LRP5 is a 1,615-residue type-I single-pass membrane coreceptor of the low-density-lipoprotein-receptor-related family. Its large extracellular region contains four beta-propeller/EGF modules and three LDL-receptor class A repeats, while its cytoplasmic tail contains phosphorylatable PPPSP motifs that recruit AXIN during ligand-dependent signaling. At the plasma membrane, LRP5 cooperates with Frizzled receptors to transduce canonical Wnt signals; this activity is a major determinant of osteoblast differentiation and bone mass and is antagonized by extracellular inhibitors including sclerostin. LRP5 also serves with FZD4 in Norrin signaling required for retinal vascular morphogenesis, and damaging human variants cause familial exudative vitreoretinopathy. Loss- and gain-of-function variants produce opposing bone phenotypes, whereas proposed direct roles in glucose or lipid metabolism remain less firmly established.
Definition: Binding to sclerostin, a secreted glycoprotein antagonist of canonical Wnt signaling.
Justification: LRP5 directly binds sclerostin through its extracellular domain, and this interaction disrupts Wnt-induced Frizzled-LRP complex formation. Current GO provides only generic protein binding for this specific receptor-antagonist interaction; a partner-specific molecular-function term would preserve the informative activity.
Parent term: protein binding
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation from GO_REF:0000033 associates LRP5 with nervous system development; evidence specificity and core relevance were reviewed. Reason: This is a broad pleiotropic developmental outcome rather than LRP5's defining molecular role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1278315 SUPPORTS TRANSFER MGI:MGI:1298218 SUPPORTS TRANSFER PANTHER:PTN008469758 SUPPORTS TRANSFER ZFIN:ZDB-GENE-050518-2 SUPPORTS TRANSFER |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with endoplasmic reticulum; evidence specificity and core relevance were reviewed. Reason: Endoplasmic-reticulum localization is retained as a trafficking or variant-retention context; LRP5's defining signaling site is the cell surface. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028672 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB-SubCell:SL-0095 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with positive regulation of cell population proliferation; evidence specificity and core relevance were reviewed. Reason: Cell proliferation is a context-dependent downstream response rather than LRP5's defining coreceptor activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027538 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0009887 animal organ morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with animal organ morphogenesis; evidence specificity and core relevance were reviewed. Reason: This broad developmental umbrella is compatible with LRP5 biology but is not a defining core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028067 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0009888 tissue development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with tissue development; evidence specificity and core relevance were reviewed. Reason: This broad developmental umbrella is compatible with LRP5 biology but is not a defining core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028065 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0015026 coreceptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with coreceptor activity; evidence specificity and core relevance were reviewed. Reason: Coreceptor activity is LRP5's defining molecular role in Frizzled-dependent canonical Wnt signaling and FZD4-dependent Norrin signaling. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026504 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000044 associates LRP5 with membrane; evidence specificity and core relevance were reviewed. Reason: Generic membrane localization is correct but less informative than the plasma-membrane location of the cell-surface coreceptor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0162 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0017147 Wnt-protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with Wnt-protein binding; evidence specificity and core relevance were reviewed. Reason: Wnt binding is intrinsic to LRP5's ligand-dependent coreceptor role and is supported by direct human and exact-orthologue evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00085836 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0042813 Wnt receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with Wnt receptor activity; evidence specificity and core relevance were reviewed. Reason: Wnt receptor activity accurately captures LRP5's central ligand-dependent role in canonical Wnt signaling. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00088232 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0045597 positive regulation of cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with positive regulation of cell differentiation; evidence specificity and core relevance were reviewed. Reason: This broad differentiation outcome is downstream and context dependent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028476 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0045667 regulation of osteoblast differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with regulation of osteoblast differentiation; evidence specificity and core relevance were reviewed. Reason: This unsigned term is less informative than the sign-specific LRP5 osteoblast annotations and is retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00084601 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0045787 positive regulation of cell cycle | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with positive regulation of cell cycle; evidence specificity and core relevance were reviewed. Reason: Cell-cycle regulation is a context-dependent downstream response, not a direct LRP5 activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026693 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0060070 canonical Wnt signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: Canonical Wnt signaling is the central pathway mediated by the LRP5-Frizzled coreceptor system. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026624 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from GO_REF:0000117 associates LRP5 with Wnt-Frizzled-LRP5/6 complex; evidence specificity and core relevance were reviewed. Reason: LRP5 is a defining component of the Wnt-Frizzled-LRP5/6 cell-surface receptor complex. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00089182 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. |
