LRP2, also called megalin, is a 4,655-residue type-I single-pass cargo receptor expressed at the apical surface of absorptive epithelia, especially renal proximal tubules and choroid plexus. Its large LDL-receptor-family ectodomain binds diverse protein, lipoprotein, vitamin-carrier, hormone, and metal-carrier cargos, often in cooperation with cubilin, while cytoplasmic sorting motifs recruit endocytic adaptors. LRP2 enters clathrin-coated carriers, releases cargo in acidic endosomes, and recycles to the cell surface; in specialized epithelia it can also support transcytosis. This receptor cycle underlies renal reclamation and tissue-specific delivery or clearance of extracellular macromolecules. Biallelic human LRP2 variants cause Donnai-Barrow/facio-oculo-acoustico-renal syndrome, consistent with important functions in kidney, brain, eye, ear, and embryonic development.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006898 receptor-mediated endocytosis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA inference associates LRP2 with receptor-mediated endocytosis; exact source entities and annotation extensions are retained for traceability. Reason: Receptor-mediated endocytosis is the defining conserved biological process of LRP2 and is supported by multiple direct ligand-uptake studies. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:95794 SUPPORTS TRANSFER PANTHER:PTN008580772 SOURCE WEAK OR INFERRED PANTHER ancestral-node provenance is informative but is not independent experimental evidence. RGD:68407 SUPPORTS TRANSFER UniProtKB:P98164 SOURCE WEAK OR INFERRED Target self-WITH/FROM is expected IBA provenance and is not independent evidence; it is not circular. |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA inference associates LRP2 with apical plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: Apical plasma-membrane localization is a defining feature of the full-length type-I receptor and is concordant with direct human placental and renal-cell evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0261260 SUPPORTS TRANSFER MGI:MGI:95794 SUPPORTS TRANSFER PANTHER:PTN008580772 SOURCE WEAK OR INFERRED PANTHER ancestral-node provenance is informative but is not independent experimental evidence. RGD:68407 SUPPORTS TRANSFER UniProtKB:P98164 SOURCE WEAK OR INFERRED Target self-WITH/FROM is expected IBA provenance and is not independent evidence; it is not circular. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retained as a correct but non-core broad location; apical plasma membrane is the more informative core localization of the epithelial cargo receptor. Reason: Plasma-membrane localization is consistent with LRP2's single-pass topology and cargo-capture role, but GO:0005886 is generic relative to the accepted direct and inferred GO:0016324 apical plasma membrane annotations used in the core model. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: FB:FBgn0261260 SUPPORTS TRANSFER MGI:MGI:95794 SUPPORTS TRANSFER PANTHER:PTN008580766 SOURCE WEAK OR INFERRED PANTHER ancestral-node provenance is informative but is not independent experimental evidence. RGD:68407 SUPPORTS TRANSFER UniProtKB:P98164 SOURCE WEAK OR INFERRED Target self-WITH/FROM is expected IBA provenance and is not independent evidence; it is not circular. |
| GO:0042562 hormone binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA inference associates LRP2 with hormone binding; exact source entities and annotation extensions are retained for traceability. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN008580772 SOURCE WEAK OR INFERRED PANTHER ancestral-node provenance is informative but is not independent experimental evidence. RGD:68407 SUPPORTS TRANSFER |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA inference associates LRP2 with signaling receptor complex; exact source entities and annotation extensions are retained for traceability. Reason: The current term requires membership in a complex that initiates signaling. The IBA sources mix exact LRP2 ortholog provenance with LRP1B and ancestral nodes; target self-WITH/FROM is expected provenance, not independent evidence. The term-to-source fit therefore remains unresolved. Propagation Review Root cause: UNRESOLVED Failure modes: COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Sources checked: PANTHER:PTN008580766 SOURCE WEAK OR INFERRED PANTHER ancestral-node provenance is informative but is not independent experimental evidence. RGD:68407 SUPPORTS TRANSFER UniProtKB:P98164 SOURCE WEAK OR INFERRED Target self-WITH/FROM is expected IBA provenance and is not independent evidence; it is not circular. UniProtKB:Q9NZR2 SUPPORTS SOURCE BUT NOT TARGET LRP1B is a paralog and cannot by itself establish LRP2 membership in a signaling receptor complex. |
| GO:0001523 retinoid metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with retinoid metabolic process; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028293 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0005041 low-density lipoprotein particle receptor activity | IEA GO_REF:0000117 | MODIFY | Summary: IEA inference associates LRP2 with low-density lipoprotein particle receptor activity; exact source entities and annotation extensions are retained for traceability. Reason: The current GO:0005041 requires low-density-lipoprotein-particle binding and uptake; family membership and this electronic rule do not establish that substrate-specific activity. The conserved multiligand uptake role supports the more defensible cargo receptor activity term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00043573 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. Proposed replacements: cargo receptor activity |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with calcium ion binding; exact source entities and annotation extensions are retained for traceability. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER InterPro:IPR018097 SUPPORTS TRANSFER |
