},{"year":2018,"finding":"In endothelial cells, the ApoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly of heterotrimeric PP2A: Dab2 recruits to the NPXY motif and promotes L309 methylation (activation) of PP2A catalytic subunit via LCMT-1; SHC1 recruits scaffolding and regulatory PP2A subunits to the proline-rich C-terminus, mediating dephosphorylation of Akt and eNOS","method":"Co-immunoprecipitation, domain-specific mutants, siRNA knockdown, endothelial cell signaling assays, in vivo thrombosis model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — detailed mechanistic dissection of protein complex assembly with domain-specific interactions and in vivo validation","pmids":["29500169"],"is_preprint":false},{"year":2005,"finding":"F-spondin interacts with ApoER2 through F-spondin's thrombospondin domain and ApoER2's ligand-binding domain (co-immunoprecipitation); F-spondin increases surface expression of APP and ApoER2, and shifts APP processing away from amyloidogenic β-secretase cleavage; this requires the ApoER2 receptor (blocked by RAP)","method":"Co-immunoprecipitation, surface biotinylation, APP CTF measurement, Aβ ELISA, primary neurons","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple biochemical readouts in transfected cells and neurons, receptor dependence confirmed by RAP","pmids":["16227578"],"is_preprint":false},{"year":2006,"finding":"FE65 adaptor protein interacts with ApoER2 via its N-terminal PTB domain, bridges a complex with APP, increases surface expression of ApoER2, and affects proteolytic processing of both ApoER2 and APP (increasing secreted forms while decreasing Aβ); both PTB domains of FE65 are required for full effect","method":"Co-immunoprecipitation in COS7 cells, surface biotinylation, CTF/secreted protein immunoblotting, Aβ measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain mapping with multiple functional readouts, single lab","pmids":["16638748"],"is_preprint":false},{"year":2005,"finding":"ApoER2 is endocytosed via a clathrin-mediated pathway dependent on the cytoplasmic FxNPXY motif and the adaptor protein Dab2; dominant-negative eps15 and Dab2 reduce ApoER2 internalization; caveolar/raft pathway is not required despite ApoER2 association with rafts","method":"Endocytosis assays, dominant-negative constructs (eps15, Dab2), nystatin treatment (caveolar inhibition), FxNPXY mutant analysis","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 — multiple inhibitory approaches (genetic and pharmacological) with domain-specific mutagenesis converge on same conclusion","pmids":["16101684"],"is_preprint":false},{"year":2007,"finding":"ApoER2 (but not VLDLR) controls migration of late-generated neocortical neurons; fate mapping in single and double receptor knockout mice shows VLDLR mediates a stop signal for migrating neurons while ApoER2 is essential for migration of late-born neurons","method":"BrdU fate mapping, layer-specific marker immunostaining, single and double receptor knockout mice","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with fate mapping distinguishing receptor-specific roles","pmids":["17913789"],"is_preprint":false},{"year":2009,"finding":"ApoER2 sorting to lipid raft domains (vs. VLDLR in non-raft domains) determines receptor fate upon Reelin stimulation: raft-associated ApoER2 produces specific receptor fragments and undergoes lysosomal degradation after Reelin binding; non-raft VLDLR internalizes Reelin for degradation without significant receptor degradation","method":"Chimeric receptor panel, lipid raft fractionation, endocytosis assays, receptor fragment tracking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — chimeric receptor approach with raft fractionation provides mechanistic insight into differential sorting","pmids":["19948739"],"is_preprint":false},{"year":2008,"finding":"Thrombospondin-1 (THBS-1) is a novel physiological ligand for ApoER2 and VLDLR; it binds both receptors and induces Dab1 phosphorylation but (unlike Reelin) does not induce Dab1 degradation or Akt phosphorylation; THBS-1 stabilizes neuronal precursor chains in rostral migratory stream independently of Reelin","method":"Ligand binding assays, Dab1 phosphorylation immunoblotting, SVZ explant chain formation assays, THBS-1 knockout mice analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding demonstrated, differential signaling compared to canonical ligand shown biochemically, functional in vitro and in vivo validation","pmids":["18946489"],"is_preprint":false},{"year":2013,"finding":"Clusterin binds to ApoER2 and VLDLR, is internalized by receptor-expressing cells, and triggers Reelin-like signaling: inducing Dab1 phosphorylation, PI3K/Akt activation, and n-cofilin activation; clusterin blockade impairs neuroblast chain formation in SVZ explants","method":"Binding/internalization assays, Dab1 phosphorylation immunoblotting, Akt phosphorylation, SVZ explant assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding and functional signaling cascade demonstrated, single lab","pmids":["24381170"],"is_preprint":false},{"year":2021,"finding":"The E2-E1 glycoproteins of multiple alphaviruses (Semliki forest virus, EEEV, Sindbis) bind to the ligand-binding domains of ApoER2 (and VLDLR), mediating viral attachment and internalization; a VLDLR LBD-Fc fusion protein blocks alphavirus infection in neurons and protects mice from lethal SFV challenge","method":"CRISPR knockout screens, virus-like particle internalization assays, neutralization with LBD-Fc fusion protein, in vivo mouse challenge model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding shown, genetic loss-of-function, in vivo protection model; multiple orthogonal methods","pmids":["34929721"],"is_preprint":false},{"year":2007,"finding":"ApoER2 physically interacts with APP and increases cell surface APP levels and APP association with lipid rafts by decreasing APP internalization rate; ApoER2 expression also increases γ-secretase activity and Aβ production; the ApoER2 NPxY motif is required for increased Aβ production","method":"Co-immunoprecipitation, surface biotinylation, APP internalization rate measurement, lipid raft fractionation, γ-secretase activity assay, Aβ ELISA, NPxY mutant analysis","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays with domain-specific mutants, single lab","pmids":["17620134"],"is_preprint":false},{"year":2012,"finding":"LRP8 positively regulates canonical Wnt/β-catenin signaling: ectopic LRP8 expression increases Wnt-induced β-catenin accumulation and transcriptional responses; LRP8 knockdown decreases β-catenin levels and suppresses Wnt target gene (Axin2) transcription; LRP8 depletion impairs osteoblast differentiation and mineralization","method":"siRNA knockdown, Wnt transcriptional reporter assay, β-catenin immunoblotting, Axin2 RT-PCR, osteoblast differentiation assay (KS483 cells), mineralization assay","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss of function with multiple readouts; pathway placement via reporter assay","pmids":["22589174"],"is_preprint":false},{"year":2009,"finding":"Factor XI (FXI) is identified as a ligand for platelet ApoER2; platelet adhesion to immobilized FXI is blocked by RAP, soluble recombinant ApoER2, or ApoER2 LDL-binding domains 1-2; ApoER2-deficient murine platelets fail to adhere to FXI; soluble FXI binds immobilized ApoER2 with ~61 nM affinity","method":"Platelet adhesion assay, RAP competition, soluble receptor domain competition, ApoER2 knockout mouse platelets, surface plasmon resonance","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding by SPR, receptor-specific knockout phenotype, domain competition; multiple approaches converge","pmids":["19661487"],"is_preprint":false},{"year":2005,"finding":"β2-glycoprotein I (β2GPI) domain V contains the binding site for ApoER2 on platelets; deletion of domain V abrogates β2GPI interaction with ApoER2 and platelet activation on collagen; domains I and II are dispensable for ApoER2 interaction","method":"Domain deletion mutants of β2GPI, immunoprecipitation with platelet ApoER2, platelet adhesion assay, whole blood flow assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping by deletion mutagenesis confirmed by immunoprecipitation and functional platelet assay","pmids":["16091370"],"is_preprint":false},{"year":2015,"finding":"Reelin binding to LRP8 triggers γ-secretase-dependent cleavage of LRP8, releasing its intracellular domain (ICD) which participates in a synapse-to-nucleus pathway to activate neuronal enhancers (LRN enhancers) governing synaptic plasticity genes; LRP8 ICD serves as a nuclear signal for chromatin remodeling during memory formation","method":"Chromatin immunoprecipitation (ChIP), enhancer profiling, γ-secretase inhibition, LRP8 knockdown, in vivo memory behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP, pharmacological, genetic) with in vivo behavioral validation","pmids":["25892301"],"is_preprint":false},{"year":2013,"finding":"Presenilin-1 (γ-secretase) processes ApoER2 sequentially (α- then γ-secretase), producing an intracellular C-terminal fragment (ICD); this ApoER2-ICD binds to the RELN promoter and suppresses reelin expression at the transcriptional level; PS1 conditional knockout mice show increased ApoER2 and reelin protein","method":"PS1 conditional knockout mice, γ-secretase inhibitor treatment, luciferase reporter assay, nuclear fractionation, chromatin immunoprecipitation (ChIP)","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP confirms direct promoter binding by ApoER2 ICD; genetic and pharmacological approaches with in vivo validation","pmids":["24344333"],"is_preprint":false},{"year":2014,"finding":"Sorting nexin 17 (SNX17) interacts with the NPxY endocytosis motif of ApoER2 via SNX17's FERM domain (GST pull-down, co-immunoprecipitation) and promotes ApoER2 recycling from early to recycling endosomes without affecting endocytic rate; SNX17 knockdown increases Reelin-induced ApoER2 degradation and impairs dendritic development and Reelin signaling in neurons","method":"GST pull-down, co-immunoprecipitation, endosomal trafficking assays, SNX17 siRNA knockdown, dendritic morphology analysis, Reelin-Dab1 phosphorylation assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct physical interaction mapped, trafficking assay with functional signaling readout, single lab","pmids":["24705369"],"is_preprint":false},{"year":2014,"finding":"Differential splicing (exon 16 encoding O-linked sugar domain) and glycosylation of ApoER2 alters its extracellular cleavage, γ-secretase-dependent ICD release, synaptic abundance, spine density, and fear memory; OLS-deficient ApoER2 has reduced ectodomain shedding preventing ICD release","method":"Splice variant knock-in mice, electrophysiology (LTP), spine density analysis, behavioral testing (Morris water maze, fear conditioning), biochemical cleavage assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — genetic knock-in model with multiple biochemical and functional phenotypes","pmids":["25429077"],"is_preprint":false},{"year":2016,"finding":"An antisense oligonucleotide (ASO) that increases ApoER2 exon 19 splicing corrects deregulated ApoER2 splicing in AD mouse brain, improving synaptic function and learning/memory; exon 19 splicing is deregulated in human AD brain postmortem","method":"ASO treatment in transgenic AD mice, LTP electrophysiology, behavioral testing (learning and memory), RT-PCR splice analysis in human postmortem brain","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — therapeutic rescue experiment in vivo with electrophysiological and behavioral readouts; splicing mechanism established","pmids":["26902204"],"is_preprint":false},{"year":2014,"finding":"ApoE3 binding to ApoER2 on endothelial cells stimulates eNOS and endothelial cell migration, and attenuates monocyte-endothelial adhesion; ApoE4 (due to its N-to-C terminal interaction) does not stimulate eNOS and acts as dominant-negative antagonist of ApoE3/ApoER2 actions; ApoER2-R952Q is a loss-of-function receptor variant in endothelium","method":"eNOS activity assays, endothelial cell migration assays, ApoER2-/- mice, adenoviral ApoE3/E4 expression, carotid reendothelialization model, neointima formation model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple in vitro and in vivo mechanistic approaches, isoform-specific functional dissection","pmids":["25197062"],"is_preprint":false},{"year":2009,"finding":"Differential functions of ApoER2 intracellular signaling motifs and selenium uptake can be dissociated: knock-in mice with disrupted signaling motifs in the Apoer2 cytoplasmic domain maintain normal selenium in brain and testis, confirming that neurological defects in signaling-impaired mice are due to disrupted Reelin signaling, not selenium deficiency","method":"Knock-in mice (cytoplasmic domain