| GO:0005515 protein binding | IPI PMID:15908424 SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor... | KEEP AS NON CORE | Summary: IPI annotation from PMID:15908424 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: PMID:15908424 directly establishes SOST binding to the LRP5 extracellular domain, but generic protein binding is not informative and no current partner-specific GO term captures this antagonist-receptor interaction. Supporting Evidence: PMID:15908424 We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. |
| GO:0005515 protein binding | IPI PMID:18762581 Caprin-2 enhances canonical Wnt signaling through regulating... | KEEP AS NON CORE | Summary: IPI annotation from PMID:18762581 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: PMID:18762581 directly supports CAPRIN2 interaction with the LRP5 cytoplasmic domain, but generic binding does not describe LRP5's coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:20393562 APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotr... | KEEP AS NON CORE | Summary: IPI annotation from PMID:20393562 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: PMID:20393562 directly supports APCDD1-LRP5 association at the cell surface, but generic binding is non-core. |
| GO:0005515 protein binding | IPI PMID:21471202 Bone overgrowth-associated mutations in the LRP4 gene impair... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21471202 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: The cached abstract centers LRP4, but the curator-made LRP5-SOST IPI is independently corroborated by direct LRP5-SOST evidence in PMID:15908424; generic binding remains non-core. Supporting Evidence: PMID:15908424 We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: IPI annotation from PMID:28514442 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: The BioPlex SOST co-association is corroborated by direct LRP5-SOST evidence in PMID:15908424, but generic binding remains non-core. Supporting Evidence: PMID:15908424 We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI annotation from PMID:33961781 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: The BioPlex SOST co-association is corroborated by direct LRP5-SOST evidence in PMID:15908424, but generic binding remains non-core. Supporting Evidence: PMID:15908424 We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. |
| GO:0035426 extracellular matrix-cell signaling | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP5 with extracellular matrix-cell signaling; evidence specificity and core relevance were reviewed. Reason: This is a broad mouse-derived tissue context and is retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0043434 response to peptide hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP5 with response to peptide hormone; evidence specificity and core relevance were reviewed. Reason: This is a broad rat-derived downstream context and is retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:F1MAD0 SUPPORTS TRANSFER ensembl:ENSRNOP00000022213 SUPPORTS TRANSFER |
| GO:0045669 positive regulation of osteoblast differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from GO_REF:0000107 associates LRP5 with positive regulation of osteoblast differentiation; evidence specificity and core relevance were reviewed. Reason: Positive regulation of osteoblast differentiation is a defining physiological output of LRP5-dependent Wnt signaling in bone. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with positive regulation of transcription by RNA polymerase II; evidence specificity and core relevance were reviewed. Reason: Transcriptional regulation is a downstream beta-catenin readout rather than a direct LRP5 activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027996 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0060348 bone development | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with bone development; evidence specificity and core relevance were reviewed. Reason: Bone development is a major conserved physiological role of LRP5 supported by human loss- and gain-of-function genetics. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00090825 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0061299 retina vasculature morphogenesis in camera-type eye | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from GO_REF:0000107 associates LRP5 with retina vasculature morphogenesis in camera-type eye; evidence specificity and core relevance were reviewed. Reason: Retinal vasculature morphogenesis is a defining physiological output of LRP5-dependent Norrin-FZD4 signaling. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:F1MAD0 SUPPORTS TRANSFER ensembl:ENSRNOP00000022213 SUPPORTS TRANSFER |
| GO:0061304 retinal blood vessel morphogenesis | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with retinal blood vessel morphogenesis; evidence specificity and core relevance were reviewed. Reason: Retinal blood-vessel morphogenesis is a defining physiological output of LRP5-dependent Norrin-FZD4 signaling. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00089494 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0110135 Norrin signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP5 with Norrin signaling pathway; evidence specificity and core relevance were reviewed. Reason: Norrin-FZD4-LRP5 signaling is a major coreceptor pathway required for retinal vascular development. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00089347 SOURCE WEAK OR INFERRED Automated rule, domain, or controlled-vocabulary source; not independent experimental support. UniProtKB:Q91VN0 SUPPORTS TRANSFER ensembl:ENSMUSP00000025856 SUPPORTS TRANSFER |