| GO:0007165 signal transduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA inference associates LRP2 with signal transduction; exact source entities and annotation extensions are retained for traceability. Reason: Generic signal transduction is too broad: LRP2 is an endocytic cargo receptor, and this electronic rule does not establish an autonomous signaling output. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00029050 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0016020 membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with membrane; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0162 SUPPORTS TRANSFER |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA inference associates LRP2 with apical plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026413 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0015 SUPPORTS TRANSFER |
| GO:0030001 metal ion transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with metal ion transport; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028072 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0030424 axon | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with axon; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0279 SUPPORTS TRANSFER |
| GO:0030425 dendrite | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with dendrite; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0283 SUPPORTS TRANSFER |
| GO:0031904 endosome lumen | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with endosome lumen; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0327 SUPPORTS TRANSFER |
| GO:0043235 signaling receptor complex | IEA GO_REF:0000117 | UNDECIDED | Summary: IEA inference associates LRP2 with signaling receptor complex; exact source entities and annotation extensions are retained for traceability. Reason: The ARBA rule does not distinguish an endocytic receptor from membership in a signaling-initiating receptor complex, so the current GO:0043235 assertion cannot be resolved confidently. Propagation Review Root cause: UNRESOLVED Failure modes: COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Sources checked: ARBA:ARBA00029086 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with protein-folding chaperone binding; exact source entities and annotation extensions are retained for traceability. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00088077 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0051180 vitamin transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with vitamin transport; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026766 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. |
| GO:0005515 protein binding | IPI PMID:12713445 Selective interaction of megalin with postsynaptic density-9... | MODIFY | Summary: PMID:12713445 provides curator-assessed IPI evidence linking LRP2 to protein binding. Reason: The direct interaction is informative, but generic protein binding obscures the mechanism: the LRP2 C-terminal PDZ-binding motif binds PDZ2 domains of PSD-95-family DLG proteins. GO:0030165 is the more specific current term. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: PMID:28514442 provides curator-assessed IPI evidence linking LRP2 to protein binding. Reason: The high-throughput physical-association result may be real, but generic protein binding is uninformative and does not establish a specific LRP2 molecular function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: PMID:33961781 provides curator-assessed IPI evidence linking LRP2 to protein binding. Reason: The high-throughput physical-association result may be real, but generic protein binding is uninformative and does not establish a specific LRP2 molecular function. |
| GO:0001843 neural tube closure | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with neural tube closure; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0003139 secondary heart field specification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with secondary heart field specification; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0003148 outflow tract septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with outflow tract septum morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0003223 ventricular compact myocardium morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with ventricular compact myocardium morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005768 endosome | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP2 with endosome; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with endoplasmic reticulum; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with Golgi apparatus; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005903 brush border | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP2 with brush border; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP2 with clathrin-coated pit; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0006898 receptor-mediated endocytosis | IEA GO_REF:0000120 | ACCEPT | Summary: IEA inference associates LRP2 with receptor-mediated endocytosis; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00044584 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0007605 sensory perception of sound | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with sensory perception of sound; exact source entities and annotation extensions are retained for traceability. Reason: The mouse-ortholog transfer is compatible with the hearing impairment seen in human LRP2 deficiency, but sensory perception of sound is a systems-level auditory role downstream of LRP2 receptor trafficking rather than its core molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0008584 male gonad development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with male gonad development; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0009897 external side of plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with external side of plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0015031 