LRP8 (ApoER2) is a type-I single-pass cell-surface receptor with seven LDL-receptor class A repeats, an extracellular beta-propeller and O-glycan-rich region, and a cytoplasmic signaling tail. It binds Reelin and apolipoprotein E-containing lipoproteins. Direct human assays establish high-affinity Reelin binding, while heterologous HEK293 experiments with murine ApoER2 provide mechanistic evidence that multivalent Reelin can cluster the receptor and initiate intracellular signaling. In parallel, lipoprotein binding supports receptor-mediated uptake. In neuronal systems, LRP8 cooperates with VLDLR and the adaptor DAB1 to control neuronal positioning and synaptic function, with many developmental outputs established most directly in mouse. Five curated human splice isoforms alter ligand-binding repeats, the O-glycan-rich region, or the cytoplasmic tail, but their endogenous functional partitioning remains incompletely defined. LRP8 can also serve as a cell-entry receptor for Semliki Forest, eastern equine encephalitis, and tick-borne encephalitis viruses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Plasma-membrane activity is safely conserved despite the heterogeneous LDLR-family IBA source set and is independently supported for human LRP8. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0030706 SUPPORTS TRANSFER FB:FBgn0051092 SUPPORTS TRANSFER MGI:MGI:1340044 SUPPORTS TRANSFER MGI:MGI:1860083 SUPPORTS TRANSFER MGI:MGI:2138856 SUPPORTS TRANSFER MGI:MGI:2442252 SUPPORTS TRANSFER MGI:MGI:96765 SUPPORTS TRANSFER MGI:MGI:96828 SUPPORTS TRANSFER PANTHER:PTN002557696 SUPPORTS TRANSFER RGD:2998 SUPPORTS TRANSFER RGD:619731 SUPPORTS TRANSFER RGD:727887 SUPPORTS TRANSFER UniProtKB:E1BGJ0 SUPPORTS TRANSFER UniProtKB:P01130 SUPPORTS TRANSFER UniProtKB:P01131 SUPPORTS TRANSFER UniProtKB:P98155 SUPPORTS TRANSFER UniProtKB:Q07954 SUPPORTS TRANSFER UniProtKB:Q14114 SUPPORTS TRANSFER UniProtKB:Q86YD5 SUPPORTS TRANSFER UniProtKB:Q9NPF0 SUPPORTS TRANSFER UniProtKB:Q9Y561 SUPPORTS TRANSFER UniProtKB:Q9Y5Q5 SUPPORTS TRANSFER WB:WBGene00003071 SUPPORTS TRANSFER WB:WBGene00015083 SUPPORTS TRANSFER WB:WBGene00019811 SUPPORTS TRANSFER |
| GO:0021517 ventral spinal cord development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation of ventral spinal cord development reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Ventral spinal cord development is a plausible Reelin-pathway outcome but is tissue- and stage-specific rather than LRP8's core molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1340044 SUPPORTS TRANSFER PANTHER:PTN002800148 SUPPORTS TRANSFER UniProtKB:Q98931 SUPPORTS TRANSFER |
| GO:0005901 caveola | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation of caveola reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Direct human evidence supports caveolar localization, but this membrane microdomain is contextual rather than universal. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002800148 SUPPORTS TRANSFER UniProtKB:Q14114 SUPPORTS TRANSFER |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: IEA annotation of transmembrane signaling receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The ARBA receptor term is unnecessarily generic; current GO:0038025 captures the established Reelin receptor activity without importing unrelated LDLR-family signaling. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00026973 SUPPORTS TRANSFER Proposed replacements: reelin receptor activity |
| GO:0005041 low-density lipoprotein particle receptor activity | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation of low-density lipoprotein particle receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Human LRP8 binds LDL much less strongly than apoE-rich beta-VLDL, so LDL-particle receptor activity is secondary and must not be generalized from LDLR, LRP1, or LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00043573 SUPPORTS TRANSFER |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA annotation of calcium ion binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Calcium coordination by LDL-receptor class A repeats is a valid structural property but not LRP8's defining receptor function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER InterPro:IPR018097 SUPPORTS TRANSFER |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation of extracellular region reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Extracellular localization applies to proteolytically shed ectodomains from cleavage-site-containing forms, not every intact membrane isoform. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0243 SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The plasma membrane is the core site for LRP8 ligand binding, signaling, and uptake. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER |
| GO:0006897 endocytosis | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation of endocytosis reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Human LRP8 directly internalizes apoE-rich beta-VLDL, so endocytosis is not merely an LDLR-family transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027119 SUPPORTS TRANSFER |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | MODIFY | Summary: IEA annotation of signal transduction reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Generic signal transduction should be replaced by the directly established Reelin-mediated signaling pathway. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00029050 SUPPORTS TRANSFER Proposed replacements: reelin-mediated signaling pathway |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000120 | MODIFY | Summary: IEA annotation of vesicle-mediated transport reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The combined rule reflects receptor internalization; endocytosis is more specific and informative than vesicle-mediated transport. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: GO:0005041 SUPPORTS TRANSFER GO:0030229 SUPPORTS TRANSFER GO:0038024 SUPPORTS TRANSFER Proposed replacements: endocytosis |