| GO:0005783 endoplasmic reticulum | EXP PMID:25920554 LRP5 variants may contribute to ADPKD. | KEEP AS NON CORE | Summary: EXP annotation from PMID:25920554 associates LRP5 with endoplasmic reticulum; evidence specificity and core relevance were reviewed. Reason: The accessible abstract does not expose the seeded endoplasmic-reticulum localization experiment, and cached full text is unavailable. The experimental assertion is retained as a non-core trafficking context under curator deference, without claiming that the accessible record independently verifies it. |
| GO:0016020 membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation from GO_REF:0000024 associates LRP5 with membrane; evidence specificity and core relevance were reviewed. Reason: Generic membrane localization is correct but less informative than the plasma-membrane location of the cell-surface coreceptor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15035989 Vascular development in the retina and inner ear: control by... | KEEP AS NON CORE | Summary: IDA annotation from PMID:15035989 associates LRP5 with positive regulation of transcription by RNA polymerase II; evidence specificity and core relevance were reviewed. Reason: Transcriptional regulation is a downstream beta-catenin readout rather than a direct LRP5 activity. |
| GO:0015026 coreceptor activity | NAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | ACCEPT | Summary: NAS annotation from PMID:24431302 associates LRP5 with coreceptor activity; evidence specificity and core relevance were reviewed. Reason: Coreceptor activity is the defining LRP5 role; the NAS citation is statement-level but agrees with extensive direct evidence. Supporting Evidence: PMID:11336703 LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. |
| GO:0015026 coreceptor activity | IPI PMID:11336703 Low-density lipoprotein receptor-related protein-5 binds to ... | ACCEPT | Summary: IPI annotation from PMID:11336703 associates LRP5 with coreceptor activity; evidence specificity and core relevance were reviewed. Reason: PMID:11336703 directly supports Wnt-dependent cooperation and Axin recruitment by LRP5, consistent with coreceptor activity. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | UNDECIDED | Summary: IDA annotation from PMID:11029007 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: The accessible abstract establishes LRP6, not LRP5, as the tested Wnt coreceptor. Because cached full text is unavailable, this LRP5-specific IDA assertion cannot be verified; UNDECIDED preserves curator deference without treating independent knowledge of LRP5 biology as evidence for this source-specific annotation. Supporting Evidence: PMID:11029007 Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5339711 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-5339711 associates LRP5 with plasma membrane; evidence specificity and core relevance were reviewed. Reason: Plasma-membrane localization is core to LRP5's single-pass cell-surface receptor architecture. |
| GO:0110135 Norrin signaling pathway | IDA PMID:15035989 Vascular development in the retina and inner ear: control by... | ACCEPT | Summary: IDA annotation from PMID:15035989 associates LRP5 with Norrin signaling pathway; evidence specificity and core relevance were reviewed. Reason: Norrin-dependent signaling is a defining LRP5 coreceptor pathway in retinal vascular biology. |
| GO:0110135 Norrin signaling pathway | IDA PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | ACCEPT | Summary: IDA annotation from PMID:17955262 associates LRP5 with Norrin signaling pathway; evidence specificity and core relevance were reviewed. Reason: Human disease variants tested in PMID:17955262 directly support LRP5 participation in Norrin signaling. |
| GO:0042813 Wnt receptor activity | IDA PMID:24706814 Whole-exome sequencing reveals LRP5 mutations and canonical ... | ACCEPT | Summary: IDA annotation from PMID:24706814 associates LRP5 with Wnt receptor activity; evidence specificity and core relevance were reviewed. Reason: The official PMID:24706814 abstract reports reduced Wnt signal activation by human LRP5 variants; established ligand biology supports Wnt receptor activity. |
| GO:0042813 Wnt receptor activity | IDA PMID:25920554 LRP5 variants may contribute to ADPKD. | ACCEPT | Summary: IDA annotation from PMID:25920554 associates LRP5 with Wnt receptor activity; evidence specificity and core relevance were reviewed. Reason: PMID:25920554 reports reduced canonical Wnt reporter activation by human LRP5 variants, consistent with Wnt receptor activity. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:24706814 Whole-exome sequencing reveals LRP5 mutations and canonical ... | ACCEPT | Summary: IDA annotation from PMID:24706814 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: The official PMID:24706814 abstract reports reduced Wnt signal activation by human LRP5 variants, supporting canonical Wnt signaling. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:25920554 LRP5 variants may contribute to ADPKD. | ACCEPT | Summary: IDA annotation from PMID:25920554 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: PMID:25920554 directly reports impaired canonical Wnt reporter activation by human LRP5 variants. |
| GO:0060070 canonical Wnt signaling pathway | IGI PMID:16805831 Inhibition of the canonical Wnt signaling pathway by apolipo... | ACCEPT | Summary: IGI annotation from PMID:16805831 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: The ApoE perturbation study tests LRP5-dependent modulation of canonical Wnt output; the pathway is core although the ApoE context is specialized. |
| GO:0060070 canonical Wnt signaling pathway | IGI PMID:11336703 Low-density lipoprotein receptor-related protein-5 binds to ... | ACCEPT | Summary: IGI annotation from PMID:11336703 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: PMID:11336703 directly links LRP5, Wnt, Axin recruitment, and beta-catenin/LEF activation. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:15908424 SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor... | ACCEPT | Summary: IDA annotation from PMID:15908424 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: PMID:15908424 demonstrates that SOST inhibits Wnt signaling through LRP5/LRP6, supporting the pathway annotation. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:18044981 An LRP5 receptor with internal deletion in hyperparathyroid ... | ACCEPT | Summary: IMP annotation from PMID:18044981 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: The tumor study directly shows Wnt/beta-catenin activation by an aberrantly spliced LRP5 construct; the pathway is valid without implying a curated normal isoform. |
