LRP3 encodes a poorly characterized 770-amino-acid member of the low-density lipoprotein receptor family. Its type-I membrane architecture comprises a signal peptide, an extracellular ectodomain predicted to contain two CUB domains and four LDL-receptor class-A domains in the order CUB1–LDLRA1–LDLRA2–CUB2–LDLRA3–LDLRA4, one transmembrane helix, and a long proline-rich cytoplasmic region containing a tyrosine-based internalization signal. LRP3 transcript is broadly detected in human tissues. In immortalized human bone-marrow stromal cells, LRP3 expression and perturbation support a context-dependent role that favors osteoblast differentiation and opposes adipocyte differentiation, with LRP3 mRNA regulated by miR-4739. Its physiological ligand, transported cargo, proximal signaling mechanism, and general relevance outside this stromal-cell model remain unknown; transfected CHO cells did not bind beta-migrating VLDL or receptor-associated protein under the reported conditions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places LRP3 at the plasma membrane, consistent with its type-I membrane topology and a family-supported coated-pit localization. Reason: Plasma membrane is a coherent active location for an LDLR-family receptor with an extracellular ligand-binding region and cytoplasmic internalization motif. The IBA is retained without importing the ligands or cargo repertoires of the many paralogous source receptors. 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:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated mapping assigns the broad membrane location from an ARBA rule and the UniProt membrane vocabulary term. Reason: The term is correct for the experimentally cloned type-I membrane protein. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028763 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0162 SUPPORTS TRANSFER |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA transfers a broad vesicle-mediated-transport process to LRP3, consistent with its cytoplasmic internalization motif and coated-pit family context. Reason: Vesicular trafficking is plausible, but no cargo has been identified and direct LRP3 uptake was not shown in the cached primary evidence. Retain this broad secondary process without treating it as a defined core receptor mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028249 SUPPORTS TRANSFER |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | UNDECIDED | Summary: The available cache is truncated after the introduction and does not expose enough of the cited review to verify or reject an LRP3-specific transport claim. Reason: The NAS cannot be confirmed from the incomplete cached article, but curator deference precludes treating the missing accessible evidence as proof of a miscitation. Full-article verification is required before accepting or removing this annotation. |
| GO:0010628 positive regulation of gene expression | IMP PMID:28340487 MicroRNA-4739 regulates osteogenic and adipocytic differenti... | MARK AS OVER ANNOTATED | Summary: LRP3 perturbation changed five osteogenic marker-expression readouts in immortalized human bone-marrow stromal cells. Reason: These transcript changes are downstream readouts of the osteoblast-differentiation phenotype; they do not establish that LRP3 directly or proximally regulates transcription of any marker gene. Treating each readout as a separate generic positive regulation of gene expression therefore overstates the mechanistic evidence. The exact occurs_in/has_input extensions are retained from the QuickGO annotation payload; the accessible abstract supports the lineage phenotype but does not enumerate these five marker entities. Supporting Evidence: PMID:28340487 Data from functional and gene expression assays demonstrated the role of LRP3 as a molecular switch promoting hBMSC lineage differentiation into osteoblasts and inhibiting differentiation into adipocytes. |
| GO:0010629 negative regulation of gene expression | IMP PMID:28340487 MicroRNA-4739 regulates osteogenic and adipocytic differenti... | MARK AS OVER ANNOTATED | Summary: LRP3 perturbation changed four adipogenic marker-expression readouts in immortalized human bone-marrow stromal cells. Reason: These transcript changes are downstream readouts of the adipocyte-differentiation phenotype; they do not establish that LRP3 directly or proximally regulates transcription of any marker gene. Treating each readout as a separate generic negative regulation of gene expression therefore overstates the mechanistic evidence. The exact occurs_in/has_input extensions are retained from the QuickGO annotation payload; the accessible abstract supports the lineage phenotype but does not enumerate these four marker entities. Supporting Evidence: PMID:28340487 Data from functional and gene expression assays demonstrated the role of LRP3 as a molecular switch promoting hBMSC lineage differentiation into osteoblasts and inhibiting differentiation into adipocytes. |
| GO:0045599 negative regulation of fat cell differentiation | IMP PMID:28340487 MicroRNA-4739 regulates osteogenic and adipocytic differenti... | KEEP AS NON CORE | Summary: LRP3 knockdown promoted adipogenic differentiation of immortalized human bone-marrow stromal cells. Reason: The direct perturbation phenotype supports negative regulation of fat-cell differentiation in the assayed stromal-cell context. It is retained as a lineage-specific downstream role rather than a defining receptor activity. Supporting Evidence: PMID:28340487 Over-expression of miR-4739 mimicked the effects of LRP3 knockdown on promoting adipogenic and suppressing osteogenic differentiation of hBMSCs. |
| GO:0045669 positive regulation of osteoblast differentiation | IMP PMID:28340487 MicroRNA-4739 regulates osteogenic and adipocytic differenti... | KEEP AS NON CORE | Summary: LRP3 knockdown suppressed osteogenic differentiation of immortalized human bone-marrow stromal cells. Reason: The direct perturbation phenotype supports positive regulation of osteoblast differentiation in the assayed stromal-cell context. It is retained as a lineage-specific downstream role rather than a defined receptor activity. Supporting Evidence: PMID:28340487 Over-expression of miR-4739 mimicked the effects of LRP3 knockdown on promoting adipogenic and suppressing osteogenic differentiation of hBMSCs. |
| GO:0006898 receptor-mediated endocytosis | TAS PMID:9693042 cDNA cloning of a new low-density lipoprotein receptor-relat... | UNDECIDED | Summary: The cloning paper identified a cytoplasmic tyrosine-based internalization signal, but the cached abstract reports no LRP3 ligand uptake experiment. Reason: Receptor-mediated endocytosis requires demonstrated cell-surface ligand binding and uptake. The abstract instead reports failure to bind beta-VLDL or LRPAP1; without the relevant full text, curator deference precludes rejecting the TAS, but the process cannot be accepted as established. Supporting Evidence: PMID:9693042 Despite the presence of the ligand-binding repeats, CHO cells transfected with LRP3 did not bind beta-migrating very-low-density lipoprotein or receptor-associated protein. |
| GO:0016020 membrane | TAS PMID:9693042 cDNA cloning of a new low-density lipoprotein receptor-relat... | ACCEPT | Summary: Human and rat LRP3 cDNAs encode a type-I membrane protein. Reason: Membrane localization is directly supported by the cloned sequence architecture and agrees with the reviewed UniProt record and automated membrane annotation. Supporting Evidence: PMID:9693042 Human and rat LRP3 cDNAs encode a 770-amino-acid type 1 membrane protein with the following regions: a putative signal sequence, two isoleucine/leucine/valine-rich regions with an RGD sequence, two ligand-binding repeat regions, a putative transmembrane region, and a proline-rich cytoplasmic region with a tyrosine-based internalization signal. |
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Download this section (compressed HTML)Q: What physiological ligand or extracellular partner, if any, engages human LRP3, given that beta-migrating VLDL and receptor-associated protein did not bind in the reported CHO-cell assay?