| GO:0030229 very-low-density lipoprotein particle receptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation of very-low-density lipoprotein particle receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Direct human data establish high-affinity binding and internalization of apoE-rich beta-VLDL. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00085597 SUPPORTS TRANSFER |
| GO:0034185 apolipoprotein binding | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation of apolipoprotein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Direct human biochemical data establish binding of apoE-containing ligands. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00090479 SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:12950167 Domains of apoE required for binding to apoE receptor 2 and ... | MODIFY | Summary: IPI annotation of protein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The APOE interaction is specifically captured by current GO:0034185 rather than uninformative protein binding. Proposed replacements: apolipoprotein binding Supporting Evidence: PMID:12950167 Specific binding to apoER2 was obtained by subtracting from the total binding to the receptor-expressing cells the nonspecific binding values of the untransfected cells. |
| GO:0005515 protein binding | IPI PMID:17548821 Structure of a receptor-binding fragment of reelin and mutat... | MODIFY | Summary: IPI annotation of protein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The mouse Reelin interaction supports the specific Reelin receptor activity term; the tested species does not imply human-ligand specificity. Proposed replacements: reelin receptor activity Supporting Evidence: PMID:17548821 We found that both receptor-binding and subsequent Dab1 phosphorylation occur solely in the segment spanning the fifth and sixth reelin repeats (R5-6). |
| GO:0005515 protein binding | IPI PMID:19116273 Activated protein C ligation of ApoER2 (LRP8) causes Dab1-de... | MODIFY | Summary: IPI annotation of protein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The paper directly establishes activated protein C binding to human ApoER2, supporting protease binding. The source WITH/FROM P25054 is retained as machine provenance but is a homonym misgrounding: the assayed ligand is PROC/P04070, not adenomatous polyposis coli protein. Proposed replacements: protease binding Supporting Evidence: PMID:19116273 In surface plasmon resonance equilibrium binding studies, APC bound with high affinity to soluble (s) ApoER2 (apparent K(d), approximately 30 nM) but not to soluble very low density lipoprotein receptor. |
| GO:0005515 protein binding | IPI PMID:20223215 Structural basis for specific recognition of reelin by its r... | MODIFY | Summary: IPI annotation of protein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The normalized row unions Reelin and LRPAP1 partners; the Reelin source and structure support reelin receptor activity, while the cached abstract does not establish the LRPAP1 partner. Proposed replacements: reelin receptor activity Supporting Evidence: PMID:20223215 Analysis of a 2.6 A crystal structure of the reelin receptor-binding fragment in complex with the LA1 of ApoER2 revealed that Lys2467 of reelin is recognized by both a conserved Trp residue and calcium-coordinating acidic residues from LA1, |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI annotation of protein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The BioPlex LRP8-LRPAP1 association is useful context, but generic binding from a proteome-scale cell-line network is not a core function. |
| GO:0005875 microtubule associated complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation of microtubule associated complex reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Downstream regulation of neuronal microtubules does not establish this membrane receptor as part of a microtubule-associated complex. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH ROLE CONFLATION Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS SOURCE BUT NOT TARGET ensembl:ENSRNOP00000087919 SUPPORTS SOURCE BUT NOT TARGET |
| GO:0008035 high-density lipoprotein particle binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of high-density lipoprotein particle binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: HDL-particle binding transferred from rat is plausible but secondary to directly established human Reelin and apoE-rich beta-VLDL functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation of response to xenobiotic stimulus reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: A rat xenobiotic-response context is not established as a conserved direct LRP8 function. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS SOURCE BUT NOT TARGET ensembl:ENSRNOP00000087919 SUPPORTS SOURCE BUT NOT TARGET |