| GO:0045669 positive regulation of osteoblast differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation from GO_REF:0000024 associates LRP5 with positive regulation of osteoblast differentiation; evidence specificity and core relevance were reviewed. Reason: Positive regulation of osteoblast differentiation is a defining physiological output of LRP5-dependent Wnt signaling in bone. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER |
| GO:0017147 Wnt-protein binding | IPI PMID:11336703 Low-density lipoprotein receptor-related protein-5 binds to ... | ACCEPT | Summary: IPI annotation from PMID:11336703 associates LRP5 with Wnt-protein binding; evidence specificity and core relevance were reviewed. Reason: Wnt binding is intrinsic to LRP5's ligand-dependent coreceptor role and is supported by direct human and exact-orthologue evidence. |
| GO:0005515 protein binding | IPI PMID:11336703 Low-density lipoprotein receptor-related protein-5 binds to ... | MODIFY | Summary: IPI annotation from PMID:11336703 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: PMID:11336703 directly demonstrates binding of the LRP5 intracellular domain to Axin, a Wnt-pathway scaffold. Current GO:0097110 scaffold protein binding is more informative. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:11336703 no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway. |
| GO:0017147 Wnt-protein binding | TAS PMID:22988876 The importance of Wnt signalling for neurodegeneration in Pa... | ACCEPT | Summary: TAS annotation from PMID:22988876 associates LRP5 with Wnt-protein binding; evidence specificity and core relevance were reviewed. Reason: Wnt binding is central to LRP5 coreceptor function; the TAS review is independently supported by primary evidence. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | TAS PMID:20093360 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex r... | UNDECIDED | Summary: TAS annotation from PMID:20093360 associates LRP5 with Wnt-Frizzled-LRP5/6 complex; evidence specificity and core relevance were reviewed. Reason: The accessible abstract reconstitutes an FZD8-WNT3A-LRP6 complex and does not assay LRP5. LRP5 membership in the alternative LRP5/6 complex is biologically well supported elsewhere, but cached full text is unavailable for this source-specific TAS assertion, so curator deference requires UNDECIDED. Supporting Evidence: PMID:20093360 reconstitute in vitro the Fz8 CRD.Wnt3a.LRP6 signaling complex. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | TAS PMID:22988876 The importance of Wnt signalling for neurodegeneration in Pa... | ACCEPT | Summary: TAS annotation from PMID:22988876 associates LRP5 with Wnt-Frizzled-LRP5/6 complex; evidence specificity and core relevance were reviewed. Reason: LRP5 is a defining member of the Wnt-Frizzled-LRP5/6 complex; the review citation is statement-level but independently corroborated. |
| GO:1990909 Wnt signalosome | NAS PMID:24115276 The regulation and deregulation of Wnt signaling by PARK gen... | ACCEPT | Summary: NAS annotation from PMID:24115276 associates LRP5 with Wnt signalosome; evidence specificity and core relevance were reviewed. Reason: Wnt signalosome membership is a core signaling-complex annotation, while the NAS evidence remains statement-level. |
| GO:0017147 Wnt-protein binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation from GO_REF:0000024 associates LRP5 with Wnt-protein binding; evidence specificity and core relevance were reviewed. Reason: Mouse Lrp5 is the exact orthologue and supports transfer of Wnt-protein binding. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER |
| GO:0042813 Wnt receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation from GO_REF:0000024 associates LRP5 with Wnt receptor activity; evidence specificity and core relevance were reviewed. Reason: Mouse Lrp5 is the exact orthologue and supports transfer of Wnt receptor activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91VN0 SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:11433302 Novel mechanism of Wnt signalling inhibition mediated by Dic... | UNDECIDED | Summary: IPI annotation from PMID:11433302 associates LRP5 with protein binding; evidence specificity and core relevance were reviewed. Reason: The accessible abstract identifies LRP6 as the DKK1-binding receptor component and does not expose an LRP5 assay. Because cached full text is unavailable, the curator-made LRP5-specific IPI cannot be verified; UNDECIDED preserves curator deference while retaining the source assertion and its recorded pathway context. Supporting Evidence: PMID:11433302 Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-201677 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-201677 associates LRP5 with plasma membrane; evidence specificity and core relevance were reviewed. Reason: Plasma-membrane localization is core to LRP5's single-pass cell-surface receptor architecture. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-1458902 | UNDECIDED | Summary: TAS annotation from Reactome:R-NUL-1458902 associates LRP5 with plasma membrane; evidence specificity and core relevance were reviewed. Reason: The cached Reactome event describes Xenopus CK1gamma modification of LRP6, not plasma-membrane localization of human LRP5. The LRP5 location is independently secure, but this source-specific TAS assertion is unsupported, so it is retained as UNDECIDED rather than overruled. Supporting Evidence: Reactome:R-NUL-1458902 Xenopus tropicalis Casein kinase 1 gamma was identified in a screen for proteins that covalently modify LRP6. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12857724 Functional characterization of WNT7A signaling in PC12 cells... | UNDECIDED | Summary: IDA annotation from PMID:12857724 associates LRP5 with positive regulation of transcription by RNA polymerase II; evidence specificity and core relevance were reviewed. Reason: Cached full text for PMID:12857724 is unavailable, and the accessible abstract describes a WNT7A-FZD5-LRP6 system without identifying an LRP5 assay. Curator deference requires UNDECIDED rather than removal. Supporting Evidence: PMID:12857724 Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5.LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:12857724 Functional characterization of WNT7A signaling in PC12 cells... | UNDECIDED | Summary: IDA annotation from PMID:12857724 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: Cached full text for PMID:12857724 is unavailable, and the accessible abstract describes a rat WNT7A-FZD5-LRP6 system without identifying an LRP5 assay. This source-specific IDA therefore receives the same conservative UNDECIDED judgment as the adjacent transcription annotation. Supporting Evidence: PMID:12857724 Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5.LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:12121999 A novel set of Wnt-Frizzled fusion proteins identifies recep... | UNDECIDED | Summary: IDA annotation from PMID:12121999 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: The accessible abstract reports reporter activation with LRP6 but not LRP5 in the tested Wnt-FZD fusion context. Cached full text is unavailable to verify any broader positive LRP5 assay, so curator deference requires UNDECIDED rather than removal or acceptance based on independent pathway knowledge. Supporting Evidence: PMID:12121999 In 293T cells, coexpression of several Wnt-Fz fusion proteins with LRP6, but not LRP5, significantly activated a Wnt-responsive promoter, Optimized TOPFlash. |
| GO:0043235 signaling receptor complex | IDA PMID:18762581 Caprin-2 enhances canonical Wnt signaling through regulating... | ACCEPT | Summary: IDA annotation from PMID:18762581 associates LRP5 with signaling receptor complex; evidence specificity and core relevance were reviewed. Reason: PMID:18762581 directly demonstrates LRP5-CAPRIN2 complex formation and signaling. |
| GO:0061304 retinal blood vessel morphogenesis | IMP PMID:15024691 Mutations in LRP5 or FZD4 underlie the common familial exuda... | ACCEPT | Summary: IMP annotation from PMID:15024691 associates LRP5 with retinal blood vessel morphogenesis; evidence specificity and core relevance were reviewed. Reason: Human LRP5 mutations causing familial exudative vitreoretinopathy support retinal blood-vessel morphogenesis. |
| GO:0019534 toxin transmembrane transporter activity | IMP NOT PMID:18350154 Evidence against a human cell-specific role for LRP6 in anth... | ACCEPT | Summary: IMP annotation from PMID:18350154 associates LRP5 with toxin transmembrane transporter activity; evidence specificity and core relevance were reviewed. Reason: This is explicitly negated: PMID:18350154 shows that LRP5 knockdown does not affect anthrax toxin entry in human HeLa cells, so the NOT assertion is correct. Supporting Evidence: PMID:18350154 knockdown of either LRP6, LRP5, or both proteins has no influence on the kinetics of anthrax lethal toxin entry or MEK1 substrate cleavage in these cells. |
| GO:0061304 retinal blood vessel morphogenesis | IMP PMID:15346351 Autosomal recessive familial exudative vitreoretinopathy is ... | ACCEPT | Summary: IMP annotation from PMID:15346351 associates LRP5 with retinal blood vessel morphogenesis; evidence specificity and core relevance were reviewed. Reason: Human recessive LRP5 mutations causing familial exudative vitreoretinopathy support retinal and retinal-vessel morphogenesis. |
| GO:0002053 positive regulation of mesenchymal cell proliferation | IMP PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | MODIFY | Summary: IMP annotation from PMID:17680723 associates LRP5 with positive regulation of mesenchymal cell proliferation; evidence specificity and core relevance were reviewed. Reason: PMID:17680723 reports that Wnt3a inhibited proliferation in human mesenchymal stem cells expressing wild-type or activating LRP5. Current GO:1902461 corrects the sign and cell-type specificity. Proposed replacements: negative regulation of mesenchymal stem cell proliferation Supporting Evidence: PMID:17680723 The hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) transduced high level of Wnt signaling. Wnt3a inhibited cell proliferation in hMSC-LRP5(WT) and hMSC-LRP5(T253), and this effect was associated with downregulation of DKK1. Both hMSC-LRP5(WT) and hMSC-LRP5(T253) showed enhanced osteoblast differentiation and inhibited adipogenesis in vitro, and the opposite effect was observed in hMSC-LRP5(T244). |
| GO:0005886 plasma membrane | IDA PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | ACCEPT | Summary: IDA annotation from PMID:17680723 associates LRP5 with plasma membrane; evidence specificity and core relevance were reviewed. Reason: Experimental plasma-membrane localization is consistent with LRP5 architecture; the abstract omits assay detail, so the curator's full-text assessment is retained. |
| GO:0006007 glucose catabolic process | IMP PMID:19673927 Low density lipoprotein receptor-related protein 5 (LRP5) mu... | MODIFY | Summary: IMP annotation from PMID:19673927 associates LRP5 with glucose catabolic process; evidence specificity and core relevance were reviewed. Reason: The official PMID:19673927 abstract reports abnormal glucose metabolism and impaired beta-cell function in people with LRP5 mutations, not a specific catabolic reaction. Current GO:0042593 glucose homeostasis is the conservative replacement. Proposed replacements: glucose homeostasis |