signaling motif mutations), selenium measurement in tissues, sperm motility analysis","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — genetic dissection using knock-in mice with defined domain mutations separating two functions","pmids":["19007311"],"is_preprint":false},{"year":2012,"finding":"ApoER2 mediates selenium uptake from selenoprotein P (Sepp1) in L8 myoblast cells via an endocytosis mechanism requiring heparin sulfate proteoglycan binding and the selenium-rich C-terminal domain of Sepp1; siRNA knockdown of ApoER2 (but not LRP1) inhibits 75Se uptake; lysosome acidification is required for Sepp1 digestion and selenium utilization","method":"Sepp1 affinity column + mass spectrometry, siRNA knockdown, 75Se-labeled Sepp1 uptake assay, lysosomal acidification inhibitors, heparin competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — receptor identified by MS, validated by siRNA; mechanism dissected with domain-specific and pharmacological approaches","pmids":["22761431"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the full-length ApoER2 ectodomain complexed with a signaling-competent Reelin fragment reveals an intermediate contracted-open conformation distinct from ligand-unbound LDLR; an auxiliary low-affinity binding interface is identified; pH-dependent weakening of this interface during endocytosis destabilizes the complex for ligand release","method":"X-ray crystallography, mutagenesis of binding interfaces, pH-dependent binding assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis and functional pH-dependent assay","pmids":["28446613"],"is_preprint":false},{"year":2015,"finding":"ApoER2 and Reelin are expressed in peripheral nerve and regulate Schwann cell migration by activating the Rac1 GEF Tiam1; Reelin induces Rac1 activation at the leading edge of SCs (FRET assay); Tiam1 and PAR3 are required for Reelin-induced SC migration; PAR3 binds preferentially to the full-length ApoER2 cytoplasmic tail containing the exon 19-encoded proline-rich insert","method":"FRET-based Rac1 activation assay, siRNA knockdown of Tiam1/PAR3, sciatic nerve injury model, ApoER2 domain-specific binding assays","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — FRET assay for direct GTPase activation, domain-specific binding, functional migration assay with knockdown","pmids":["26386179"],"is_preprint":false},{"year":2017,"finding":"GRIP1 binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors at the postsynapse; neuronal activity induces ephrinB2 Ser-9 phosphorylation which stabilizes the complex; mutation of ephrinB2 Ser-9 disrupts complex formation, abolishes ApoER2 downstream signaling, and impairs activity-induced AMPA receptor insertion and LTP","method":"Co-immunoprecipitation, phospho-mutant knock-in mice, compound genetics, LTP electrophysiology, AMPA receptor surface insertion assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — complex identified biochemically, functional role confirmed by phospho-mutant knock-in with electrophysiology","pmids":["28978486"],"is_preprint":false},{"year":2017,"finding":"The E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation; IDOL-dependent changes in ApoER2 regulate dendritic spine morphogenesis, filopodia initiation, synapse maturation, and LTP; IDOL-deficient mice show impaired experience-dependent synaptic remodeling and spatial/associative learning","method":"IDOL knockout mice, LTP electrophysiology in slices and primary neurons, dendritic spine imaging, barrel cortex plasticity assay, behavioral tests","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — genetic loss-of-function with multiple functional phenotypes (electrophysiology, morphology, behavior), replication of IDOL-ApoER2 regulatory relationship","pmids":["28891791"],"is_preprint":false},{"year":2019,"finding":"ApoER2 interacts with the catalytic subunit of PP2A (co-immunoprecipitation); in the absence of ApoER2, PP2A-C fails to interact with CDC20, resulting in inactive anaphase-promoting complex (APC/CDC20), cell cycle arrest at metaphase/anaphase, impaired cytokinesis, and premature smooth muscle cell senescence","method":"Co-immunoprecipitation, cell cycle protein immunoblotting, β-galactosidase senescence assay, p16INK4a immunofluorescence, multinucleated cell counting, Lrp8-/- mouse vascular injury model","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP establishes interaction, functional consequence in knockout cells/mice; single lab","pmids":["31412739"],"is_preprint":false},{"year":2019,"finding":"SFRS11 RNA-binding protein directly binds LRP8 mRNA 3' UTR, stabilizing it; SFRS11 deficiency in the prefrontal cortex reduces LRP8 and apoE mRNA levels, activates JNK signaling, and causes learning/memory deficits; restoration of LRP8 and apoE reduces JNK activation and rescues aging-like phenotypes","method":"RNA immunoprecipitation (RIP), 3' UTR binding assay, SFRS11 knockdown in PFC, JNK signaling immunoblotting, behavioral tests","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-protein interaction demonstrated by RIP, functional rescue experiment with in vivo behavioral readout","pmids":["31269452"],"is_preprint":false},{"year":2023,"finding":"LRP8 is identified as a CRISPR-activation screen hit protecting MYCN-amplified neuroblastoma from ferroptosis; LRP8 deletion causes ferroptosis by reducing selenoprotein P (SELENOP) uptake, insufficient selenocysteine supply for GPX4 translation; this is caused by low expression of alternative selenium uptake pathways (system Xc-)","method":"CRISPR-activation screen, LRP8 knockout (constitutive and inducible), xenograft models, selenoprotein/GPX4 immunoblotting, ferroptosis cell death assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 — genome-scale screen followed by constitutive and inducible KO with mechanistic link to GPX4 via selenocysteine supply, in vivo xenograft validation","pmids":["37435859"],"is_preprint":false},{"year":2025,"finding":"LRP8 is identified as a receptor for tick-borne encephalitis virus (TBEV) by genome-scale CRISPR-Cas9 screen; LRP8 binds directly to TBEV E glycoprotein and mediates viral attachment and internalization; LRP8 downregulation reduces TBEV infection; an LRP8-based soluble decoy blocks TBEV infection in human cell lines, neuronal cells, and protects mice from lethal TBEV challenge","method":"Genome-scale CRISPR-Cas9 screen, LRP8 overexpression/knockdown infection assays, direct binding assay (E glycoprotein), LRP8-based decoy receptor, in vivo mouse challenge","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — genome-scale screen, direct binding shown, gain/loss of function, in vivo validation with decoy protection","pmids":["40993380"],"is_preprint":false},{"year":2019,"finding":"In the off-state, ApoER2 and VLDLR form homo- or hetero-oligomers; full-length Reelin binding rearranges ApoER2 homo-oligomers into higher-order receptor clusters, leading to Dab1 phosphorylation; the Reelin central fragment does not increase cluster size or induce Dab1 phosphorylation but can induce hetero-oligomerization and cell shape changes via an alternative Dab1-independent mechanism","method":"Time-resolved anisotropy, fluorescence lifetime imaging microscopy (FLIM), FRET-based receptor oligomerization analysis in HEK293 cells","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 1 — advanced optical methods (FLIM/FRET) used to directly measure receptor oligomerization dynamics; single lab","pmids":["30873003"],"is_preprint":false},{"year":2014,"finding":"Neurotrophins regulate ApoER2 proteolysis: TrkA activation by NGF in PC12 cells induces ApoER2 ectodomain shedding (metalloproteinase-dependent); TrkB activation by BDNF similarly induces ApoER2 proteolysis in cortical neurons; this effect is independent of MAPK and PI3K activity","method":"Pharmacological TrkA/TrkB activation, metalloproteinase inhibitors, MAPK/PI3K inhibitors, ApoER2 shedding immunoblotting, primary cortical neurons","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological dissection of signaling pathway with multiple inhibitors; single lab","pmids":["25233900"],"is_preprint":false},{"year":2023,"finding":"A high-affinity ApoER2 variant in Jurkat cells (with highly glycosylated O-linked sugar domain, Kd ~0.67 nM) mediates selenium transport from selenoprotein P (SeP) via a Sec lyase-independent mechanism requiring vesicle acidification; in contrast, low-affinity ApoER2 variants use a Sec lyase-dependent lysosomal degradation mechanism","method":"Binding affinity measurements (Kd determination), siRNA knockdown, Sec lyase inhibitor, lysosomal acidification inhibitors, 75Se uptake assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — quantitative binding measurements with mechanistic dissection of two distinct transport routes; single lab","pmids":["37406814"],"is_preprint":false},{"year":2009,"finding":"Splice variants of ApoER2 differ in ligand-binding domain composition: ApoER2-LA1237 binds Reelin central fragment more strongly than the RR8-containing fragment, whereas ApoER2-LA12378 binds comparably to all Reelin fragments lacking the C-terminal region; LA8 of ApoER2 and Reelin repeat 8 interfere with central fragment-ApoER2 binding","method":"Quantitative binding assays with purified Reelin fragments and ApoER2 variants, monoclonal antibody specific for LA12378 isoform, in situ expression analysis","journal":"Neuroscience research","confidence":"Medium","confidence_rationale":"Tier 1-2 — quantitative binding with defined protein fragments; single lab","pmids":["19167437"],"is_preprint":false},{"year":2022,"finding":"Human APOER2 isoforms lacking exons 5-8 (Δex5-8) generate the highest CTF amounts and those lacking exons 4-6 (Δex4-6) the lowest in response to APOE, correlating with ICD-mediated transcriptional activation; Apoer2 knockout neurons show decreased miniature excitatory event frequency, restored by lentiviral APOER2-FL or Δex4-6 but not Δex5-8 isoform","method":"Gene-specific long-read sequencing (25 isoform identification), CTF immunoblotting, ICD transcriptional reporter assay, miniature excitatory event recording in Apoer2-KO neurons, lentiviral rescue","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 1-2 — comprehensive isoform survey with functional rescue electrophysiology; single lab","pmids":["35414534"],"is_preprint":false},{"year":2013,"finding":"CIN85 (multi-adaptor protein) colocalizes with ApoER2 in neurons in a Dab1-mediated manner; Reelin stimulation increases CIN85-ApoER2 colocalization and recruits CIN85 from plasma membrane domains to EEA1-positive early endosomes; Tyr phosphorylation of Dab1 strengthens CIN85 binding","method":"Co-immunoprecipitation, immunofluorescence colocalization, Reelin stimulation assay, early endosome marker co-staining","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP and imaging-based colocalization with functional Reelin stimulation; single lab","pmids":["23506116"],"is_preprint":false},{"year":2008,"finding":"LRP8-deficient mice show reduced platelet activation in response to ADP or thrombin and prolonged carotid artery occlusion time (in vivo thrombosis); lipidated apoE3 inhibits platelet activation in a dose-dependent and largely LRP8-dependent manner; LRP8 function in thrombosis is partly apoE-independent","method":"Flow cytometry, aggregometry, intravital microscopy (carotid FeCl3 injury), tail bleeding assay, LRP8-/- and LRP8+/- mice","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with multiple in vitro and in vivo functional platelet/thrombosis readouts; single lab","pmids":["18706682"],"is_preprint":false},{"year":2016,"finding":"The ApoER2/Dab1 interaction with PSD95 maintains stable dendritic architecture in mature hippocampal neurons; expression of a tailless ApoER2 mutant (unable to interact with PSD95) increases dendritogenesis and reduces spine density in mature neurons; interference reduces synaptic PSD95 and leads to synaptic re-insertion of NR2B-containing NMDARs","method":"Mutant ApoER2 (tailless) overexpression in mature hippocampal neurons, dendritic morphology analysis (in vitro and in vivo), PSD95 immunofluorescence, NMDAR subunit analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — dominant-negative receptor approach with in vitro and in vivo morphological readouts; single lab","pmids":["27653801"],"is_preprint":false},{"year":2021,"finding":"Protein phosphatase 2A (PP2A) activation via ApoER2 in trophoblasts drives preeclampsia in a mouse model of antiphospholipid syndrome, extending the apoER2-PP2A signaling axis to placental biology","method":"Mouse model of APS-related preeclampsia, ApoER2-specific genetic and pharmacological interventions","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model; single lab extending established ApoER2-PP2A mechanism to new cell type","pmids":["34404233"],"is_preprint":false}],"current_model":"LRP8 (ApoER2) is a multifunctional type I transmembrane receptor of the LDL receptor family that acts as a signal transduction hub: it binds Reelin (and alternative ligands including thrombospondin-1, clusterin, selenoprotein P, activated protein C, FXI, and viral glycoproteins) to assemble signaling complexes at the plasma membrane involving Dab1 phosphorylation, PI3K/Akt activation, and NMDA receptor modulation for neuronal migration and synaptic plasticity; undergoes regulated proteolytic cleavage (ectodomain shedding by metalloproteinases followed by γ-secretase) to release a transcriptionally active ICD that controls reelin expression and neuronal enhancers; mediates selenium transport via selenoprotein P endocytosis into brain and testis; in endothelial cells and platelets activates a PP2A-dependent pathway to regulate eNOS and thrombosis; is subject to post-translational degradation by PCSK9 and the E3 ligase IDOL; and is subject to extensive alternative splicing that critically modifies its ligand binding, proteolytic processing, and synaptic functions."