protein transport | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with protein transport; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026546 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0030139 endocytic vesicle | IEA GO_REF:0000120 | ACCEPT | Summary: IEA inference associates LRP2 with endocytic vesicle; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027489 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0030514 negative regulation of BMP signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with negative regulation of BMP signaling pathway; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0031526 brush border membrane | IEA GO_REF:0000107 | ACCEPT | Summary: IEA inference associates LRP2 with brush border membrane; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0044321 response to leptin | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with response to leptin; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00084772 SOURCE WEAK OR INFERRED ARBA rule provenance is electronic and must be judged against LRP2 biology. UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0045177 apical part of cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with apical part of cell; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0050769 positive regulation of neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with positive regulation of neurogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0060068 vagina development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with vagina development; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0060982 coronary artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with coronary artery morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0061156 pulmonary artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with pulmonary artery morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0070447 positive regulation of oligodendrocyte progenitor proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with positive regulation of oligodendrocyte progenitor proliferation; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0140058 neuron projection arborization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with neuron projection arborization; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:1904447 folate import across plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA inference associates LRP2 with folate import across plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER ensembl:ENSMUSP00000079752 SUPPORTS TRANSFER |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-975634 | KEEP AS NON CORE | Summary: Reactome:R-HSA-975634 provides statement-level support for the LRP2 annotation to retinoid metabolic process. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0015889 cobalamin transport | TAS Reactome:R-HSA-9758890 | KEEP AS NON CORE | Summary: Reactome:R-HSA-9758890 provides statement-level support for the LRP2 annotation to cobalamin transport. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0042359 vitamin D metabolic process | TAS Reactome:R-HSA-196791 | KEEP AS NON CORE | Summary: Reactome:R-HSA-196791 provides statement-level support for the LRP2 annotation to vitamin D metabolic process. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0038024 cargo receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP2 with cargo receptor activity; exact source entities and annotation extensions are retained for traceability. Reason: Cargo receptor activity directly captures LRP2's defining role in binding extracellular ligands and delivering them into the endocytic pathway. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0016324 apical plasma membrane | EXP PMID:27798286 Megalin Is Predominantly Observed in Vesicular Structures in... | ACCEPT | Summary: PMID:27798286 provides curator-assessed EXP evidence linking LRP2 to apical plasma membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0038024 cargo receptor activity | EXP PMID:14528014 The adaptor protein ARH escorts megalin to and through endos... | ACCEPT | Summary: PMID:14528014 provides curator-assessed EXP evidence linking LRP2 to cargo receptor activity. Reason: Cargo receptor activity directly captures LRP2's defining role in binding extracellular ligands and delivering them into the endocytic pathway. |
| GO:0038024 cargo receptor activity | EXP PMID:8710919 Megalin-mediated endocytosis of transcobalamin-vitamin-B12 c... | ACCEPT | Summary: PMID:8710919 provides curator-assessed EXP evidence linking LRP2 to cargo receptor activity. Reason: Cargo receptor activity directly captures LRP2's defining role in binding extracellular ligands and delivering them into the endocytic pathway. |
| GO:0038024 cargo receptor activity | TAS Reactome:R-HSA-350168 | ACCEPT | Summary: Reactome:R-HSA-350168 provides statement-level support for the LRP2 annotation to cargo receptor activity. Reason: Cargo receptor activity directly captures LRP2's defining role in binding extracellular ligands and delivering them into the endocytic pathway. |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | IGI PMID:27241555 MicroRNA-146a represses LRP2 translation and leads to cell a... | MARK AS OVER ANNOTATED | Summary: PMID:27241555 provides curator-assessed IGI evidence linking LRP2 to phosphatidylinositol 3-kinase/protein kinase B signal transduction. Reason: miR-146a overexpression in SH-SY5Y cells reduced LRP2 expression and Akt activation. This indirect loss-of-expression phenotype does not establish LRP2 as a component of PI3K/AKT signal transduction, so the action is aligned with the over-annotated parent signal-transduction row. The IGI supporting entity is the amyloid-beta 42 peptide rather than a gene product. |