| GO:0008217 regulation of blood pressure | IMP PMID:18721193 LRP5 in premature adrenarche and in metabolic characteristic... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:18721193 associates LRP5 with regulation of blood pressure; evidence specificity and core relevance were reviewed. Reason: The official PMID:18721193 abstract reports cross-sectional SNP association with systolic blood pressure, not a causal perturbation establishing regulation. The annotation is over-specific but is not removed. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:9790987 Molecular cloning and characterization of LR3, a novel LDL r... | KEEP AS NON CORE | Summary: IDA annotation from PMID:9790987 associates LRP5 with positive regulation of cell population proliferation; evidence specificity and core relevance were reviewed. Reason: PMID:9790987 reports increased proliferation after full-length LRP5/LR3 or ectodomain expression; this artificial-expression phenotype is retained as non-core. |
| GO:0042632 cholesterol homeostasis | IMP PMID:18721193 LRP5 in premature adrenarche and in metabolic characteristic... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:18721193 associates LRP5 with cholesterol homeostasis; evidence specificity and core relevance were reviewed. Reason: The official PMID:18721193 abstract reports SNP association with cholesterol levels, not a causal homeostatic function. The annotation is over-specific. |
| GO:0042632 cholesterol homeostasis | IMP PMID:20146170 Association of LPR5 polymorphism with bone mass density and ... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:20146170 associates LRP5 with cholesterol homeostasis; evidence specificity and core relevance were reviewed. Reason: PMID:20146170 is a human association study linking an LRP5 allele to cholesterol level; association alone does not establish cholesterol homeostasis. Supporting Evidence: PMID:20146170 We observed a significant association between rs3736228 in LRP5 and hip BMD, total BMD, and T score. The level of hip BMD, total BMD, and T score was significantly reduced with the number of at risk T alleles (p=0.006, p=0.003, and p=0.006, respectively). This finding was still significant after accounting for gender and age. We also observed a significant association between rs3736228 and total cholesterol (CHO) levels in our sample. The CHO levels of the CC, CT, and TT genotypes were 4.71, 4.76, and 5.24, respectively (p=0.031). For OPG rs4355801, the level of hip BMD, spine BMD, and total BMD was consistently reduced in persons with the copy of A allele, but none of these findings were statistically significant. We also did not observe a significant association between the above two polymorphisms and body mass index, glucose, and triglyceride levels in Chinese Han subjects. Thus, our observations support the association between rs3736228 and BMD in Han subjects. We also provide first evidence that the T allele of rs3736228 increases the total cholesterol level in a general Han population. |
| GO:0045600 positive regulation of fat cell differentiation | IMP PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | MODIFY | Summary: IMP annotation from PMID:17680723 associates LRP5 with positive regulation of fat cell differentiation; evidence specificity and core relevance were reviewed. Reason: PMID:17680723 reports that wild-type and activating LRP5 enhanced osteoblast differentiation and inhibited adipogenesis. Current GO:0045599 corrects the sign. Proposed replacements: negative regulation of fat cell differentiation Supporting Evidence: PMID:17680723 The hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) transduced high level of Wnt signaling. Wnt3a inhibited cell proliferation in hMSC-LRP5(WT) and hMSC-LRP5(T253), and this effect was associated with downregulation of DKK1. Both hMSC-LRP5(WT) and hMSC-LRP5(T253) showed enhanced osteoblast differentiation and inhibited adipogenesis in vitro, and the opposite effect was observed in hMSC-LRP5(T244). |
| GO:0045668 negative regulation of osteoblast differentiation | IMP PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | MODIFY | Summary: IMP annotation from PMID:17680723 associates LRP5 with negative regulation of osteoblast differentiation; evidence specificity and core relevance were reviewed. Reason: PMID:17680723 reports enhanced osteoblast differentiation with wild-type and activating LRP5, whereas the inactivating mutant had the opposite effect. Current GO:0045669 corrects the sign. Proposed replacements: positive regulation of osteoblast differentiation Supporting Evidence: PMID:17680723 The hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) transduced high level of Wnt signaling. Wnt3a inhibited cell proliferation in hMSC-LRP5(WT) and hMSC-LRP5(T253), and this effect was associated with downregulation of DKK1. Both hMSC-LRP5(WT) and hMSC-LRP5(T253) showed enhanced osteoblast differentiation and inhibited adipogenesis in vitro, and the opposite effect was observed in hMSC-LRP5(T244). |
| GO:0045840 positive regulation of mitotic nuclear division | IDA PMID:9790987 Molecular cloning and characterization of LR3, a novel LDL r... | MARK AS OVER ANNOTATED | Summary: IDA annotation from PMID:9790987 associates LRP5 with positive regulation of mitotic nuclear division; evidence specificity and core relevance were reviewed. Reason: PMID:9790987 reports increased proliferation after ectopic full-length LRP5/LR3 or ectodomain expression in NIH 3T3 cells, but a proliferation readout does not establish regulation of mitotic nuclear division. The term is therefore more specific than the evidence supports. Supporting Evidence: PMID:9790987 NIH 3T3 cells transfected with either full length LR3 or its ectodomain showed significantly increased proliferation, whereas transfection of intracellular domain had no proliferative effect. |
| GO:0048539 bone marrow development | IMP PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | KEEP AS NON CORE | Summary: IMP annotation from PMID:17680723 associates LRP5 with bone marrow development; evidence specificity and core relevance were reviewed. Reason: Human high-bone-mass phenotypes and altered marrow fat support a bone-marrow context, but it is non-core. |