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying ApoER2-specific cytoplasmic interactors established that LRP8 assembles signaling scaffolds distinct from VLDLR, revealing JIP-1/JIP-2 as intracellular binding partners that could link ApoER2 to JNK-dependent signaling cascades.","evidence":"Yeast two-hybrid and co-immunoprecipitation with domain mapping in neuronal cells","pmids":["10827199"],"confidence":"Medium","gaps":["Functional consequence of JIP binding on Reelin signaling not tested","No in vivo confirmation of ApoER2-JIP complex relevance"]},{"year":2003,"claim":"Demonstrating that purified Reelin binds ApoER2 with higher affinity than VLDLR and that both receptors jointly mediate Dab1 phosphorylation established the cooperative yet non-redundant receptor model for Reelin signaling.","evidence":"Purified Reelin binding assays with cortical neurons from single and double receptor knockout mice, Dab1 phosphorylation immunoblotting","pmids":["12670700"],"confidence":"High","gaps":["Structural basis for differential Reelin affinity between receptors unknown at this time","Downstream pathway divergence between receptors not fully resolved"]},{"year":2005,"claim":"Four contemporaneous studies established fundamental aspects of ApoER2 cell biology: its postsynaptic localization with NMDA receptors and dependence on exon 19 for LTP; its clathrin-dependent endocytosis via Dab2 and the NPxY motif; and its interaction with F-spondin and β2GPI domain V, broadening the receptor's ligand repertoire and signaling contexts.","evidence":"Co-immunoprecipitation, LTP electrophysiology, exon 19 knock-in mice, endocytosis assays with dominant-negative constructs, platelet adhesion assays with domain-deletion mutants","pmids":["16102539","16101684","16227578","16091370"],"confidence":"High","gaps":["How exon 19 structurally couples ApoER2 to NMDA receptor tyrosine phosphorylation machinery was unclear","Whether Dab2-mediated endocytosis is the sole internalization route in all cell types"]},{"year":2007,"claim":"Three advances expanded ApoER2 function beyond brain signaling: identification as the testicular selenoprotein P receptor mediating selenium uptake; discovery that PCSK9 targets ApoER2 for lysosomal degradation independently of catalytic activity; demonstration that ApoER2 (not VLDLR) specifically controls late-born neuronal migration; and that ApoER2 interacts with APP to modulate Aβ production.","evidence":"Affinity chromatography/MS identification of Sepp1 receptor confirmed by ApoER2-KO mice with selenium deficiency; PCSK9 chimeras and catalytic mutants; BrdU fate mapping in single/double KO mice; co-IP and surface biotinylation with APP processing assays","pmids":["17314095","18039658","17913789","17620134"],"confidence":"High","gaps":["Mechanism of selenium release from Sepp1 after ApoER2-mediated endocytosis not established","Whether PCSK9-mediated ApoER2 degradation occurs in neurons in vivo","Relative contribution of ApoER2-APP interaction to AD pathogenesis unclear"]},{"year":2008,"claim":"Identification of thrombospondin-1 and activated protein C as new ApoER2 ligands revealed ligand-specific signaling diversity: THBS-1 induces Dab1 phosphorylation without degradation or Akt activation, while APC signals through Dab1-Y220/PI3K/Akt/GSK3β, establishing ApoER2 as a context-dependent signaling hub.","evidence":"Direct binding assays, SVZ explant chain assays with THBS-1-KO mice; SPR binding (Kd ~30 nM for APC), siRNA knockdown, kinase inhibitor dissection","pmids":["18946489","19116273","18706682"],"confidence":"High","gaps":["How different ligands activate distinct downstream cascades through the same receptor is mechanistically unexplained","In vivo significance of APC-ApoER2 axis in neuroprotection not fully tested"]},{"year":2009,"claim":"Genetic dissection using cytoplasmic domain knock-in mice showed that ApoER2's selenium transport and Reelin signaling functions are separable, resolving whether neurological phenotypes arise from selenium deficiency or impaired Reelin signaling. Concurrently, Factor XI was identified as a platelet ApoER2 ligand, and splice variant-specific Reelin binding profiles were characterized.","evidence":"Knock-in mice with signaling motif mutations retaining normal tissue selenium; SPR showing FXI binds ApoER2 with ~61 nM affinity confirmed by KO platelet adhesion assays; quantitative binding with purified Reelin fragments and ApoER2 splice variants","pmids":["19007311","19661487","19167437","19948739"],"confidence":"High","gaps":["Whether selenium transport requires specific splice variants of ApoER2 unknown","In vivo thrombotic consequence of FXI-ApoER2 interaction not fully characterized"]},{"year":2010,"claim":"Two discoveries established post-translational regulatory mechanisms controlling ApoER2 surface levels: the E3 ligase IDOL ubiquitinates ApoER2 for lysosomal degradation under LXR control, directly modulating Reelin signaling; and β2GPI-aPL antibody engagement of endothelial ApoER2 activates PP2A to dephosphorylate eNOS, identifying a pathogenic signaling axis in antiphospholipid syndrome with thrombosis protection in ApoER2-KO mice.","evidence":"Ubiquitination assays and LXR activation in vivo; ApoER2-KO mice with intravital microscopy and PP2A activity assays","pmids":["20427281","21123944"],"confidence":"High","gaps":["Whether IDOL regulation of ApoER2 occurs in neurons with physiological relevance to Reelin was not yet tested","Cell-type specificity of PP2A assembly on ApoER2 tail unknown"]},{"year":2012,"claim":"Three findings expanded ApoER2's cellular roles: muscle cell selenium uptake via Sepp1 endocytosis requiring lysosomal acidification; positive regulation of Wnt/β-catenin signaling affecting osteoblast differentiation; and endothelial ApoE-mediated angiogenic control through LRP8.","evidence":"75Se-Sepp1 uptake with siRNA and lysosomal inhibitors in L8 myoblasts; Wnt reporter and osteoblast mineralization assays; in vivo LNA inhibition and cancer-endothelial co-culture","pmids":["22761431","22589174","23142051"],"confidence":"Medium","gaps":["Structural basis for ApoER2 participation in Wnt signaling unclear","Whether LRP8-Wnt interaction is direct or through co-receptor mechanisms unknown"]},{"year":2013,"claim":"The discovery that γ-secretase cleavage of ApoER2 produces an ICD that binds the RELN promoter and suppresses reelin transcription established a negative feedback loop in Reelin signaling; concurrently, CIN85 was identified as a Dab1-dependent adaptor recruited to ApoER2-positive early endosomes.","evidence":"ChIP showing ICD binding to RELN promoter, PS1 conditional KO mice, luciferase reporter; co-IP and immunofluorescence colocalization with Reelin stimulation","pmids":["24344333","23506116","24381170"],"confidence":"High","gaps":["Whether ICD-mediated RELN repression operates in all brain regions","CIN85 functional role in ApoER2 trafficking vs. signaling not resolved"]},{"year":2014,"claim":"Multiple studies refined ApoER2's splicing-dependent functions and trafficking: O-linked sugar domain splicing (exon 16) controls ectodomain shedding, ICD release, spine density, and fear memory; SNX17 promotes ApoER2 recycling via the NPxY motif; neurotrophin-TrkB signaling induces ApoER2 shedding independently of MAPK/PI3K; and ApoE isoform-specific signaling through endothelial ApoER2 reveals ApoE4 as a dominant-negative antagonist.","evidence":"Splice variant knock-in mice with behavioral/electrophysiological phenotypes; GST pull-down and trafficking assays; pharmacological TrkA/TrkB dissection; eNOS assays with ApoER2-KO mice and carotid reendothelialization model","pmids":["25429077","24705369","25233900","25197062"],"confidence":"High","gaps":["How O-linked glycosylation mechanistically regulates metalloproteinase access for shedding","Whether neurotrophin-induced shedding occurs in vivo and its functional significance"]},{"year":2015,"claim":"The synapse-to-nucleus signaling model was completed by demonstrating that Reelin-triggered γ-secretase release of the ApoER2 ICD activates neuronal enhancers (LRN enhancers) controlling synaptic plasticity genes during memory formation; separately, Reelin-ApoER2 was shown to regulate Schwann cell migration through Rac1/Tiam1/PAR3.","evidence":"ChIP with enhancer profiling, γ-secretase inhibition, LRP8 knockdown, in vivo behavioral assays; FRET-based Rac1 activation and siRNA knockdown in Schwann cells","pmids":["25892301","26386179"],"confidence":"High","gaps":["Identity of transcription factors cooperating with ApoER2 ICD at LRN enhancers unknown","Whether ApoER2 ICD genomic targets differ between brain regions"]},{"year":2016,"claim":"Two studies connected ApoER2 splicing and postsynaptic scaffolding to disease-relevant function: antisense oligonucleotides correcting exon 19 splicing rescued synaptic and memory deficits in AD mice, and disruption of ApoER2/Dab1/PSD95 interaction destabilized dendritic architecture and reintroduced immature NR2B-NMDARs.","evidence":"ASO treatment with LTP and behavioral rescue in AD mouse model; tailless ApoER2 mutant with dendritic morphology and NMDAR subunit analysis","pmids":["26902204","27653801"],"confidence":"Medium","gaps":["Mechanism by which exon 19 mis-splicing occurs in AD brain not identified","Whether ASO approach is viable for human therapeutic development"]},{"year":2017,"claim":"Three advances provided structural and mechanistic depth: the crystal structure of the ApoER2 ectodomain–Reelin complex revealed a contracted-open conformation with pH-dependent ligand release; IDOL was shown to regulate synaptic ApoER2 levels for experience-dependent spine remodeling and LTP; and GRIP1 was found to bridge ApoER2 with ephrinB2 and AMPA receptors in an activity-dependent postsynaptic complex essential for LTP.","evidence":"X-ray crystallography with mutagenesis and pH-binding assays; IDOL-KO mice with spine imaging, barrel cortex plasticity, and behavioral tests; phospho-mutant knock-in mice with co-IP and LTP electrophysiology","pmids":["28446613","28891791","28978486"],"confidence":"High","gaps":["Full-length Reelin–receptor complex structure not yet available","How IDOL activity is regulated by neuronal firing patterns unknown"]},{"year":2018,"claim":"Detailed dissection of the ApoER2 cytoplasmic tail as a PP2A scaffolding platform in endothelial cells revealed that Dab2 recruits to NPxY to activate PP2A-C via LCMT-1 methylation, while SHC1 recruits PP2A regulatory subunits to the proline-rich C-terminus, mediating aPL-induced eNOS and Akt dephosphorylation.","evidence":"Domain-specific mutants, co-IP, siRNA knockdown, in vivo thrombosis model","pmids":["29500169"],"confidence":"High","gaps":["Whether this PP2A assembly mechanism operates identically in platelets and trophoblasts","Structural basis for the bipartite PP2A recruitment unknown"]},{"year":2019,"claim":"Three studies addressed receptor oligomerization dynamics, cell cycle regulation, and post-transcriptional control: Reelin rearranges ApoER2 homo-oligomers into higher-order clusters required for Dab1 phosphorylation; ApoER2 scaffolds PP2A-CDC20 interaction for APC activation and smooth muscle cell cycle progression; and SFRS11 stabilizes LRP8 mRNA via 3′ UTR binding, linking RNA metabolism to cognitive function.","evidence":"FLIM/FRET oligomerization analysis; co-IP with cell cycle arrest phenotyping in Lrp8-KO vascular model; RNA immunoprecipitation and behavioral rescue","pmids":["30873003","31412739","31269452"],"confidence":"Medium","gaps":["Whether receptor clustering stoichiometry differs across cell types","PP2A-CDC20 scaffolding by ApoER2 awaits independent confirmation","How SFRS11 deficiency selectively affects LRP8 among its targets"]},{"year":2021,"claim":"Two