| GO:0043235 signaling receptor complex | ISS GO_REF:0000024 | UNDECIDED | Summary: ISS inference associates LRP2 with signaling receptor complex; exact source entities and annotation extensions are retained for traceability. Reason: The rat similarity source may support receptor association, but it does not by itself establish that human LRP2 is part of a signaling-initiating receptor complex under the current GO definition. Propagation Review Root cause: UNRESOLVED Failure modes: COMPARTMENT OR COMPLEX MISMATCH SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0005041 low-density lipoprotein particle receptor activity | TAS Reactome:R-HSA-2404131 | MODIFY | Summary: Reactome:R-HSA-2404131 provides statement-level support for the LRP2 annotation to low-density lipoprotein particle receptor activity. Reason: The current GO:0005041 requires low-density-lipoprotein-particle binding and uptake; the pathway statement does not establish that substrate-specific activity. The demonstrated multiligand uptake role supports the more defensible cargo receptor activity term. Proposed replacements: cargo receptor activity |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | KEEP AS NON CORE | Summary: PMID:30280653 provides statement-level support for the LRP2 annotation to transport across blood-brain barrier. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0150104 transport across blood-brain barrier | NAS PMID:26590417 Establishment and Dysfunction of the Blood-Brain Barrier. | KEEP AS NON CORE | Summary: PMID:26590417 provides statement-level support for the LRP2 annotation to transport across blood-brain barrier. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0015031 protein transport | IDA PMID:17324488 Megalin mediates the transport of leptin across the blood-CS... | KEEP AS NON CORE | Summary: PMID:17324488 provides curator-assessed IDA evidence linking LRP2 to protein transport. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0044321 response to leptin | IDA PMID:17324488 Megalin mediates the transport of leptin across the blood-CS... | KEEP AS NON CORE | Summary: PMID:17324488 provides curator-assessed IDA evidence linking LRP2 to response to leptin. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0031994 insulin-like growth factor I binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with insulin-like growth factor I binding; exact source entities and annotation extensions are retained for traceability. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0045056 transcytosis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP2 with transcytosis; exact source entities and annotation extensions are retained for traceability. Reason: Transcytosis is a core transport mode for LRP2 in polarized epithelia, with the transferred rat evidence retaining its species boundary. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0071363 cellular response to growth factor stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with cellular response to growth factor stimulus; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0097242 amyloid-beta clearance | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with amyloid-beta clearance; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0043066 negative regulation of apoptotic process | IGI PMID:27241555 MicroRNA-146a represses LRP2 translation and leads to cell a... | MARK AS OVER ANNOTATED | Summary: PMID:27241555 provides curator-assessed IGI evidence linking LRP2 to negative regulation of apoptotic process. Reason: miR-146a overexpression in SH-SY5Y cells reduced LRP2 while increasing caspase-3 and apoptosis. This is an indirect cell-line perturbation phenotype, not evidence that LRP2 itself acts upstream to negatively regulate apoptosis; the unusual IGI supporting entity is the amyloid-beta 42 peptide. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | ACCEPT | Summary: Reactome:R-HSA-8868658 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | ACCEPT | Summary: Reactome:R-HSA-8868659 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | ACCEPT | Summary: Reactome:R-HSA-8868660 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: Reactome:R-HSA-8868661 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | ACCEPT | Summary: Reactome:R-HSA-8869438 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | ACCEPT | Summary: Reactome:R-HSA-8871193 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | ACCEPT | Summary: Reactome:R-HSA-8871194 provides statement-level support for the LRP2 annotation to clathrin-coated endocytic vesicle membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0051087 protein-folding chaperone binding | IPI PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | KEEP AS NON CORE | Summary: PMID:9228033 provides curator-assessed IPI evidence linking LRP2 to protein-folding chaperone binding. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. |
| GO:0051087 protein-folding chaperone binding | ISS PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with protein-folding chaperone binding; exact source entities and annotation extensions are retained for traceability. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:C0HL13 SUPPORTS TRANSFER |
| GO:0006898 receptor-mediated endocytosis | ISS PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | ACCEPT | Summary: ISS inference associates LRP2 with receptor-mediated endocytosis; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:C0HL13 SUPPORTS TRANSFER |
| GO:1905167 positive regulation of lysosomal protein catabolic process | ISS PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex... | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with positive regulation of lysosomal protein catabolic process; exact source entities and annotation extensions are retained for traceability. Reason: The pig-ortholog transfer is tied to LRP2-mediated internalization and lysosomal degradation of apoJ-amyloid-beta cargo. It captures downstream cargo processing after receptor uptake, not a broad intrinsic role for LRP2 as a regulator of lysosomal protein catabolism, and is therefore non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:C0HL13 SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:23825075 Renal uptake of the antiapoptotic protein survivin is mediat... | KEEP AS NON CORE | Summary: PMID:23825075 provides curator-assessed IPI evidence linking LRP2 to protein binding. Reason: Surface plasmon resonance directly demonstrates megalin/LRP2 binding survivin, but the accessible evidence does not map the interaction to survivin's BIR domain and no supported survivin-specific GO binding term is available. The targeted association is therefore retained as non-core, while the separate uptake annotation captures LRP2's cargo-receptor role. |