| GO:0019894 kinesin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of kinesin binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Rat kinesin binding may reflect cytoplasmic-tail trafficking but is not a defining receptor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0021987 cerebral cortex development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of cerebral cortex development reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Cerebral cortex development is consistent with conserved Reelin signaling but is a downstream organismal outcome. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of axon reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Axonal localization transferred from rat is plausible but cell-type and developmental-context dependent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of dendrite reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Dendritic localization is compatible with synaptic ApoER2 roles but is contextual. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of neuronal cell body reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Neuronal-cell-body localization is plausible but less informative than the core plasma-membrane location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0071363 cellular response to growth factor stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation of cellular response to growth factor stimulus reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Growth-factor-responsive expression or behavior does not establish LRP8 as a conserved causal component of this broad response. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS SOURCE BUT NOT TARGET ensembl:ENSRNOP00000087919 SUPPORTS SOURCE BUT NOT TARGET |
| GO:0071397 cellular response to cholesterol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation of cellular response to cholesterol reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Cholesterol response is compatible with lipoprotein-receptor signaling but remains contextual. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A8I6GFL9 SUPPORTS TRANSFER ensembl:ENSRNOP00000087919 SUPPORTS TRANSFER |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-975634 | KEEP AS NON CORE | Summary: TAS annotation of retinoid metabolic process reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Reactome pathway membership is retained as secondary context; LRP8 is not a retinoid-metabolic enzyme and LRP2 biology must not be transferred. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of extracellular region reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Mouse transfer supports shed ectodomain localization but not extracellular residence of every intact human isoform. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | EXP PMID:30873003 Differential Action of Reelin on Oligomerization of ApoER2 a... | ACCEPT | Summary: EXP annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The HEK293 system supports membrane location, while independent evidence establishes human LRP8 at the plasma membrane; it does not establish neuronal physiology. |
| GO:0005886 plasma membrane | IDA Q14114-4 PMID:30873003 Differential Action of Reelin on Oligomerization of ApoER2 a... | ACCEPT | Summary: IDA annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Q14114-4 identifies the tested product but does not show that plasma-membrane activity is unique to isoform 4. |
| GO:0021819 layer formation in cerebral cortex | ISS Q14114-4 GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of layer formation in cerebral cortex reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: This single Q14114-4 row transfers mouse Lrp8 evidence for a downstream cortical-development outcome. It is biologically plausible but non-core, and the tested isoform does not establish isoform-specific function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1340044 SUPPORTS TRANSFER |
| GO:0038025 reelin receptor activity | ISS Q14114-4 GO_REF:0000024 | ACCEPT | Summary: ISS annotation of reelin receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Reelin binding is core LRP8 biology; the first-normalized Q14114-4 tag records the tested product, while unioned mouse and canonical sources do not prove isoform exclusivity. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1340044 SUPPORTS TRANSFER UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0038026 reelin-mediated signaling pathway | ISS Q14114-4 GO_REF:0000024 | ACCEPT | Summary: ISS annotation of reelin-mediated signaling pathway reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Reelin signaling is core LRP8 biology; the Q14114-4 tag records the tested product and does not show that other isoforms lack signaling activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1340044 SUPPORTS TRANSFER UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0021541 ammon gyrus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of ammon gyrus development reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Ammon gyrus development is a tissue-specific downstream consequence of Reelin signaling. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0061003 positive regulation of dendritic spine morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of positive regulation of dendritic spine morphogenesis reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Dendritic-spine morphogenesis is a credible neuronal outcome but not the receptor's core molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0005041 low-density lipoprotein particle receptor activity | TAS Reactome:R-HSA-2404131 | KEEP AS NON CORE | Summary: TAS annotation of low-density lipoprotein particle receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The LRP-mediated Reactome event is secondary context and must not import LDLR, LRP1, or LRP2 cargo repertoires into LRP8. |