discoveries extended ApoER2 biology to viral entry and placental pathology: alphavirus E2-E1 glycoproteins bind ApoER2/VLDLR ligand-binding domains for neuronal infection (blockable by soluble LBD-Fc), and ApoER2-PP2A signaling in trophoblasts drives preeclampsia in antiphospholipid syndrome.","evidence":"CRISPR KO screen, virus-like particle assays, in vivo SFV protection with LBD-Fc; APS mouse preeclampsia model with ApoER2-specific interventions","pmids":["34929721","34404233"],"confidence":"High","gaps":["Whether ApoER2 versus VLDLR differentially determines neurotropism of specific alphaviruses","Molecular determinants of PP2A activation in trophoblasts vs. endothelium"]},{"year":2022,"claim":"Comprehensive long-read sequencing identified 25 human APOER2 splice isoforms, revealing that exon 5–8 deletion variants produce maximal CTF/ICD and transcriptional activation, while isoform-specific rescue of Apoer2-KO neurons showed differential ability to restore miniature excitatory events, establishing isoform-specific synaptic functions.","evidence":"Gene-specific long-read sequencing, CTF immunoblotting, ICD transcriptional reporter, miniature excitatory event recording with lentiviral rescue in KO neurons","pmids":["35414534"],"confidence":"Medium","gaps":["Isoform-specific contributions to non-neuronal ApoER2 functions untested","Regulation of isoform selection during development or disease not characterized"]},{"year":2023,"claim":"Two studies revealed mechanistic details of ApoER2-dependent selenium biology: LRP8 protects MYCN-amplified neuroblastoma from ferroptosis by supplying selenocysteine for GPX4 translation via selenoprotein P uptake; and high-affinity glycosylated ApoER2 variants use a Sec lyase-independent selenium transport mechanism distinct from low-affinity variants.","evidence":"CRISPR-activation screen with inducible KO and xenograft models; Kd measurements with 75Se uptake and Sec lyase/lysosomal inhibitors","pmids":["37435859","37406814"],"confidence":"High","gaps":["Whether ferroptosis resistance via LRP8-SELENOP axis operates in normal neural stem cells","Structural basis for affinity-dependent routing through different selenium release pathways"]},{"year":2025,"claim":"Genome-scale CRISPR screening identified LRP8 as a direct entry receptor for tick-borne encephalitis virus, binding the TBEV E glycoprotein and mediating attachment and internalization — extending ApoER2's role as a broad viral receptor.","evidence":"Genome-scale CRISPR-Cas9 screen, direct E glycoprotein binding, gain/loss-of-function infection assays, LRP8-based decoy receptor protection in mice","pmids":["40993380"],"confidence":"High","gaps":["Whether LRP8 serves as receptor for additional flaviviruses beyond TBEV","Mechanism of viral genome release after ApoER2-mediated endocytosis unknown"]},{"year":null,"claim":"Key unresolved questions include: how the same receptor activates distinct downstream pathways depending on ligand identity; the full structural basis of ApoER2 ICD nuclear function and its chromatin targets across brain regions; and the therapeutic potential of splice-switching or decoy receptor strategies in neurodegeneration and viral infection.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length Reelin–ApoER2 complex structure available","ICD cofactors and chromatin remodeling partners at LRN enhancers unidentified","Cell-type-specific isoform expression maps not systematically generated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,7,8,15,16,17,37]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,34]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[17,37]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,12,14,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,23]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,24,43]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,7,8,9,15,16,19,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,31]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,22,25,32,45]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4,28,29,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,37]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[8,20,44]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[36]}],"complexes":["ApoER2-NMDAR postsynaptic complex","ApoER2-GRIP1-ephrinB2-AMPAR complex","ApoER2-PP2A signaling complex"],"partners":["RELN","DAB1","SELENOP","GRIP1","PSD95","PCSK9","IDOL","SNX17"],"other_free_text":[]},"mechanistic_narrative":"LRP8 (ApoER2) is a multifunctional LDL receptor family member that serves as a signaling receptor, endocytic transporter, and viral entry receptor across neuronal, endothelial, platelet, and testicular cell types. In the brain, LRP8 binds Reelin (and alternative ligands including thrombospondin-1 and clusterin) to induce Dab1 tyrosine phosphorylation, PI3K/Akt activation, and NMDA receptor modulation, thereby controlling neuronal migration, dendritic architecture, and synaptic plasticity including LTP — functions that depend critically on alternatively spliced exon 19 and lipid raft localization [PMID:16102539, PMID:12670700, PMID:17913789, PMID:19948739]. Regulated intramembrane proteolysis by metalloproteinases and γ-secretase releases a transcriptionally active intracellular domain (ICD) that suppresses reelin transcription and activates neuronal enhancers governing memory-related genes [PMID:24344333, PMID:25892301, PMID:25429077]. Beyond the nervous system, LRP8 mediates selenoprotein P-dependent selenium uptake essential for GPX4 translation and ferroptosis resistance [PMID:17314095, PMID:37435859], scaffolds PP2A assembly to regulate eNOS phosphorylation and thrombosis in endothelial cells and platelets [PMID:21123944, PMID:29500169], and functions as an entry receptor for alphaviruses and tick-borne encephalitis virus [PMID:34929721, PMID:40993380]."},"prefetch_data":{"uniprot":{"accession":"Q14114","full_name":"Low-density lipoprotein receptor-related protein 8","aliases":["Apolipoprotein E receptor 2"],"length_aa":963,"mass_kda":105.6,"function":"Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands (PubMed:12899622, PubMed:12950167, PubMed:20223215, PubMed:30873003). LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail (By similarity). Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons (By similarity). LRP8 has higher affinity for Reelin than VLDLR (By similarity). LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development (By similarity). Binds the endoplasmic reticulum resident receptor-associated protein (RAP) (By similarity). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature (PubMed:12807892). Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation (By similarity). May also function as an endocytic receptor (By similarity). Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2 (By similarity). Together with its ligand, apolipoprotein E (apoE), may indirectly play a role in the suppression of the innate immune response by controlling the survival of myeloid-derived suppressor cells (By similarity) (Microbial infection) Acts as a receptor for Semliki Forest virus (Microbial infection) Acts as a receptor for tick-borne encephalitis virus by mediating viral cell attachment and internalization","subcellular_location":"Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q14114/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRP8","classification":"Not Classified","n_dependent_lines":80,"n_total_lines":1208,"dependency_fraction":0.06622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRP8","total_profiled":1310},"omim":[{"mim_id":"608446","title":"MYOCARDIAL INFARCTION, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/608446"},{"mim_id":"603490","title":"WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 4; WNT4","url":"https://www.omim.org/entry/603490"},{"mim_id":"603448","title":"DAB ADAPTOR PROTEIN 1; DAB1","url":"https://www.omim.org/entry/603448"},{"mim_id":"602600","title":"LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 8; LRP8","url":"https://www.omim.org/entry/602600"},{"mim_id":"157140","title":"MICROTUBULE-ASSOCIATED PROTEIN TAU; MAPT","url":"https://www.omim.org/entry/157140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":22.5},{"tissue":"thyroid gland","ntpm":38.8}],"url":"https://www.proteinatlas.org/search/LRP8"},"hgnc":{"alias_symbol":["APOER2","MCI1","LRP-8","HSZ75190"],"prev_symbol":[]},"alphafold":{"accession":"Q14114","domains":[{"cath_id":"-","chopping":"80-112","consensus_level":"medium","plddt":75.2997,"start":80,"end":112},{"cath_id":"-","chopping":"380-409","consensus_level":"medium","plddt":88.216,"start":380,"end":409},{"cath_id":"2.120.10.30","chopping":"422-687","consensus_level":"high","plddt":94.331,"start":422,"end":687}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14114","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14114-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14114-F1-predicted_aligned_error_v6.png","plddt_mean":72.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRP8","jax_strain_url":"https://www.jax.org/strain/search?query=LRP8"},"sequence":{"accession":"Q14114","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14114.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14114/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14114"}},"corpus_meta":[{"pmid":"18039658","id":"PMC_18039658","title":"The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18039658","citation_count":394,"is_preprint":false},{"pmid":"16102539","id":"PMC_16102539","title":"Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2.","date":"2005","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/16102539","citation_count":382,"is_preprint":false},{"pmid":"23142051","id":"PMC_23142051","title":"Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23142051","citation_count":344,"is_preprint":false},{"pmid":"14715136","id":"PMC_14715136","title":"Reelin promotes hippocampal dendrite development through the VLDLR/ApoER2-Dab1 pathway.","date":"2004","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/14715136","citation_count":313,"is_preprint":false},{"pmid":"10827199","id":"PMC_10827199","title":"The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and -2.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10827199","citation_count":214,"is_preprint":false},{"pmid":"17314095","id":"PMC_17314095","title":"Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17314095","citation_count":182,"is_preprint":false},{"pmid":"21123944","id":"PMC_21123944","title":"Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2.","date":"2010","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/21123944","citation_count":160,"is_preprint":false},{"pmid":"17913789","id":"PMC_17913789","title":"Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17913789","citation_count":134,"is_preprint":false},{"pmid":"25892301","id":"PMC_25892301","title":"LRP8-Reelin-Regulated Neuronal Enhancer Signature Underlying Learning and Memory Formation.