| GO:0006898 receptor-mediated endocytosis | IDA PMID:23825075 Renal uptake of the antiapoptotic protein survivin is mediat... | ACCEPT | Summary: PMID:23825075 provides curator-assessed IDA evidence linking LRP2 to receptor-mediated endocytosis. Reason: Receptor-mediated endocytosis is the defining conserved biological process of LRP2 and the survivin study directly establishes uptake. |
| GO:0016324 apical plasma membrane | IDA PMID:23825075 Renal uptake of the antiapoptotic protein survivin is mediat... | ACCEPT | Summary: PMID:23825075 provides curator-assessed IDA evidence linking LRP2 to apical plasma membrane. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. |
| GO:0030424 axon | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with axon; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0030425 dendrite | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with dendrite; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0070447 positive regulation of oligodendrocyte progenitor proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with positive regulation of oligodendrocyte progenitor proliferation; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0140058 neuron projection arborization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with neuron projection arborization; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0005509 calcium ion binding | IDA PMID:23275343 Gentamicin binds to the megalin receptor as a competitive in... | KEEP AS NON CORE | Summary: PMID:23275343 provides curator-assessed IDA evidence linking LRP2 to calcium ion binding. Reason: The molecular interaction or structural feature is compatible with LRP2, but it is cargo-specific, generic, or ancillary rather than the receptor's defining activity. |
| GO:0001843 neural tube closure | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with neural tube closure; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0003139 secondary heart field specification | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with secondary heart field specification; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0003148 outflow tract septum morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with outflow tract septum morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0003223 ventricular compact myocardium morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with ventricular compact myocardium morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0060982 coronary artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with coronary artery morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0061156 pulmonary artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with pulmonary artery morphogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:1904447 folate import across plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with folate import across plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0008584 male gonad development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with male gonad development; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0009897 external side of plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with external side of plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0030514 negative regulation of BMP signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with negative regulation of BMP signaling pathway; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0050769 positive regulation of neurogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with positive regulation of neurogenesis; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0060068 vagina development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with vagina development; exact source entities and annotation extensions are retained for traceability. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0030001 metal ion transport | IDA PMID:15126248 Megalin mediates renal uptake of heavy metal metallothionein... | KEEP AS NON CORE | Summary: PMID:15126248 provides curator-assessed IDA evidence linking LRP2 to metal ion transport. Reason: This is a cargo-, tissue-, developmental-, or physiological context of LRP2-mediated uptake rather than the receptor's core evolved function. |
| GO:0006898 receptor-mediated endocytosis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP2 with receptor-mediated endocytosis; exact source entities and annotation extensions are retained for traceability. Reason: Receptor-mediated endocytosis is the defining conserved biological process of LRP2, with the rat transfer retaining its species boundary. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0007605 sensory perception of sound | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS inference associates LRP2 with sensory perception of sound; exact source entities and annotation extensions are retained for traceability. Reason: Similarity to mouse Lrp2 supports a conserved contribution to auditory physiology and is compatible with hearing impairment in human LRP2 deficiency. Sensory perception is nevertheless an organismal consequence of receptor function, not LRP2's core molecular activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP2 with apical plasma membrane; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER UniProtKB:A2ARV4 SUPPORTS TRANSFER |