| GO:0060042 retina morphogenesis in camera-type eye | IMP PMID:15346351 Autosomal recessive familial exudative vitreoretinopathy is ... | ACCEPT | Summary: IMP annotation from PMID:15346351 associates LRP5 with retina morphogenesis in camera-type eye; evidence specificity and core relevance were reviewed. Reason: Human LRP5 mutations causing familial exudative vitreoretinopathy support a defining role in retina morphogenesis. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:19673927 Low density lipoprotein receptor-related protein 5 (LRP5) mu... | ACCEPT | Summary: IMP annotation from PMID:19673927 associates LRP5 with canonical Wnt signaling pathway; evidence specificity and core relevance were reviewed. Reason: Canonical Wnt signaling is established for LRP5. The official PMID:19673927 abstract does not expose a pathway assay, but the term is independently secure and retained with curator deference. |
| GO:0060349 bone morphogenesis | IMP PMID:19673927 Low density lipoprotein receptor-related protein 5 (LRP5) mu... | ACCEPT | Summary: IMP annotation from PMID:19673927 associates LRP5 with bone morphogenesis; evidence specificity and core relevance were reviewed. Reason: Human LRP5 loss-of-function mutations in PMID:19673927 cause osteoporosis, fractures, and low bone mineral density, supporting bone morphogenesis. |
| GO:0060349 bone morphogenesis | IMP PMID:20146170 Association of LPR5 polymorphism with bone mass density and ... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:20146170 associates LRP5 with bone morphogenesis; evidence specificity and core relevance were reviewed. Reason: PMID:20146170 reports statistical association of an LRP5 polymorphism with bone mineral density, not a perturbation demonstrating bone morphogenesis. Supporting Evidence: PMID:20146170 We observed a significant association between rs3736228 in LRP5 and hip BMD, total BMD, and T score. The level of hip BMD, total BMD, and T score was significantly reduced with the number of at risk T alleles (p=0.006, p=0.003, and p=0.006, respectively). This finding was still significant after accounting for gender and age. We also observed a significant association between rs3736228 and total cholesterol (CHO) levels in our sample. The CHO levels of the CC, CT, and TT genotypes were 4.71, 4.76, and 5.24, respectively (p=0.031). For OPG rs4355801, the level of hip BMD, spine BMD, and total BMD was consistently reduced in persons with the copy of A allele, but none of these findings were statistically significant. We also did not observe a significant association between the above two polymorphisms and body mass index, glucose, and triglyceride levels in Chinese Han subjects. Thus, our observations support the association between rs3736228 and BMD in Han subjects. We also provide first evidence that the T allele of rs3736228 increases the total cholesterol level in a general Han population. |
| GO:0060349 bone morphogenesis | IMP PMID:20630166 Low-density lipoprotein receptor-related protein 5 polymorph... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:20630166 associates LRP5 with bone morphogenesis; evidence specificity and core relevance were reviewed. Reason: PMID:20630166 is a polymorphism study and reports no association with osteoporosis, fractures, or hip bone mineral density; it does not establish bone morphogenesis. Supporting Evidence: PMID:20630166 None of the polymorphisms was associated with the presence of osteoporosis, fractures, and hip BMD. All polymorphisms were associated with unadjusted spine BMD, with the exception of rs4988330. Only rs4988321 was associated with adjusted spine BMD, where the presence of the A allele was associated with significantly lower spine BMD compared with the GG genotype (P=0.002). An interaction of the rs4988321 polymorphism with calcium intake (P=0.016) was found. The carriers of the A allele demonstrated significantly lower spine BMD compared to GG homozygotes (P=0.001) only in the lowest calcium intake group (<680 mg/day), whereas in the highest calcium intake group no differences were found in BMD between genotypes. These findings demonstrate that both rs4988321 polymorphism and its interaction with calcium intake are associated with BMD, whereas higher calcium intake was shown to decrease the negative effect of this polymorphism on BMD. |
| GO:0060612 adipose tissue development | IMP PMID:17680723 Patients with high bone mass phenotype exhibit enhanced oste... | KEEP AS NON CORE | Summary: IMP annotation from PMID:17680723 associates LRP5 with adipose tissue development; evidence specificity and core relevance were reviewed. Reason: Adipose development is a valid context of LRP5-dependent mesenchymal lineage choice, but it is a secondary outcome. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | KEEP AS NON CORE | Summary: IDA annotation from PMID:17955262 associates LRP5 with positive regulation of DNA-templated transcription; evidence specificity and core relevance were reviewed. Reason: PMID:17955262 uses Norrin-dependent reporter activity; transcriptional regulation is a downstream readout rather than a direct LRP5 activity. |
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Download this section (compressed HTML)Q: Which Wnt and Frizzled combinations signal preferentially through LRP5 rather than LRP6 in human osteoblast-lineage cells, and which extracellular or cytoplasmic receptor features determine that preference?
Q: Does Norrin-FZD4 engage LRP5 directly in a stable ternary complex, and can LRP6 substitute quantitatively for LRP5 in human retinal endothelial cells?
Q: Is RefSeq LRP5 isoform 2 translated in any human tissue, and if so how does a product lacking the canonical signal peptide and first two beta-propeller/EGF modules enter the secretory pathway and reach a functional membrane topology?
Q: Are the reported glucose and lipid phenotypes caused by a direct LRP5 signaling program in metabolic tissues or are they secondary to skeletal, endocrine, or general canonical Wnt effects?
Experiment: Create isogenic LRP5-null, LRP6-null, and double-null human mesenchymal stem cells, rescue them at endogenous abundance with each coreceptor, and challenge differentiating osteoblasts with a matrix of purified Wnt and Frizzled contexts. Measure receptor phosphorylation, AXIN membrane recruitment, beta-catenin dynamics, transcriptional output, osteoblast differentiation, and mineralization; include domain-swap receptors to localize LRP5-selective determinants.
Hypothesis: LRP5 and LRP6 have nonidentical ligand and Frizzled preferences in human osteoblast-lineage cells.