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25892301","citation_count":131,"is_preprint":false},{"pmid":"22481440","id":"PMC_22481440","title":"PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling.","date":"2012","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/22481440","citation_count":118,"is_preprint":false},{"pmid":"20427281","id":"PMC_20427281","title":"The E3 ubiquitin ligase 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mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/23506116","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49837,"output_tokens":11528,"usd":0.161216},"stage2":{"model":"claude-opus-4-6","input_tokens":15599,"output_tokens":5830,"usd":0.335618},"total_usd":0.496834,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"ApoER2 (LRP8) is present in the postsynaptic densities of excitatory synapses where it forms a functional complex with NMDA receptors; Reelin signaling through ApoER2 enhances LTP through an alternatively spliced intracellular exon (exon 19) that is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits\",\n      \"method\": \"Co-immunoprecipitation, alternative splicing analysis, LTP electrophysiology, knock-in mice lacking the exon, behavioral testing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (biochemistry, electrophysiology, genetics, behavior) in a single rigorous study\",\n      \"pmids\": [\"16102539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ApoER2 (but not VLDLR) binds JNK-interacting proteins JIP-1 and JIP-2 through its intracellular domain, assembling a multiprotein complex at the neuronal cell surface that may participate in ApoER2-specific Reelin signaling\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal pulldowns with domain mapping, single lab\",\n      \"pmids\": [\"10827199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Purified Reelin binds ApoER2 more readily than VLDLR and induces tyrosine phosphorylation of Dab1 through both receptors; ApoER2 and VLDLR are jointly essential for Reelin-induced Dab1 phosphorylation with no compensatory receptor\",\n      \"method\": \"Purified Reelin binding assays, cortical neuron cultures from single/double receptor knockout mice, Dab1 phosphorylation immunoblotting, layer-specific marker analysis\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding with purified protein, genetic knockouts with multiple readouts, replicated across receptor combinations\",\n      \"pmids\": [\"12670700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PCSK9 binds to ApoER2 (as well as LDLR and VLDLR) and induces its lysosomal degradation either by cellular co-expression or re-internalization of secreted PCSK9; membrane-bound PCSK9 chimeras greatly enhance receptor targeting to late endosomes/lysosomes; catalytic activity of PCSK9 is not required for degradation\",\n      \"method\": \"Co-expression experiments, secreted PCSK9 re-internalization assay, membrane-bound PCSK9 chimera constructs, lysosomal inhibitor studies, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple mechanistic dissections (catalytic mutants, chimeras, re-internalization) in a single study with strong controls\",\n      \"pmids\": [\"18039658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ApoER2 in Sertoli cells is a selenoprotein P (Sepp1) receptor that mediates receptor-dependent uptake of selenium into the testis; co-immunoprecipitation confirmed ApoER2-Sepp1 interaction; ApoER2 knockout mice have sharply reduced testis selenium and identical sperm defects as Sepp1 knockout mice\",\n      \"method\": \"Sepp1 affinity chromatography + mass spectrometry, co-immunoprecipitation, in situ hybridization, selenium measurement in ApoER2-/- mice, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — affinity chromatography/MS identification confirmed by Co-IP, validated in vivo with knockout mice showing matching phenotypes\",\n      \"pmids\": [\"17314095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The E3 ubiquitin ligase IDOL induces ubiquitination of ApoER2 (and VLDLR) on their cytoplasmic tails, leading to their lysosomal degradation; LXR activation increases IDOL expression and decreases ApoER2/VLDLR levels; reduced IDOL-dependent ApoER2 levels decrease Reelin-induced Dab1 phosphorylation\",\n      \"method\": \"Ubiquitination assays, immunoblotting, siRNA knockdown, pharmacological LXR activation in mice, Dab1 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct ubiquitination demonstrated biochemically, confirmed in vivo; functional consequence on Reelin signaling shown\",\n      \"pmids\": [\"20427281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ApoE-secreted by melanoma cells suppresses metastatic endothelial recruitment by engaging endothelial cell LRP8 receptors; miR-1908, miR-199a-5p, and miR-199a-3p convergently target ApoE, and their inhibition suppresses LRP8-mediated angiogenesis\",\n      \"method\": \"In vivo selection, locked nucleic acid (LNA) inhibition, cancer cell-endothelial co-culture assays, receptor-specific functional studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo validation with LNA treatment and functional receptor engagement, single lab\",\n      \"pmids\": [\"23142051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Activated protein C (APC) binds directly to ApoER2 (LRP8) with ~30 nM affinity (surface plasmon resonance) and signals via Dab1 Tyr-220 phosphorylation, followed by PI3K/Akt activation and GSK3β Ser-9 phosphorylation; siRNA knockdown of ApoER2 ablates APC-induced Dab1 phosphorylation\",\n      \"method\": \"Surface plasmon resonance, siRNA knockdown, phospho-specific immunoblotting, kinase inhibitors, receptor-associated protein (RAP) competition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding measured by SPR, mechanistic pathway confirmed by siRNA and pharmacological inhibitors with multiple readouts\",\n      \"pmids\": [\"19116273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In antiphospholipid syndrome, aPL antibodies bind β2GPI which dimerizes and engages ApoER2 on endothelial cells; this activates PP2A which dephosphorylates eNOS at Ser1179, suppressing NO production; ApoER2-/- mice are protected from aPL-induced thrombosis and leukocyte-endothelial adhesion\",\n      \"method\": \"Endothelial cell culture, RAP competition, ApoER2 knockout mice, eNOS phosphorylation immunoblotting, PP2A activity assays, intravital microscopy\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection in cells and validated in ApoER2-/- mice with multiple functional readouts\",\n      \"pmids\": [\"21123944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In endothelial cells, the ApoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly of heterotrimeric PP2A: Dab2 recruits to the NPXY motif and promotes L309 methylation (activation) of PP2A catalytic subunit via LCMT-1; SHC1 recruits scaffolding and regulatory PP2A subunits to the proline-rich C-terminus, mediating dephosphorylation of Akt and eNOS\",\n      \"method\": \"Co-immunoprecipitation, domain-specific mutants, siRNA knockdown, endothelial cell signaling assays, in vivo thrombosis model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — detailed mechanistic dissection of protein complex assembly with domain-specific interactions and in vivo validation\",\n      \"pmids\": [\"29500169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"F-spondin interacts with ApoER2 through F-spondin's thrombospondin domain and ApoER2's ligand-binding domain (co-immunoprecipitation); F-spondin increases surface expression of APP and ApoER2, and shifts APP processing away from amyloidogenic β-secretase cleavage; this requires the ApoER2 receptor (blocked by RAP)\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, APP CTF measurement, Aβ ELISA, primary neurons\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple biochemical readouts in transfected cells and neurons, receptor dependence confirmed by RAP\",\n      \"pmids\": [\"16227578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FE65 adaptor protein interacts with ApoER2 via its N-terminal PTB domain, bridges a complex with APP, increases surface expression of ApoER2, and affects proteolytic processing of both ApoER2 and APP (increasing secreted forms while decreasing Aβ); both PTB domains of FE65 are required for full effect\",\n      \"method\": \"Co-immunoprecipitation in COS7 cells, surface biotinylation, CTF/secreted protein immunoblotting, Aβ measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain mapping with multiple functional readouts, single lab\",\n      \"pmids\": [\"16638748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ApoER2 is endocytosed via a clathrin-mediated pathway dependent on the cytoplasmic FxNPXY motif and the adaptor protein Dab2; dominant-negative eps15 and Dab2 reduce ApoER2 internalization; caveolar/raft pathway is not required despite ApoER2 association with rafts\",\n      \"method\": \"Endocytosis assays, dominant-negative constructs (eps15, Dab2), nystatin treatment (caveolar inhibition), FxNPXY mutant analysis\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple inhibitory approaches (genetic and pharmacological) with domain-specific mutagenesis converge on same conclusion\",\n      \"pmids\": [\"16101684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ApoER2 (but not VLDLR) controls migration of late-generated neocortical neurons; fate mapping in single and double receptor knockout mice shows VLDLR mediates a stop signal for migrating neurons while ApoER2 is essential for migration of late-born neurons\",\n      \"method\": \"BrdU fate mapping, layer-specific marker immunostaining, single and double receptor knockout mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with fate mapping distinguishing receptor-specific roles\",\n      \"pmids\": [\"17913789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ApoER2 sorting to lipid raft domains (vs. VLDLR in non-raft domains) determines receptor fate upon Reelin stimulation: raft-associated ApoER2 produces specific receptor fragments and undergoes lysosomal degradation after Reelin binding; non-raft VLDLR internalizes Reelin for degradation without significant receptor degradation\",\n      \"method\": \"Chimeric receptor panel, lipid raft fractionation, endocytosis assays, receptor fragment tracking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chimeric receptor approach with raft fractionation provides mechanistic insight into differential sorting\",\n      \"pmids\": [\"19948739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Thrombospondin-1 (THBS-1) is a novel physiological ligand for ApoER2 and VLDLR; it binds both receptors and induces Dab1 phosphorylation but (unlike Reelin) does not induce Dab1 degradation or Akt phosphorylation; THBS-1 stabilizes neuronal precursor chains in rostral migratory stream independently of Reelin\",\n      \"method\": \"Ligand binding assays, Dab1 phosphorylation immunoblotting, SVZ explant chain formation assays, THBS-1 knockout mice analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated, differential signaling compared to canonical ligand shown biochemically, functional in vitro and in vivo validation\",\n      \"pmids\": [\"18946489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Clusterin binds to ApoER2 and VLDLR, is internalized by receptor-expressing cells, and triggers Reelin-like signaling: inducing Dab1 phosphorylation, PI3K/Akt activation, and n-cofilin activation; clusterin blockade impairs neuroblast chain formation in SVZ explants\",\n      \"method\": \"Binding/internalization assays, Dab1 phosphorylation immunoblotting, Akt phosphorylation, SVZ explant assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and functional signaling cascade demonstrated, single lab\",\n      \"pmids\": [\"24381170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The E2-E1 glycoproteins of multiple alphaviruses (Semliki forest virus, EEEV, Sindbis) bind to the ligand-binding domains of ApoER2 (and VLDLR), mediating viral attachment and internalization; a VLDLR LBD-Fc fusion protein blocks alphavirus infection in neurons and protects mice from lethal SFV challenge\",\n      \"method\": \"CRISPR knockout screens, virus-like particle internalization assays, neutralization with LBD-Fc fusion protein, in vivo mouse challenge model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding shown, genetic loss-of-function, in vivo protection model; multiple orthogonal methods\",\n      \"pmids\": [\"34929721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ApoER2 physically interacts with APP and increases cell surface APP levels and APP association with lipid rafts by decreasing APP internalization rate; ApoER2 expression also increases γ-secretase activity and Aβ production; the ApoER2 NPxY motif is required for increased Aβ production\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation, APP internalization rate measurement, lipid raft fractionation, γ-secretase activity assay, Aβ ELISA, NPxY mutant analysis\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays with domain-specific mutants, single lab\",\n      \"pmids\": [\"17620134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRP8 positively regulates canonical Wnt/β-catenin signaling: ectopic LRP8 expression increases Wnt-induced β-catenin accumulation and transcriptional responses; LRP8 knockdown decreases β-catenin levels and suppresses Wnt target gene (Axin2) transcription; LRP8 depletion impairs osteoblast differentiation and mineralization\",\n      \"method\": \"siRNA knockdown, Wnt transcriptional reporter assay, β-catenin immunoblotting, Axin2 RT-PCR, osteoblast differentiation assay (KS483 cells), mineralization assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss of function with multiple readouts; pathway placement via reporter assay\",\n      \"pmids\": [\"22589174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Factor XI (FXI) is identified as a ligand for platelet ApoER2; platelet adhesion to immobilized FXI is blocked by RAP, soluble recombinant ApoER2, or ApoER2 LDL-binding domains 1-2; ApoER2-deficient murine platelets fail to adhere to FXI; soluble FXI binds immobilized ApoER2 with ~61 nM affinity\",\n      \"method\": \"Platelet adhesion assay, RAP competition, soluble receptor domain competition, ApoER2 knockout mouse platelets, surface plasmon resonance\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding by SPR, receptor-specific knockout phenotype, domain competition; multiple approaches converge\",\n      \"pmids\": [\"19661487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"β2-glycoprotein