| GO:0031526 brush border membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS inference associates LRP2 with brush border membrane; exact source entities and annotation extensions are retained for traceability. Reason: The annotation describes a conserved component of LRP2's polarized multiligand uptake and endocytic trafficking role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P98158 SUPPORTS TRANSFER |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: PMID:23533145 provides curator-assessed HDA evidence linking LRP2 to extracellular exosome. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | UNDECIDED | Summary: PMID:23382219 provides curator-assessed IDA evidence linking LRP2 to signaling receptor complex. Reason: The cached PMID:23382219 body discusses PX-FERM cargo-motif recognition broadly but contains no explicit LRP2 text. Under curator-deference rules, the experimental annotation is retained as UNDECIDED rather than rejected. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: PMID:19056867 provides curator-assessed HDA evidence linking LRP2 to extracellular exosome. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: PMID:17897319 provides curator-assessed HDA evidence linking LRP2 to lysosomal membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2404131 | KEEP AS NON CORE | Summary: Reactome:R-HSA-2404131 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-350168 | KEEP AS NON CORE | Summary: Reactome:R-HSA-350168 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8863472 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8863472 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8867754 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8867756 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868071 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868072 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868230 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868236 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868648 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868651 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: Reactome:R-HSA-8868661 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9759202 | KEEP AS NON CORE | Summary: Reactome:R-HSA-9759202 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9759209 | KEEP AS NON CORE | Summary: Reactome:R-HSA-9759209 provides statement-level support for the LRP2 annotation to plasma membrane. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0005515 protein binding | IPI PMID:9773776 Megalin is an endocytic receptor for insulin. | MODIFY | Summary: PMID:9773776 provides curator-assessed IPI evidence linking LRP2 to protein binding. Reason: Chemical cross-linking and immunoprecipitation identify megalin/LRP2 as an insulin-binding site. Insulin binding preserves the experimentally identified ligand and is more informative than generic protein binding; the separate endocytosis evidence captures subsequent uptake. Proposed replacements: insulin binding |
| GO:0005764 lysosome | TAS PMID:7768901 Identification of glycoprotein 330 as an endocytic receptor ... | KEEP AS NON CORE | Summary: PMID:7768901 provides statement-level support for the LRP2 annotation to lysosome. Reason: The location is biologically compatible, but it is broad, secondary, or tissue-contextual rather than the defining apical-plasma-membrane/endocytic route of LRP2. |
| GO:0006629 lipid metabolic process | TAS PMID:7768901 Identification of glycoprotein 330 as an endocytic receptor ... | MODIFY | Summary: PMID:7768901 provides statement-level support for the LRP2 annotation to lipid metabolic process. Reason: The ApoJ/clusterin study directly demonstrates LRP2-mediated binding, internalization, and lysosomal degradation. Receptor-mediated endocytosis is the specific process, whereas lipid metabolic process is an indirect cargo-context label. Proposed replacements: receptor-mediated endocytosis |
| GO:0006897 endocytosis | TAS PMID:7768901 Identification of glycoprotein 330 as an endocytic receptor ... | MODIFY | Summary: PMID:7768901 provides statement-level support for the LRP2 annotation to endocytosis. Reason: The ApoJ/clusterin study establishes receptor-mediated uptake; GO:0006898 is the appropriately specific child of generic endocytosis. Proposed replacements: receptor-mediated endocytosis |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:7768901 Identification of glycoprotein 330 as an endocytic receptor ... | ACCEPT | Summary: PMID:7768901 provides statement-level support for the LRP2 annotation to receptor-mediated endocytosis. Reason: Receptor-mediated endocytosis is the defining conserved biological process of LRP2 and PMID:7768901 directly establishes ApoJ/clusterin uptake. |
Loading supporting content…
Download this section (compressed HTML)Q: Which extracellular cargos are directly internalized by endogenous human LRP2 in kidney, choroid plexus, placenta, eye, and inner ear?
Suggested experts: Renal epithelial transport experts, LDL-receptor-family biologists
Q: How do pH-dependent LRP2 conformational changes coordinate ligand release, adaptor exchange, and receptor recycling in human cells?
Suggested experts: Structural biologists, Endocytic trafficking experts
Q: Which LRP2-dependent cargo pathways explain individual renal, neural, ocular, and auditory features of Donnai-Barrow syndrome?
Suggested experts: Human geneticists, Developmental physiologists
Q: Does endogenous human LRP2 undergo regulated ectodomain shedding and cytoplasmic-tail nuclear signaling, and in which tissues?
Suggested experts: Receptor proteolysis experts, Nuclear signaling experts
Q: Are any noncanonical human LRP2 transcripts translated into stable receptors with distinct localization or cargo preferences?
Suggested experts: Long-read transcriptomics experts, Proteogenomics experts
Experiment: Generate matched LRP2 knockout and rescue models from human proximal-tubule, choroid-plexus, and placental organoids, then perform quantitative ligand uptake, surface proteomics, and endosomal cargo profiling.