| GO:0038024 cargo receptor activity | NAS PMID:10571240 Reelin is a ligand for lipoprotein receptors. | KEEP AS NON CORE | Summary: NAS annotation of cargo receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Cargo receptor activity is supported by LRP8-mediated lipoprotein uptake and is compatible with the accepted VLDL-particle receptor child term. The source does not, however, establish the attached has_input RELN extension for LRP8 because vesicular Reelin internalization was shown only after VLDLR binding. Supporting Evidence: PMID:10571240 After binding to VLDLR on the cell surface, Reelin is internalized into vesicles. |
| GO:0042981 regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of regulation of apoptotic process reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Apoptosis regulation is plausible only in defined immune or activated-protein-C contexts and is non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0045088 regulation of innate immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of regulation of innate immune response reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: UniProt limits innate-immune regulation to an apoE-dependent myeloid-cell model by similarity; it should not be generalized across tissues. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0005041 low-density lipoprotein particle receptor activity | TAS PMID:20005821 Overexpression of low-density lipoprotein receptor in the br... | KEEP AS NON CORE | Summary: TAS annotation of low-density lipoprotein particle receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The cached abstract assays LDLR rather than LRP8, so this citation cannot independently establish LRP8; however, the same secondary activity is supported by other LRP8 annotations and curator deference favors retention rather than removal. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: HDA annotation of membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The NK-like-cell membrane proteome supports contextual membrane residence but is less specific than direct plasma-membrane evidence. |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | KEEP AS NON CORE | Summary: IDA annotation of signaling receptor complex reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The full-text cache supports LDLR-family cargo-adaptor complexes but not a defining LRP8 signaling-receptor complex; retain the experimental annotation non-core with curator deference. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-432129 | ACCEPT | Summary: TAS annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The Reactome FGR-phosphorylation event uses the expected core plasma-membrane receptor location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2404131 | ACCEPT | Summary: TAS annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The Reactome LRP cargo event uses the independently supported core plasma-membrane location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-432121 | ACCEPT | Summary: TAS annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The Reactome LDL-binding event uses the independently supported core plasma-membrane location. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8948034 | ACCEPT | Summary: TAS annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The Reactome FGR-LDL-LRP8 event uses the correct receptor location despite its platelet context. |
| GO:0034185 apolipoprotein binding | IC PMID:8626535 Human apolipoprotein E receptor 2. A novel lipoprotein recep... | ACCEPT | Summary: IC annotation of apolipoprotein binding reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The human study directly shows high-affinity binding of apoE-rich beta-VLDL, supporting this curator inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: GO:0030229 SUPPORTS TRANSFER Supporting Evidence: PMID:8626535 LDL receptor deficient Chinese hamster ovary cells expressing human apoER2 bound apoE rich beta-migrating VLDL with high affinity and internalized. |
| GO:0050804 modulation of chemical synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of modulation of chemical synaptic transmission reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Synaptic-transmission modulation is a conserved but downstream neuronal role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:1900006 positive regulation of dendrite development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation of positive regulation of dendrite development reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Dendrite development is a plausible conserved neuronal phenotype but a secondary outcome. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q924X6 SUPPORTS TRANSFER |
| GO:0016020 membrane | IC PMID:11152697 Identification of a novel exon in apolipoprotein E receptor ... | KEEP AS NON CORE | Summary: IC annotation of membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: LRP8 is an integral membrane receptor, but plasma membrane is the more informative independently supported location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: GO:0030229 SUPPORTS TRANSFER |
| GO:0005901 caveola | IDA PMID:11369809 Localization of apolipoprotein E receptor 2 to caveolae in t... | KEEP AS NON CORE | Summary: IDA annotation of caveola reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Direct evidence distinguishes ApoER2 caveolar localization from LDLR, but this microdomain may vary by cell type. Supporting Evidence: PMID:11369809 Here, we show that apoER2, but not LDL-R, is localized to caveolae, supporting the concept that its physiological role is in cell signaling, rather than in endocytosing ligands. |