I (β2GPI) domain V contains the binding site for ApoER2 on platelets; deletion of domain V abrogates β2GPI interaction with ApoER2 and platelet activation on collagen; domains I and II are dispensable for ApoER2 interaction\",\n      \"method\": \"Domain deletion mutants of β2GPI, immunoprecipitation with platelet ApoER2, platelet adhesion assay, whole blood flow assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping by deletion mutagenesis confirmed by immunoprecipitation and functional platelet assay\",\n      \"pmids\": [\"16091370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Reelin binding to LRP8 triggers γ-secretase-dependent cleavage of LRP8, releasing its intracellular domain (ICD) which participates in a synapse-to-nucleus pathway to activate neuronal enhancers (LRN enhancers) governing synaptic plasticity genes; LRP8 ICD serves as a nuclear signal for chromatin remodeling during memory formation\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), enhancer profiling, γ-secretase inhibition, LRP8 knockdown, in vivo memory behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP, pharmacological, genetic) with in vivo behavioral validation\",\n      \"pmids\": [\"25892301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Presenilin-1 (γ-secretase) processes ApoER2 sequentially (α- then γ-secretase), producing an intracellular C-terminal fragment (ICD); this ApoER2-ICD binds to the RELN promoter and suppresses reelin expression at the transcriptional level; PS1 conditional knockout mice show increased ApoER2 and reelin protein\",\n      \"method\": \"PS1 conditional knockout mice, γ-secretase inhibitor treatment, luciferase reporter assay, nuclear fractionation, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP confirms direct promoter binding by ApoER2 ICD; genetic and pharmacological approaches with in vivo validation\",\n      \"pmids\": [\"24344333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sorting nexin 17 (SNX17) interacts with the NPxY endocytosis motif of ApoER2 via SNX17's FERM domain (GST pull-down, co-immunoprecipitation) and promotes ApoER2 recycling from early to recycling endosomes without affecting endocytic rate; SNX17 knockdown increases Reelin-induced ApoER2 degradation and impairs dendritic development and Reelin signaling in neurons\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, endosomal trafficking assays, SNX17 siRNA knockdown, dendritic morphology analysis, Reelin-Dab1 phosphorylation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct physical interaction mapped, trafficking assay with functional signaling readout, single lab\",\n      \"pmids\": [\"24705369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Differential splicing (exon 16 encoding O-linked sugar domain) and glycosylation of ApoER2 alters its extracellular cleavage, γ-secretase-dependent ICD release, synaptic abundance, spine density, and fear memory; OLS-deficient ApoER2 has reduced ectodomain shedding preventing ICD release\",\n      \"method\": \"Splice variant knock-in mice, electrophysiology (LTP), spine density analysis, behavioral testing (Morris water maze, fear conditioning), biochemical cleavage assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic knock-in model with multiple biochemical and functional phenotypes\",\n      \"pmids\": [\"25429077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An antisense oligonucleotide (ASO) that increases ApoER2 exon 19 splicing corrects deregulated ApoER2 splicing in AD mouse brain, improving synaptic function and learning/memory; exon 19 splicing is deregulated in human AD brain postmortem\",\n      \"method\": \"ASO treatment in transgenic AD mice, LTP electrophysiology, behavioral testing (learning and memory), RT-PCR splice analysis in human postmortem brain\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — therapeutic rescue experiment in vivo with electrophysiological and behavioral readouts; splicing mechanism established\",\n      \"pmids\": [\"26902204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ApoE3 binding to ApoER2 on endothelial cells stimulates eNOS and endothelial cell migration, and attenuates monocyte-endothelial adhesion; ApoE4 (due to its N-to-C terminal interaction) does not stimulate eNOS and acts as dominant-negative antagonist of ApoE3/ApoER2 actions; ApoER2-R952Q is a loss-of-function receptor variant in endothelium\",\n      \"method\": \"eNOS activity assays, endothelial cell migration assays, ApoER2-/- mice, adenoviral ApoE3/E4 expression, carotid reendothelialization model, neointima formation model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple in vitro and in vivo mechanistic approaches, isoform-specific functional dissection\",\n      \"pmids\": [\"25197062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Differential functions of ApoER2 intracellular signaling motifs and selenium uptake can be dissociated: knock-in mice with disrupted signaling motifs in the Apoer2 cytoplasmic domain maintain normal selenium in brain and testis, confirming that neurological defects in signaling-impaired mice are due to disrupted Reelin signaling, not selenium deficiency\",\n      \"method\": \"Knock-in mice (cytoplasmic domain signaling motif mutations), selenium measurement in tissues, sperm motility analysis\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic dissection using knock-in mice with defined domain mutations separating two functions\",\n      \"pmids\": [\"19007311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ApoER2 mediates selenium uptake from selenoprotein P (Sepp1) in L8 myoblast cells via an endocytosis mechanism requiring heparin sulfate proteoglycan binding and the selenium-rich C-terminal domain of Sepp1; siRNA knockdown of ApoER2 (but not LRP1) inhibits 75Se uptake; lysosome acidification is required for Sepp1 digestion and selenium utilization\",\n      \"method\": \"Sepp1 affinity column + mass spectrometry, siRNA knockdown, 75Se-labeled Sepp1 uptake assay, lysosomal acidification inhibitors, heparin competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor identified by MS, validated by siRNA; mechanism dissected with domain-specific and pharmacological approaches\",\n      \"pmids\": [\"22761431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the full-length ApoER2 ectodomain complexed with a signaling-competent Reelin fragment reveals an intermediate contracted-open conformation distinct from ligand-unbound LDLR; an auxiliary low-affinity binding interface is identified; pH-dependent weakening of this interface during endocytosis destabilizes the complex for ligand release\",\n      \"method\": \"X-ray crystallography, mutagenesis of binding interfaces, pH-dependent binding assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis and functional pH-dependent assay\",\n      \"pmids\": [\"28446613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ApoER2 and Reelin are expressed in peripheral nerve and regulate Schwann cell migration by activating the Rac1 GEF Tiam1; Reelin induces Rac1 activation at the leading edge of SCs (FRET assay); Tiam1 and PAR3 are required for Reelin-induced SC migration; PAR3 binds preferentially to the full-length ApoER2 cytoplasmic tail containing the exon 19-encoded proline-rich insert\",\n      \"method\": \"FRET-based Rac1 activation assay, siRNA knockdown of Tiam1/PAR3, sciatic nerve injury model, ApoER2 domain-specific binding assays\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — FRET assay for direct GTPase activation, domain-specific binding, functional migration assay with knockdown\",\n      \"pmids\": [\"26386179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GRIP1 binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors at the postsynapse; neuronal activity induces ephrinB2 Ser-9 phosphorylation which stabilizes the complex; mutation of ephrinB2 Ser-9 disrupts complex formation, abolishes ApoER2 downstream signaling, and impairs activity-induced AMPA receptor insertion and LTP\",\n      \"method\": \"Co-immunoprecipitation, phospho-mutant knock-in mice, compound genetics, LTP electrophysiology, AMPA receptor surface insertion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — complex identified biochemically, functional role confirmed by phospho-mutant knock-in with electrophysiology\",\n      \"pmids\": [\"28978486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation; IDOL-dependent changes in ApoER2 regulate dendritic spine morphogenesis, filopodia initiation, synapse maturation, and LTP; IDOL-deficient mice show impaired experience-dependent synaptic remodeling and spatial/associative learning\",\n      \"method\": \"IDOL knockout mice, LTP electrophysiology in slices and primary neurons, dendritic spine imaging, barrel cortex plasticity assay, behavioral tests\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic loss-of-function with multiple functional phenotypes (electrophysiology, morphology, behavior), replication of IDOL-ApoER2 regulatory relationship\",\n      \"pmids\": [\"28891791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ApoER2 interacts with the catalytic subunit of PP2A (co-immunoprecipitation); in the absence of ApoER2, PP2A-C fails to interact with CDC20, resulting in inactive anaphase-promoting complex (APC/CDC20), cell cycle arrest at metaphase/anaphase, impaired cytokinesis, and premature smooth muscle cell senescence\",\n      \"method\": \"Co-immunoprecipitation, cell cycle protein immunoblotting, β-galactosidase senescence assay, p16INK4a immunofluorescence, multinucleated cell counting, Lrp8-/- mouse vascular injury model\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP establishes interaction, functional consequence in knockout cells/mice; single lab\",\n      \"pmids\": [\"31412739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SFRS11 RNA-binding protein directly binds LRP8 mRNA 3' UTR, stabilizing it; SFRS11 deficiency in the prefrontal cortex reduces LRP8 and apoE mRNA levels, activates JNK signaling, and causes learning/memory deficits; restoration of LRP8 and apoE reduces JNK activation and rescues aging-like phenotypes\",\n      \"method\": \"RNA immunoprecipitation (RIP), 3' UTR binding assay, SFRS11 knockdown in PFC, JNK signaling immunoblotting, behavioral tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-protein interaction demonstrated by RIP, functional rescue experiment with in vivo behavioral readout\",\n      \"pmids\": [\"31269452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRP8 is identified as a CRISPR-activation screen hit protecting MYCN-amplified neuroblastoma from ferroptosis; LRP8 deletion causes ferroptosis by reducing selenoprotein P (SELENOP) uptake, insufficient selenocysteine supply for GPX4 translation; this is caused by low expression of alternative selenium uptake pathways (system Xc-)\",\n      \"method\": \"CRISPR-activation screen, LRP8 knockout (constitutive and inducible), xenograft models, selenoprotein/GPX4 immunoblotting, ferroptosis cell death assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-scale screen followed by constitutive and inducible KO with mechanistic link to GPX4 via selenocysteine supply, in vivo xenograft validation\",\n      \"pmids\": [\"37435859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRP8 is identified as a receptor for tick-borne encephalitis virus (TBEV) by genome-scale CRISPR-Cas9 screen; LRP8 binds directly to TBEV E glycoprotein and mediates viral attachment and internalization; LRP8 downregulation reduces TBEV infection; an LRP8-based soluble decoy blocks TBEV infection in human cell lines, neuronal cells, and protects mice from lethal TBEV challenge\",\n      \"method\": \"Genome-scale CRISPR-Cas9 screen, LRP8 overexpression/knockdown infection assays, direct binding assay (E glycoprotein), LRP8-based decoy receptor, in vivo mouse challenge\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-scale screen, direct binding shown, gain/loss of function, in vivo validation with decoy protection\",\n      \"pmids\": [\"40993380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the off-state, ApoER2 and VLDLR form homo- or hetero-oligomers; full-length Reelin binding rearranges ApoER2 homo-oligomers into higher-order receptor clusters, leading to Dab1 phosphorylation; the Reelin central fragment does not increase cluster size or induce Dab1 phosphorylation but can induce hetero-oligomerization and cell shape changes via an alternative Dab1-independent mechanism\",\n      \"method\": \"Time-resolved anisotropy, fluorescence lifetime imaging microscopy (FLIM), FRET-based receptor oligomerization analysis in HEK293 cells\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — advanced optical methods (FLIM/FRET) used to directly measure receptor