LRP6 is a 1,613-amino-acid type-I single-pass cell-surface glycoprotein and a coreceptor for canonical Wnt/beta-catenin signaling. Its extracellular beta-propeller-EGF modules bind Wnt proteins, Frizzled receptors, and extracellular regulators, while its cytoplasmic PPPSP-rich tail is phosphorylated after receptor-complex assembly. Phosphorylated LRP6 clusters into Wnt signalosomes and recruits Dishevelled and the AXIN-GSK3 destruction complex to the plasma membrane, thereby stabilizing beta-catenin; phosphorylated PPPSPxS motifs can also directly inhibit GSK3. LRP6 is a non-enzymatic coreceptor, not a protein kinase or autonomous receptor enzyme. Its canonical Wnt function contributes to human development and tissue homeostasis. Human LRP6 variants are associated with disorders of retinal vascularization, dentition, bone mass, and cardiometabolic physiology, with evidence and mechanisms that vary by allele.
| 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 LRP6 with nervous system development; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000033 supports or infers nervous system development, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. 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:0005769 early endosome | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with early endosome; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028567 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000044 associates LRP6 with endoplasmic reticulum; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000044 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0095 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from GO_REF:0000044 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000044 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic 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 LRP6 with tissue development; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers tissue development, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028065 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0015026 coreceptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with coreceptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports coreceptor activity; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026504 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with vesicle-mediated transport; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers vesicle-mediated transport, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028249 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0017147 Wnt-protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP6 with Wnt-protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000120 supports Wnt-protein binding; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00085836 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0030901 midbrain development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with midbrain development; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers midbrain development, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00088343 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0042813 Wnt receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from GO_REF:0000002 associates LRP6 with Wnt receptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000002 supports Wnt receptor activity; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with regulation of apoptotic process; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers regulation of apoptotic process, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027086 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0043009 chordate embryonic development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with chordate embryonic development; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers chordate embryonic development, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027425 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000044 associates LRP6 with membrane raft; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000044 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0370 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0045202 synapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000108 associates LRP6 with synapse; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000108 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: GO:0007268 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic 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 LRP6 with positive regulation of cell cycle; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers positive regulation of cell cycle, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026693 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with positive regulation of transcription by RNA polymerase II; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers positive regulation of transcription by RNA polymerase II, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027996 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0048646 anatomical structure formation involved in morphogenesis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with anatomical structure formation involved in morphogenesis; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers anatomical structure formation involved in morphogenesis, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028539 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000108 | REMOVE | Summary: IEA annotation from GO_REF:0000108 associates LRP6 with transmembrane transport; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000108 derives this broad transmembrane-transport process electronically from GO:0019534 toxin transmembrane transporter activity. LRP6 is a receptor required for toxin entry in some contexts, not the transporter that translocates toxin across a membrane, and the review also preserves a human-HeLa NOT assertion against GO:0019534. The propagated process therefore reflects role conflation and should be removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: GO:0019534 SOURCE WEAK OR INFERRED Inter-ontology inference from a context-dependent toxin-entry activity; it does not establish that LRP6 itself performs transmembrane transport. |
| GO:0060070 canonical Wnt signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from GO_REF:0000120 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000120 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026624 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. InterPro:IPR017049 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0071542 dopaminergic neuron differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000117 associates LRP6 with dopaminergic neuron differentiation; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports or infers dopaminergic neuron differentiation, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00092424 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic 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 LRP6 with Wnt-Frizzled-LRP5/6 complex; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000117 supports Wnt-Frizzled-LRP5/6 complex; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00089182 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0005515 protein binding | IPI PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | MODIFY | Summary: IPI annotation from PMID:11029007 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 records WNT1 among the physical interaction partners. GO:0005515 protein binding is too generic for that interaction; GO:0017147 Wnt-protein binding is the more informative replacement while the complete machine-sourced partner list remains preserved. Proposed replacements: Wnt-protein binding |
| GO:0005515 protein binding | IPI PMID:11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. | KEEP AS NON CORE | Summary: IPI annotation from PMID:11448771 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11448771 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:12897152 A novel mechanism for Wnt activation of canonical signaling ... | MODIFY | Summary: IPI annotation from PMID:12897152 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:12897152 records WNT3A among the physical interaction partners. GO:0005515 protein binding is too generic for that interaction; GO:0017147 Wnt-protein binding is the more informative replacement while the complete machine-sourced partner list remains preserved. Proposed replacements: Wnt-protein binding |