| GO:0030229 very-low-density lipoprotein particle receptor activity | IDA PMID:8626535 Human apolipoprotein E receptor 2. A novel lipoprotein recep... | ACCEPT | Summary: IDA annotation of very-low-density lipoprotein particle receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The original human study directly establishes high-affinity beta-VLDL binding and internalization without paralog transfer. Supporting Evidence: PMID:8626535 LDL receptor deficient Chinese hamster ovary cells expressing human apoER2 bound apoE rich beta-migrating VLDL with high affinity and internalized. |
| GO:0006508 proteolysis | NAS PMID:11152697 Identification of a novel exon in apolipoprotein E receptor ... | UNDECIDED | Summary: NAS annotation of proteolysis reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The cached abstract concerns alternative splicing, not LRP8 acting in proteolysis; incomplete full-text access requires UNDECIDED. |
| GO:0006629 lipid metabolic process | NAS PMID:11152697 Identification of a novel exon in apolipoprotein E receptor ... | KEEP AS NON CORE | Summary: NAS annotation of lipid metabolic process reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The splice-study abstract does not independently establish a metabolic role, but human beta-VLDL binding and uptake support the same broad secondary process, so curator deference favors retention as non-core. |
| GO:0019221 cytokine-mediated signaling pathway | NAS PMID:11152697 Identification of a novel exon in apolipoprotein E receptor ... | UNDECIDED | Summary: NAS annotation of cytokine-mediated signaling pathway reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The cached splice-study abstract contains no cytokine experiment, but incomplete access precludes confident removal. |
| GO:0005886 plasma membrane | NAS PMID:10380922 Reeler/Disabled-like disruption of neuronal migration in kno... | ACCEPT | Summary: NAS annotation of plasma membrane reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The mouse study describes ApoER2 as a cell-surface receptor; this broad topology is conserved in human and independently corroborated. |
| GO:0004888 transmembrane signaling receptor activity | TAS PMID:8626535 Human apolipoprotein E receptor 2. A novel lipoprotein recep... | MODIFY | Summary: TAS annotation of transmembrane signaling receptor activity reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The paper directly assays a VLDL-particle receptor, not generic signaling; use GO:0030229 rather than importing later Reelin evidence into this citation. Proposed replacements: very-low-density lipoprotein particle receptor activity |
| GO:0006629 lipid metabolic process | TAS PMID:8626535 Human apolipoprotein E receptor 2. A novel lipoprotein recep... | KEEP AS NON CORE | Summary: TAS annotation of lipid metabolic process reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: Lipid metabolism is a broad downstream consequence of lipoprotein handling, not an enzymatic activity or the most informative core term. |
| GO:0007165 signal transduction | TAS PMID:10380922 Reeler/Disabled-like disruption of neuronal migration in kno... | MODIFY | Summary: TAS annotation of signal transduction reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The mouse knockout study supports the specific Reelin-mediated signaling pathway in human ortholog LRP8 but does not make all VLDLR functions transferable. Proposed replacements: reelin-mediated signaling pathway Supporting Evidence: PMID:10380922 These findings suggest that VLDLR and ApoER2 participate in transmitting the extracellular Reelin signal to intracellular signaling processes initiated by mDab1. |
| GO:0006897 endocytosis | IDA PMID:8626535 Human apolipoprotein E receptor 2. A novel lipoprotein recep... | ACCEPT | Summary: IDA annotation of endocytosis reviewed against the cached source, UniProt record, and LRP8-specific biology. Reason: The original human study directly demonstrates internalization of apoE-rich beta-VLDL. Supporting Evidence: PMID:8626535 LDL receptor deficient Chinese hamster ovary cells expressing human apoER2 bound apoE rich beta-migrating VLDL with high affinity and internalized. |
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Download this section (compressed HTML)Q: Which human neural cell types require LRP8 rather than VLDLR for proximal Reelin-DAB1 signaling and its developmental or synaptic outputs?
Q: Which of the five human LRP8 isoforms are translated endogenously, and how do the deleted ligand-binding, O-glycan-rich, and cytoplasmic segments alter receptor function?
Q: What is the full-length membrane architecture of Reelin-bound and apoE-particle-bound LRP8, and do the two ligand classes impose different receptor stoichiometries?
Q: In which primary human tissues and viral strains is LRP8 necessary rather than redundant for entry, and which receptor isoforms are used?
Experiment: Generate isogenic LRP8-null, VLDLR-null, and double-null human neural progenitors and neurons, rescue with expression-matched receptors, and quantify Reelin binding, DAB1 phosphorylation, migration, dendritic maturation, and synaptic physiology.
Hypothesis: Human neural Reelin signaling has a cell-type-specific requirement for LRP8 that is only partly redundant with VLDLR.