oligomerization dynamics; single lab\",\n      \"pmids\": [\"30873003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neurotrophins regulate ApoER2 proteolysis: TrkA activation by NGF in PC12 cells induces ApoER2 ectodomain shedding (metalloproteinase-dependent); TrkB activation by BDNF similarly induces ApoER2 proteolysis in cortical neurons; this effect is independent of MAPK and PI3K activity\",\n      \"method\": \"Pharmacological TrkA/TrkB activation, metalloproteinase inhibitors, MAPK/PI3K inhibitors, ApoER2 shedding immunoblotting, primary cortical neurons\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological dissection of signaling pathway with multiple inhibitors; single lab\",\n      \"pmids\": [\"25233900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A high-affinity ApoER2 variant in Jurkat cells (with highly glycosylated O-linked sugar domain, Kd ~0.67 nM) mediates selenium transport from selenoprotein P (SeP) via a Sec lyase-independent mechanism requiring vesicle acidification; in contrast, low-affinity ApoER2 variants use a Sec lyase-dependent lysosomal degradation mechanism\",\n      \"method\": \"Binding affinity measurements (Kd determination), siRNA knockdown, Sec lyase inhibitor, lysosomal acidification inhibitors, 75Se uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative binding measurements with mechanistic dissection of two distinct transport routes; single lab\",\n      \"pmids\": [\"37406814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Splice variants of ApoER2 differ in ligand-binding domain composition: ApoER2-LA1237 binds Reelin central fragment more strongly than the RR8-containing fragment, whereas ApoER2-LA12378 binds comparably to all Reelin fragments lacking the C-terminal region; LA8 of ApoER2 and Reelin repeat 8 interfere with central fragment-ApoER2 binding\",\n      \"method\": \"Quantitative binding assays with purified Reelin fragments and ApoER2 variants, monoclonal antibody specific for LA12378 isoform, in situ expression analysis\",\n      \"journal\": \"Neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative binding with defined protein fragments; single lab\",\n      \"pmids\": [\"19167437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human APOER2 isoforms lacking exons 5-8 (Δex5-8) generate the highest CTF amounts and those lacking exons 4-6 (Δex4-6) the lowest in response to APOE, correlating with ICD-mediated transcriptional activation; Apoer2 knockout neurons show decreased miniature excitatory event frequency, restored by lentiviral APOER2-FL or Δex4-6 but not Δex5-8 isoform\",\n      \"method\": \"Gene-specific long-read sequencing (25 isoform identification), CTF immunoblotting, ICD transcriptional reporter assay, miniature excitatory event recording in Apoer2-KO neurons, lentiviral rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — comprehensive isoform survey with functional rescue electrophysiology; single lab\",\n      \"pmids\": [\"35414534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CIN85 (multi-adaptor protein) colocalizes with ApoER2 in neurons in a Dab1-mediated manner; Reelin stimulation increases CIN85-ApoER2 colocalization and recruits CIN85 from plasma membrane domains to EEA1-positive early endosomes; Tyr phosphorylation of Dab1 strengthens CIN85 binding\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Reelin stimulation assay, early endosome marker co-staining\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP and imaging-based colocalization with functional Reelin stimulation; single lab\",\n      \"pmids\": [\"23506116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRP8-deficient mice show reduced platelet activation in response to ADP or thrombin and prolonged carotid artery occlusion time (in vivo thrombosis); lipidated apoE3 inhibits platelet activation in a dose-dependent and largely LRP8-dependent manner; LRP8 function in thrombosis is partly apoE-independent\",\n      \"method\": \"Flow cytometry, aggregometry, intravital microscopy (carotid FeCl3 injury), tail bleeding assay, LRP8-/- and LRP8+/- mice\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple in vitro and in vivo functional platelet/thrombosis readouts; single lab\",\n      \"pmids\": [\"18706682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ApoER2/Dab1 interaction with PSD95 maintains stable dendritic architecture in mature hippocampal neurons; expression of a tailless ApoER2 mutant (unable to interact with PSD95) increases dendritogenesis and reduces spine density in mature neurons; interference reduces synaptic PSD95 and leads to synaptic re-insertion of NR2B-containing NMDARs\",\n      \"method\": \"Mutant ApoER2 (tailless) overexpression in mature hippocampal neurons, dendritic morphology analysis (in vitro and in vivo), PSD95 immunofluorescence, NMDAR subunit analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — dominant-negative receptor approach with in vitro and in vivo morphological readouts; single lab\",\n      \"pmids\": [\"27653801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Protein phosphatase 2A (PP2A) activation via ApoER2 in trophoblasts drives preeclampsia in a mouse model of antiphospholipid syndrome, extending the apoER2-PP2A signaling axis to placental biology\",\n      \"method\": \"Mouse model of APS-related preeclampsia, ApoER2-specific genetic and pharmacological interventions\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model; single lab extending established ApoER2-PP2A mechanism to new cell type\",\n      \"pmids\": [\"34404233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRP8 (ApoER2) is a multifunctional type I transmembrane receptor of the LDL receptor family that acts as a signal transduction hub: it binds Reelin (and alternative ligands including thrombospondin-1, clusterin, selenoprotein P, activated protein C, FXI, and viral glycoproteins) to assemble signaling complexes at the plasma membrane involving Dab1 phosphorylation, PI3K/Akt activation, and NMDA receptor modulation for neuronal migration and synaptic plasticity; undergoes regulated proteolytic cleavage (ectodomain shedding by metalloproteinases followed by γ-secretase) to release a transcriptionally active ICD that controls reelin expression and neuronal enhancers; mediates selenium transport via selenoprotein P endocytosis into brain and testis; in endothelial cells and platelets activates a PP2A-dependent pathway to regulate eNOS and thrombosis; is subject to post-translational degradation by PCSK9 and the E3 ligase IDOL; and is subject to extensive alternative splicing that critically modifies its ligand binding, proteolytic processing, and synaptic functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRP8 (ApoER2) is a multifunctional LDL receptor family member that serves as a signaling receptor, endocytic transporter, and viral entry receptor across neuronal, endothelial, platelet, and testicular cell types. In the brain, LRP8 binds Reelin (and alternative ligands including thrombospondin-1 and clusterin) to induce Dab1 tyrosine phosphorylation, PI3K/Akt activation, and NMDA receptor modulation, thereby controlling neuronal migration, dendritic architecture, and synaptic plasticity including LTP — functions that depend critically on alternatively spliced exon 19 and lipid raft localization [PMID:16102539, PMID:12670700, PMID:17913789, PMID:19948739]. Regulated intramembrane proteolysis by metalloproteinases and γ-secretase releases a transcriptionally active intracellular domain (ICD) that suppresses reelin transcription and activates neuronal enhancers governing memory-related genes [PMID:24344333, PMID:25892301, PMID:25429077]. Beyond the nervous system, LRP8 mediates selenoprotein P-dependent selenium uptake essential for GPX4 translation and ferroptosis resistance [PMID:17314095, PMID:37435859], scaffolds PP2A assembly to regulate eNOS phosphorylation and thrombosis in endothelial cells and platelets [PMID:21123944, PMID:29500169], and functions as an entry receptor for alphaviruses and tick-borne encephalitis virus [PMID:34929721, PMID:40993380].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying ApoER2-specific cytoplasmic interactors established that LRP8 assembles signaling scaffolds distinct from VLDLR, revealing JIP-1/JIP-2 as intracellular binding partners that could link ApoER2 to JNK-dependent signaling cascades.\",\n      \"evidence\": \"Yeast two-hybrid and co-immunoprecipitation with domain mapping in neuronal cells\",\n      \"pmids\": [\"10827199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of JIP binding on Reelin signaling not tested\", \"No in vivo confirmation of ApoER2-JIP complex relevance\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that purified Reelin binds ApoER2 with higher affinity than VLDLR and that both receptors jointly mediate Dab1 phosphorylation established the cooperative yet non-redundant receptor model for Reelin signaling.\",\n      \"evidence\": \"Purified Reelin binding assays with cortical neurons from single and double receptor knockout mice, Dab1 phosphorylation immunoblotting\",\n      \"pmids\": [\"12670700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential Reelin affinity between receptors unknown at this time\", \"Downstream pathway divergence between receptors not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Four contemporaneous studies established fundamental aspects of ApoER2 cell biology: its postsynaptic localization with NMDA receptors and dependence on exon 19 for LTP; its clathrin-dependent endocytosis via Dab2 and the NPxY motif; and its interaction with F-spondin and β2GPI domain V, broadening the receptor's ligand repertoire and signaling contexts.\",\n      \"evidence\": \"Co-immunoprecipitation, LTP electrophysiology, exon 19 knock-in mice, endocytosis assays with dominant-negative constructs, platelet adhesion assays with domain-deletion mutants\",\n      \"pmids\": [\"16102539\", \"16101684\", \"16227578\", \"16091370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How exon 19 structurally couples ApoER2 to NMDA receptor tyrosine phosphorylation machinery was unclear\", \"Whether Dab2-mediated endocytosis is the sole internalization route in all cell types\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Three advances expanded ApoER2 function beyond brain signaling: identification as the testicular selenoprotein P receptor mediating selenium uptake; discovery that PCSK9 targets ApoER2 for lysosomal degradation independently of catalytic activity; demonstration that ApoER2 (not VLDLR) specifically controls late-born neuronal migration; and that ApoER2 interacts with APP to modulate Aβ production.\",\n      \"evidence\": \"Affinity chromatography/MS identification of Sepp1 receptor confirmed by ApoER2-KO mice with selenium deficiency; PCSK9 chimeras and catalytic mutants; BrdU fate mapping in single/double KO mice; co-IP and surface biotinylation with APP processing assays\",\n      \"pmids\": [\"17314095\", \"18039658\", \"17913789\", \"17620134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of selenium release from Sepp1 after ApoER2-mediated endocytosis not established\", \"Whether PCSK9-mediated ApoER2 degradation occurs in neurons in vivo\", \"Relative contribution of ApoER2-APP interaction to AD pathogenesis unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of thrombospondin-1 and activated protein C as new ApoER2 ligands revealed ligand-specific signaling diversity: THBS-1 induces Dab1 phosphorylation without degradation or Akt activation, while APC signals through Dab1-Y220/PI3K/Akt/GSK3β, establishing ApoER2 as a context-dependent signaling hub.\",\n      \"evidence\": \"Direct binding assays, SVZ explant chain assays with THBS-1-KO mice; SPR binding (Kd ~30 nM for APC), siRNA knockdown, kinase inhibitor dissection\",\n      \"pmids\": [\"18946489\", \"19116273\", \"18706682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How different ligands activate distinct downstream cascades through the same receptor is mechanistically unexplained\", \"In vivo significance of APC-ApoER2 axis in neuroprotection not fully tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic dissection using cytoplasmic domain knock-in mice showed that ApoER2's selenium transport and Reelin signaling functions are separable, resolving whether neurological phenotypes arise from selenium deficiency or impaired Reelin signaling. Concurrently, Factor XI was identified as a platelet ApoER2 ligand, and splice variant-specific Reelin binding profiles were characterized.