Suggested experts: H. Ishii, T. T. Yamamoto
Q: Does the cytoplasmic tyrosine-based signal drive constitutive or ligand-induced LRP3 internalization, and what cargo and adaptor machinery are involved?
Suggested experts: H. Ishii, T. T. Yamamoto
Q: Which proximal LRP3-dependent signaling event shifts immortalized human bone-marrow stromal cells between osteogenic and adipogenic differentiation, and does the same mechanism operate in primary human stromal cells?
Suggested experts: M. Elsafadi, A. Mahmood, M. Kassem
Experiment: Use purified human LRP3 ectodomain for unbiased cell-surface and secreted-protein ligand capture, then test candidate binding and uptake in matched LRP3-null cells rescued with wild-type LRP3 or a tyrosine-signal mutant. Quantify surface loss, cargo internalization, endosomal delivery, and competition with soluble ectodomain.
Hypothesis: Human LRP3 recognizes a ligand distinct from beta-migrating VLDL and LRPAP1 and internalizes it through the cytoplasmic tyrosine-based signal.
Type: ligand discovery and internalization-rescue assay
Experiment: Compare endogenous or equivalently expressed wild-type and tyrosine-signal-mutant LRP3 by surface biotinylation pulse-chase and live-cell imaging, coupled to proximity labeling or immunoprecipitation of adaptor proteins. Include expression, topology, and plasma-membrane delivery controls so a trafficking defect is not confused with misfolding.
Hypothesis: The cytoplasmic tyrosine-based signal recruits endocytic adaptors and is required for LRP3 movement from the plasma membrane into coated vesicles.
Type: motif separation-of-function trafficking assay
Experiment: Generate independent LRP3 knockout clones in primary human bone-marrow stromal cells from multiple donors, rescue them with wild-type LRP3, and profile early phosphoproteomic and transcriptional responses before lineage markers diverge. Compare osteogenic and adipogenic differentiation with matched proliferation and viability controls, and test whether miR-4739 effects are rescued by an LRP3 cDNA lacking its 3' UTR.
Hypothesis: The stromal differentiation phenotype is caused by a proximal LRP3-dependent signaling pathway rather than nonspecific effects of the original knockdown.
Type: primary-cell knockout-rescue and pathway-identification study
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The direct molecular activity and physiological extracellular ligand of LRP3 are unknown.
OPEN BIOLOGY MF_DARK
What is known: LRP3 has a predicted compact CUB/LDLRA ectodomain architecture that makes LRP10 a closer comparator than the larger LDLR-family receptors, but shared subfamily architecture does not identify an LRP3 ligand or license functional transfer. Transfected CHO cells did not bind beta-migrating VLDL or receptor-associated protein.
Significance: Without a direct ligand or activity, receptor-family terminology cannot be turned into an informative molecular-function annotation.
What would resolve it: Direct biochemical ligand binding followed by LRP3-dependent cellular response or uptake, with knockout and rescue controls, would resolve this gap.
Provenance (the field's own admissions):
Gap: It is unknown whether the cytoplasmic tyrosine-based signal mediates LRP3 endocytosis, which adaptors it recruits, and whether any physiological cargo is internalized.
OPEN BIOLOGY MF_DARK
What is known: The cloned sequence contains an internalization-compatible motif. UniProt asserts GGA1/GGA2 binding only by similarity (ECO:0000250), not from direct human LRP3 experiments, and the accessible primary abstract reports no cargo-uptake experiment.
Significance: Resolving this distinction determines whether LRP3 is an endocytic receptor, a signaling membrane protein, or both.
What would resolve it: Quantitative internalization assays with wild-type and motif-mutant LRP3, an identified cargo, and adaptor perturbations would resolve the mechanism.
Provenance (the field's own admissions):
Gap: The proximal pathway connecting LRP3 to osteogenic-versus-adipogenic fate and the generality of this phenotype beyond immortalized human stromal-cell clones are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: LRP3 knockdown and miR-4739 perturbation alter lineage differentiation and marker expression in immortalized human bone-marrow stromal cells, but the abstract does not identify a ligand or early signaling event.
Significance: A proximal mechanism is needed to distinguish an evolved LRP3 signaling role from a model-specific downstream phenotype and to assess relevance in primary cells.
What would resolve it: Multi-donor primary-cell knockout-rescue experiments with early time-course signaling measurements would establish causality and generalizability.
Provenance (the field's own admissions):
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