Type: isogenic receptor-complementation signaling study
Experiment: Use long-read RNA sequencing and isoform-specific proteomics to identify endogenous products, then introduce each verified isoform at its native locus and compare surface delivery, ligand affinity, endocytosis, proteolysis, DAB1 signaling, and adaptor binding.
Hypothesis: Human LRP8 splice isoforms partition ligand uptake, Reelin signaling, and cytoplasmic-adaptor recruitment.
Type: isoform-resolved endogenous functional comparison
Experiment: Reconstitute full-length human LRP8 in nanodiscs with defined ligands, measure stoichiometry by single-particle and biophysical methods, determine structures, and test interface mutants in matched cell-signaling and cargo-uptake assays.
Hypothesis: Reelin and apoE-containing particles stabilize distinct full-length LRP8 assemblies.
Type: membrane-receptor reconstitution and structural analysis
Experiment: Map viral and endogenous ligand contacts across the human LRP8 ectodomain using binding assays and receptor mutants, then test separation-of-function alleles in primary human neural and vascular models while monitoring receptor trafficking and endogenous ligand responses.
Hypothesis: Viral entry depends on a separable LRP8 ligand-binding surface that can be disrupted without impairing Reelin or lipoprotein receptor functions.
Type: comparative receptor-interface and separation-of-function study
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The extent to which endogenous human LRP8 couples Reelin binding to DAB1-dependent developmental and synaptic outputs in defined neural cell types remains unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human ApoER2 directly binds Reelin and receptor clustering has been studied in engineered HEK293 cells. Cortical layering, hippocampal development, dendritic spine, and synaptic phenotypes are established principally in mouse and often jointly with VLDLR.
Significance: Resolving this boundary is necessary to distinguish conserved human receptor signaling from mouse developmental phenotypes and from redundant VLDLR activity.
What would resolve it: Perturb LRP8 and VLDLR separately and together in human neural lineage models, rescue with expression-matched human LRP8, and measure proximal DAB1 signaling, neuronal positioning, and synaptic maturation.
Provenance (the field's own admissions):
Gap: Endogenous functions of the five curated human LRP8 splice isoforms are not resolved at protein, tissue, or signaling level.
OPEN BIOLOGY
What is known: The isoforms alter LDL-receptor class A repeats, the O-glycan-rich region, or a large segment of the cytoplasmic tail. Human transcript studies establish alternative splicing, but most processing and adaptor-coupling claims are transferred from mouse and isoform 5 has no described reviewed sequence.
Significance: Isoform composition could change ligand selectivity, surface retention, proteolysis, and intracellular signaling, so canonical-product annotations cannot automatically be assigned to every proteoform.
What would resolve it: Establish isoform-resolved transcripts and proteins in human tissues, then compare surface delivery, ligand binding, cleavage, internalization, DAB1 coupling, and cytoplasmic-adaptor recruitment at endogenous abundance.
Gap: The architecture and stoichiometry of full-length LRP8 ligand complexes in a membrane remain unknown.
OPEN BIOLOGY
What is known: Experimental structures cover isolated LDL-receptor class A modules or an ectodomain fragment, and HEK293 imaging supports ligand-dependent receptor rearrangement. No experimental structure includes the complete ectodomain, transmembrane helix, cytoplasmic tail, membrane, and signaling adaptors together.
Significance: A full receptor assembly is needed to connect ligand-specific extracellular recognition to oligomerization and intracellular signaling.
What would resolve it: Reconstitute full-length human LRP8 in a membrane with Reelin or apoE particles and determine ligand-dependent stoichiometry and structure, coupled to interface mutagenesis and signaling assays.
Gap: The physiological importance and tissue range of LRP8-mediated viral entry in humans remain incompletely defined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Direct cell-based evidence establishes receptor activity for several enveloped viruses, including a mapped tick-borne encephalitis virus interaction with the first two ligand-binding repeats. These specialized infection contexts do not establish that viral entry is an endogenous core function or define the relevant human tissues in vivo.
Significance: Tissue expression, receptor isoform usage, and redundancy with related LDLR-family receptors will determine whether LRP8 is a useful antiviral target.
What would resolve it: Compare endogenous LRP8 dependence, isoform usage, and receptor redundancy in primary human neural and vascular models across viral strains, then validate receptor-interface mutants that preserve endogenous ligand functions.
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