\",\n      \"evidence\": \"Knock-in mice with signaling motif mutations retaining normal tissue selenium; SPR showing FXI binds ApoER2 with ~61 nM affinity confirmed by KO platelet adhesion assays; quantitative binding with purified Reelin fragments and ApoER2 splice variants\",\n      \"pmids\": [\"19007311\", \"19661487\", \"19167437\", \"19948739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether selenium transport requires specific splice variants of ApoER2 unknown\", \"In vivo thrombotic consequence of FXI-ApoER2 interaction not fully characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two discoveries established post-translational regulatory mechanisms controlling ApoER2 surface levels: the E3 ligase IDOL ubiquitinates ApoER2 for lysosomal degradation under LXR control, directly modulating Reelin signaling; and β2GPI-aPL antibody engagement of endothelial ApoER2 activates PP2A to dephosphorylate eNOS, identifying a pathogenic signaling axis in antiphospholipid syndrome with thrombosis protection in ApoER2-KO mice.\",\n      \"evidence\": \"Ubiquitination assays and LXR activation in vivo; ApoER2-KO mice with intravital microscopy and PP2A activity assays\",\n      \"pmids\": [\"20427281\", \"21123944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDOL regulation of ApoER2 occurs in neurons with physiological relevance to Reelin was not yet tested\", \"Cell-type specificity of PP2A assembly on ApoER2 tail unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Three findings expanded ApoER2's cellular roles: muscle cell selenium uptake via Sepp1 endocytosis requiring lysosomal acidification; positive regulation of Wnt/β-catenin signaling affecting osteoblast differentiation; and endothelial ApoE-mediated angiogenic control through LRP8.\",\n      \"evidence\": \"75Se-Sepp1 uptake with siRNA and lysosomal inhibitors in L8 myoblasts; Wnt reporter and osteoblast mineralization assays; in vivo LNA inhibition and cancer-endothelial co-culture\",\n      \"pmids\": [\"22761431\", \"22589174\", \"23142051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for ApoER2 participation in Wnt signaling unclear\", \"Whether LRP8-Wnt interaction is direct or through co-receptor mechanisms unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery that γ-secretase cleavage of ApoER2 produces an ICD that binds the RELN promoter and suppresses reelin transcription established a negative feedback loop in Reelin signaling; concurrently, CIN85 was identified as a Dab1-dependent adaptor recruited to ApoER2-positive early endosomes.\",\n      \"evidence\": \"ChIP showing ICD binding to RELN promoter, PS1 conditional KO mice, luciferase reporter; co-IP and immunofluorescence colocalization with Reelin stimulation\",\n      \"pmids\": [\"24344333\", \"23506116\", \"24381170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ICD-mediated RELN repression operates in all brain regions\", \"CIN85 functional role in ApoER2 trafficking vs. signaling not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple studies refined ApoER2's splicing-dependent functions and trafficking: O-linked sugar domain splicing (exon 16) controls ectodomain shedding, ICD release, spine density, and fear memory; SNX17 promotes ApoER2 recycling via the NPxY motif; neurotrophin-TrkB signaling induces ApoER2 shedding independently of MAPK/PI3K; and ApoE isoform-specific signaling through endothelial ApoER2 reveals ApoE4 as a dominant-negative antagonist.\",\n      \"evidence\": \"Splice variant knock-in mice with behavioral/electrophysiological phenotypes; GST pull-down and trafficking assays; pharmacological TrkA/TrkB dissection; eNOS assays with ApoER2-KO mice and carotid reendothelialization model\",\n      \"pmids\": [\"25429077\", \"24705369\", \"25233900\", \"25197062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How O-linked glycosylation mechanistically regulates metalloproteinase access for shedding\", \"Whether neurotrophin-induced shedding occurs in vivo and its functional significance\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The synapse-to-nucleus signaling model was completed by demonstrating that Reelin-triggered γ-secretase release of the ApoER2 ICD activates neuronal enhancers (LRN enhancers) controlling synaptic plasticity genes during memory formation; separately, Reelin-ApoER2 was shown to regulate Schwann cell migration through Rac1/Tiam1/PAR3.\",\n      \"evidence\": \"ChIP with enhancer profiling, γ-secretase inhibition, LRP8 knockdown, in vivo behavioral assays; FRET-based Rac1 activation and siRNA knockdown in Schwann cells\",\n      \"pmids\": [\"25892301\", \"26386179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of transcription factors cooperating with ApoER2 ICD at LRN enhancers unknown\", \"Whether ApoER2 ICD genomic targets differ between brain regions\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two studies connected ApoER2 splicing and postsynaptic scaffolding to disease-relevant function: antisense oligonucleotides correcting exon 19 splicing rescued synaptic and memory deficits in AD mice, and disruption of ApoER2/Dab1/PSD95 interaction destabilized dendritic architecture and reintroduced immature NR2B-NMDARs.\",\n      \"evidence\": \"ASO treatment with LTP and behavioral rescue in AD mouse model; tailless ApoER2 mutant with dendritic morphology and NMDAR subunit analysis\",\n      \"pmids\": [\"26902204\", \"27653801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which exon 19 mis-splicing occurs in AD brain not identified\", \"Whether ASO approach is viable for human therapeutic development\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three advances provided structural and mechanistic depth: the crystal structure of the ApoER2 ectodomain–Reelin complex revealed a contracted-open conformation with pH-dependent ligand release; IDOL was shown to regulate synaptic ApoER2 levels for experience-dependent spine remodeling and LTP; and GRIP1 was found to bridge ApoER2 with ephrinB2 and AMPA receptors in an activity-dependent postsynaptic complex essential for LTP.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis and pH-binding assays; IDOL-KO mice with spine imaging, barrel cortex plasticity, and behavioral tests; phospho-mutant knock-in mice with co-IP and LTP electrophysiology\",\n      \"pmids\": [\"28446613\", \"28891791\", \"28978486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length Reelin–receptor complex structure not yet available\", \"How IDOL activity is regulated by neuronal firing patterns unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Detailed dissection of the ApoER2 cytoplasmic tail as a PP2A scaffolding platform in endothelial cells revealed that Dab2 recruits to NPxY to activate PP2A-C via LCMT-1 methylation, while SHC1 recruits PP2A regulatory subunits to the proline-rich C-terminus, mediating aPL-induced eNOS and Akt dephosphorylation.\",\n      \"evidence\": \"Domain-specific mutants, co-IP, siRNA knockdown, in vivo thrombosis model\",\n      \"pmids\": [\"29500169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this PP2A assembly mechanism operates identically in platelets and trophoblasts\", \"Structural basis for the bipartite PP2A recruitment unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Three studies addressed receptor oligomerization dynamics, cell cycle regulation, and post-transcriptional control: Reelin rearranges ApoER2 homo-oligomers into higher-order clusters required for Dab1 phosphorylation; ApoER2 scaffolds PP2A-CDC20 interaction for APC activation and smooth muscle cell cycle progression; and SFRS11 stabilizes LRP8 mRNA via 3′ UTR binding, linking RNA metabolism to cognitive function.\",\n      \"evidence\": \"FLIM/FRET oligomerization analysis; co-IP with cell cycle arrest phenotyping in Lrp8-KO vascular model; RNA immunoprecipitation and behavioral rescue\",\n      \"pmids\": [\"30873003\", \"31412739\", \"31269452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether receptor clustering stoichiometry differs across cell types\", \"PP2A-CDC20 scaffolding by ApoER2 awaits independent confirmation\", \"How SFRS11 deficiency selectively affects LRP8 among its targets\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two discoveries extended ApoER2 biology to viral entry and placental pathology: alphavirus E2-E1 glycoproteins bind ApoER2/VLDLR ligand-binding domains for neuronal infection (blockable by soluble LBD-Fc), and ApoER2-PP2A signaling in trophoblasts drives preeclampsia in antiphospholipid syndrome.\",\n      \"evidence\": \"CRISPR KO screen, virus-like particle assays, in vivo SFV protection with LBD-Fc; APS mouse preeclampsia model with ApoER2-specific interventions\",\n      \"pmids\": [\"34929721\", \"34404233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ApoER2 versus VLDLR differentially determines neurotropism of specific alphaviruses\", \"Molecular determinants of PP2A activation in trophoblasts vs. endothelium\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Comprehensive long-read sequencing identified 25 human APOER2 splice isoforms, revealing that exon 5–8 deletion variants produce maximal CTF/ICD and transcriptional activation, while isoform-specific rescue of Apoer2-KO neurons showed differential ability to restore miniature excitatory events, establishing isoform-specific synaptic functions.\",\n      \"evidence\": \"Gene-specific long-read sequencing, CTF immunoblotting, ICD transcriptional reporter, miniature excitatory event recording with lentiviral rescue in KO neurons\",\n      \"pmids\": [\"35414534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific contributions to non-neuronal ApoER2 functions untested\", \"Regulation of isoform selection during development or disease not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies revealed mechanistic details of ApoER2-dependent selenium biology: LRP8 protects MYCN-amplified neuroblastoma from ferroptosis by supplying selenocysteine for GPX4 translation via selenoprotein P uptake; and high-affinity glycosylated ApoER2 variants use a Sec lyase-independent selenium transport mechanism distinct from low-affinity variants.\",\n      \"evidence\": \"CRISPR-activation screen with inducible KO and xenograft models; Kd measurements with 75Se uptake and Sec lyase/lysosomal inhibitors\",\n      \"pmids\": [\"37435859\", \"37406814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ferroptosis resistance via LRP8-SELENOP axis operates in normal neural stem cells\", \"Structural basis for affinity-dependent routing through different selenium release pathways\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genome-scale CRISPR screening identified LRP8 as a direct entry receptor for tick-borne encephalitis virus, binding the TBEV E glycoprotein and mediating attachment and internalization — extending ApoER2's role as a broad viral receptor.\",\n      \"evidence\": \"Genome-scale CRISPR-Cas9 screen, direct E glycoprotein binding, gain/loss-of-function infection assays, LRP8-based decoy receptor protection in mice\",\n      \"pmids\": [\"40993380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LRP8 serves as receptor for additional flaviviruses beyond TBEV\", \"Mechanism of viral genome release after ApoER2-mediated endocytosis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how the same receptor activates distinct downstream pathways depending on ligand identity; the full structural basis of ApoER2 ICD nuclear function and its chromatin targets across brain regions; and the therapeutic potential of splice-switching or decoy receptor strategies in neurodegeneration and viral infection.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length Reelin–ApoER2 complex structure available\", \"ICD cofactors and chromatin remodeling partners at LRN enhancers unidentified\", \"Cell-type-specific isoform expression maps not systematically generated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 7, 8, 15, 16, 17, 37]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 34]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [17, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 12, 14, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 23]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 24, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 7, 8, 9, 15, 16, 19, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 31]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 22, 25, 32, 45]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 28, 29, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 37]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [8, 20, 44]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"complexes\": [\n      \"ApoER2-NMDAR postsynaptic complex\",\n      \"ApoER2-GRIP1-ephrinB2-AMPAR complex\",\n      \"ApoER2-PP2A signaling complex\"\n    ],\n    \"partners\": [\n      \"RELN\",\n      \"DAB1\",\n      \"SELENOP\",\n      \"GRIP1\",\n      \"PSD95\",\n      \"PCSK9\",\n      \"IDOL\",\n      \"SNX17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}