Type: isogenic receptor-complementation signaling matrix
Experiment: Reconstitute purified Norrin-FZD4-LRP5 and Norrin-FZD4-LRP6 ectodomain complexes for surface-plasmon-resonance or biolayer-interferometry measurements and structural analysis. Mutate candidate interfaces and test matched constructs in LRP5/LRP6-edited human retinal endothelial cells for proximal receptor activation, beta-catenin signaling, barrier maturation, and vascular-network formation.
Hypothesis: Human LRP5 forms a direct Norrin-FZD4 coreceptor complex that is quantitatively distinct from the corresponding LRP6 complex.
Type: quantitative complex reconstitution plus retinal endothelial rescue
Experiment: First confirm the isoform-specific junction and coding potential by long-read RNA sequencing, targeted ribosome profiling, and junction-specific proteomics in bone and retinal tissues. Only if endogenous translation is detected, compare its signal-peptide usage, glycosylation, protease protection, surface delivery, ligand binding, and signaling with canonical LRP5.
Hypothesis: The truncated RefSeq isoform 2 is either not translated or fails to acquire the membrane topology required for ligand-dependent signaling.
Type: isoform-resolved transcriptomics, proteomics, and topology analysis
Experiment: Introduce representative damaging and signaling-separation LRP5 alleles into isogenic human hepatocytes, adipocytes, and beta cells, with wild-type rescue and LRP6 controls. Measure receptor-proximal Wnt signaling together with isotope-traced glucose and lipid fluxes; require concordant proximal and metabolic rescue before assigning a direct metabolic role.
Hypothesis: Reported metabolic phenotypes require proximal LRP5 signaling in a specific human metabolic cell type rather than reflecting indirect systemic effects.
Type: isogenic variant-rescue metabolic flux analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular features that make a ligand-receptor complex prefer LRP5 rather than the closely related LRP6, and the extent to which the two coreceptors are interchangeable in human osteoblasts, remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human LRP5 directly supports Wnt-dependent AXIN recruitment, and LRP5/LRP6 are jointly implicated in several antagonist and phosphorylation studies. However, prominent biochemical systems in the cited literature reconstituted or assayed LRP6 alone, and there is no experimental structure of O75197; the current AlphaFold model is prediction-only.
Significance: LRP5-selective signaling explains why paralogous coreceptors have overlapping pathway assignments yet distinct human skeletal phenotypes and is essential for interpreting extracellular antagonist and gain-of-function variants.
What would resolve it: Reconstitute matched human Wnt-FZD-LRP5 and Wnt-FZD-LRP6 complexes with full extracellular and cytoplasmic signaling readouts, then determine ligand, antagonist, phosphorylation, AXIN-recruitment, and structural differences.
Provenance (the field's own admissions):
Gap: Direct assembly, stoichiometry, and coreceptor selectivity of a human Norrin-FZD4-LRP5 signaling complex have not been established biochemically or structurally.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Norrin activates an FZD4- and LRP-dependent classical pathway, human LRP5 variants cause FEVR, and disease-associated LRP5 missense substitutions reduce Norrin-dependent signaling. The accessible ligand-system evidence does not distinguish LRP5 from LRP6 in the assayed LRP requirement.
Significance: Resolving the receptor complex would connect human variant effects to a defined retinal signaling mechanism and establish whether LRP5 has a nonredundant biochemical role in this ligand context.
What would resolve it: Purify human Norrin, FZD4, and LRP5 ectodomains for quantitative binding and complex reconstruction, compare LRP6 directly, and validate the resulting interfaces with endogenous retinal endothelial signaling assays.
Provenance (the field's own admissions):
Gap: It is unknown whether the 1,034-residue RefSeq isoform 2 is translated and produces a stable membrane protein with any signaling activity.
OPEN BIOLOGY
What is known: The reviewed canonical product is a 1,615-residue type-I membrane coreceptor with an N-terminal signal peptide and four beta-propeller/EGF modules. RefSeq isoform 2 has a 19-residue alternative N-terminus followed by canonical residues 601-1615, so it lacks the canonical signal peptide and first two propeller modules. UniProt curates no alternative products, and no direct topology or functional evidence for the shorter product was identified.
Significance: Without evidence of translation and topology, the shorter sequence cannot be assigned canonical receptor functions or used to explain variant-specific signaling.
What would resolve it: Establish transcript and translation evidence in relevant tissues before testing signal-peptide usage, membrane topology, ligand binding, and canonical signaling with isoform-specific reagents.
Gap: Whether LRP5 has a direct, cell-autonomous role in glucose or lipid metabolism, distinct from secondary effects of skeletal and canonical Wnt signaling, remains unresolved.
OPEN BIOLOGY BP_DARK
What is known: Damaging variants and common alleles have been associated with glucose, cholesterol, or blood-pressure traits, but the cited studies are small clinical or population associations and do not define a direct metabolic molecular mechanism.
Significance: Separating direct receptor biology from pleiotropic association is necessary before metabolic-process GO annotations or therapeutic interpretations can be justified.
What would resolve it: Test isogenic loss-, rescue-, and signaling-separation alleles in the relevant human metabolic cell types while measuring proximal LRP5 signaling and direct glucose and lipid fluxes.
Provenance (the field's own admissions):
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