Hypothesis: Human LRP2 has a tissue-specific endogenous cargo repertoire rather than a uniform set of ligands across all absorptive epithelia.
Type: tissue-resolved receptor cargo profiling
Experiment: Determine full-length human LRP2 structures with selected cargos and cytoplasmic adaptors at extracellular and endosomal pH, then test interface variants by uptake, release, and recycling kinetics.
Hypothesis: The pH-regulated LRP2 homodimer reorganizes cargo and adaptor interfaces during the surface-to-endosome transition.
Type: structural endocytic-cycle analysis
Experiment: Introduce representative patient variants into isogenic kidney, neural, ocular, and inner-ear organoids, quantify cargo-specific transport, and rescue with wild-type or interface-selective receptor constructs.
Hypothesis: Distinct cargo-uptake defects drive separable components of Donnai-Barrow syndrome.
Type: variant-resolved organoid physiology
Experiment: Combine pulse-chase labeling, N-terminomics, subcellular fractionation, protease perturbation, and nuclear transcriptomics in naturally expressing human epithelia.
Hypothesis: Endogenous human LRP2 processing generates tissue-restricted extracellular and cytoplasmic products with distinct functions.
Type: endogenous receptor processing analysis
Experiment: Integrate long-read transcript sequencing with junction-specific targeted proteomics and isoform-specific surface-delivery and cargo-uptake assays across multiple human tissues.
Hypothesis: The reviewed 4,655-residue receptor is the predominant functional human LRP2 protein product.
Type: isoform-resolved transcript and protein validation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous human LRP2 cargo repertoire and quantitative uptake contribution in each expressing tissue are incompletely defined.
OPEN BIOLOGY MF_DARK
Significance: LRP2 binds many chemically distinct cargos, but much of the mechanistic evidence is from mouse, rat, rabbit, or heterologous minireceptor systems. Family architecture alone cannot assign every proposed ligand to human LRP2.
What would resolve it: Endogenously perturb and rescue LRP2 in human proximal-tubule, choroid-plexus, and placental models, then quantify uptake of a defined ligand panel together with surface and endosomal proteomics.
Provenance (the field's own admissions):
Gap: Ligand-specific interfaces and the complete adaptor architecture of full-length human LRP2 during its endocytic conformational cycle remain unresolved.
OPEN BIOLOGY MF_DARK
Significance: A full-length human cryo-EM entry is available without an associated publication, while the published pH-dependent structural mechanism used receptor purified from mouse kidney. Neither resource defines all human cargo or adaptor interfaces.
What would resolve it: Determine ligand- and adaptor-bound structures of endogenous human LRP2 at surface and endosomal pH, and test interface variants by quantitative uptake and recycling assays.
Provenance (the field's own admissions):
Gap: The cargo-specific mechanisms linking LRP2 loss to the pleiotropic features of Donnai-Barrow/facio-oculo-acoustico-renal syndrome are not established.
OPEN BIOLOGY BP_DARK
Significance: Human genetics establishes disease causality, but kidney, neural, ocular, auditory, and developmental phenotypes may reflect different cargos and tissue-specific transport routes.
What would resolve it: Pair patient-derived isogenic organoid models with cargo-resolved uptake assays and tissue-specific rescue to connect individual receptor defects to defined developmental and homeostatic pathways.
Provenance (the field's own admissions):
Gap: Proteolytic processing, soluble-receptor release, and nuclear-tail signaling by endogenous human LRP2 remain insufficiently characterized.
OPEN BIOLOGY CC_DARK
Significance: These processing routes are prominent in transferred annotations and non-human studies, but they should not be confused with named human isoforms or assumed to occur uniformly across tissues.
What would resolve it: Map endogenous human LRP2 cleavage products by N-terminomics and pulse-chase proteomics, localize each product, identify responsible proteases, and test transcriptional consequences of the released cytoplasmic fragment.
Gap: It is unknown whether any human LRP2 splice transcripts produce stable functional protein isoforms with distinct trafficking or cargo specificity.
OPEN BIOLOGY RESIDUAL_SUBGAP
Significance: The reviewed human record contains no curated alternative products, so soluble or processed receptor forms and non-human splice products cannot be treated as human isoforms.
What would resolve it: Use long-read RNA sequencing and junction-specific proteomics across LRP2-expressing human epithelia, followed by isoform-resolved surface delivery and cargo-uptake assays for any reproducibly detected products.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)