| 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 LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:15908424 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:16365045 The low density lipoprotein receptor-related protein 6 inter... | MODIFY | Summary: IPI annotation from PMID:16365045 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16365045 records GSK3A and GSK3B as physical interaction partners. GO:0005515 protein binding is too generic for these kinase interactions; GO:0019901 protein kinase binding is the more informative replacement. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:16564009 The LDL receptor-related protein LRP6 mediates internalizati... | KEEP AS NON CORE | Summary: IPI annotation from PMID:16564009 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16564009 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | MODIFY | Summary: IPI annotation from PMID:16890161 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 records GSK3B among the physical interaction partners. GO:0005515 protein binding is too generic for that kinase interaction; GO:0019901 protein kinase binding is the more informative replacement while the complete machine-sourced partner list and plasma-membrane extension remain preserved. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:16989816 Modulation of LRP6-mediated Wnt signaling by molecular chape... | KEEP AS NON CORE | Summary: IPI annotation from PMID:16989816 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16989816 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:18528331 IGFBP-4 is an inhibitor of canonical Wnt signalling required... | MODIFY | Summary: IPI annotation from PMID:18528331 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:18528331 records WNT3A among the physical interaction partners. GO:0005515 protein binding is too generic for that interaction; GO:0017147 Wnt-protein binding is the more informative replacement while the complete machine-sourced partner list remains preserved. Proposed replacements: Wnt-protein binding |
| GO:0005515 protein binding | IPI PMID:19107203 Direct inhibition of GSK3beta by the phosphorylated cytoplas... | KEEP AS NON CORE | Summary: IPI annotation from PMID:19107203 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:19107203 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:21245321 Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21245321 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21245321 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:21304492 Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to ... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21304492 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21304492 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| 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 LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The cached abstract for PMID:21471202 centers LRP4, but the curator-made LRP6-SOST interaction is independently corroborated by direct LRP6-SOST evidence in PMID:15908424; generic binding remains non-core. Supporting Evidence: PMID:15908424 the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting |
| GO:0005515 protein binding | IPI PMID:21727895 Lgr5 homologues associate with Wnt receptors and mediate R-s... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21727895 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21727895 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:21944579 Wnt antagonists bind through a short peptide to the first Ξ²-... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21944579 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21944579 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:21984209 Crystal structures of the extracellular domain of LRP6 and i... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21984209 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21984209 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:22491013 Disabled-2 (Dab2) inhibits Wnt/Ξ²-catenin signalling by bindi... | KEEP AS NON CORE | Summary: IPI annotation from PMID:22491013 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22491013 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:22575959 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensiti... | MODIFY | Summary: IPI annotation from PMID:22575959 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22575959 records the ubiquitin protein ligase ZNRF3 as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0031625 ubiquitin protein ligase binding is the more informative replacement. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:22726442 Tiki1 is required for head formation via Wnt cleavage-oxidat... | MODIFY | Summary: IPI annotation from PMID:22726442 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22726442 records WNT3A as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0017147 Wnt-protein binding is the more informative replacement. Proposed replacements: Wnt-protein binding |
| GO:0005515 protein binding | IPI PMID:22899650 LRRK2 functions as a Wnt signaling scaffold, bridging cytoso... | MODIFY | Summary: IPI annotation from PMID:22899650 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22899650 records the protein kinase LRRK2 as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0019901 protein kinase binding is the more informative replacement, with the machine-sourced plasma-membrane extension retained. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:23791946 structural Studies of Wnts and identification of an LRP6 bin... | MODIFY | Summary: IPI annotation from PMID:23791946 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:23791946 records WNT3A as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0017147 Wnt-protein binding is the more informative replacement. Proposed replacements: Wnt-protein binding |
| GO:0005515 protein binding | IPI PMID:23892894 Small-molecule modulation of Wnt signaling via modulating th... | KEEP AS NON CORE | Summary: IPI annotation from PMID:23892894 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:23892894 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:27013965 Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Sign... | MODIFY | Summary: IPI annotation from PMID:27013965 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:27013965 records the protein kinase LRRK2 as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0019901 protein kinase binding is the more informative replacement, with the machine-sourced plasma-membrane extension retained. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:27524201 Structure of the Dual-Mode Wnt Regulator Kremen1 and Insight... | KEEP AS NON CORE | Summary: IPI annotation from PMID:27524201 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:27524201 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| 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 LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:28514442 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:30824926 Isoform-specific GSK3A activity is negatively correlated wit... | MODIFY | Summary: IPI annotation from PMID:30824926 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:30824926 records the protein kinase GSK3A as the physical interaction partner. GO:0005515 protein binding is too generic; GO:0019901 protein kinase binding is the more informative replacement. This does not imply an LRP6 isoform-specific function from the paper's GSK3A isoform study. Proposed replacements: protein kinase binding |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IPI annotation from PMID:32296183 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:32296183 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| 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 LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:33961781 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: IPI annotation from PMID:40205054 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:40205054 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0042802 identical protein binding | IPI PMID:12897152 A novel mechanism for Wnt activation of canonical signaling ... | KEEP AS NON CORE | Summary: IPI annotation from PMID:12897152 associates LRP6 with identical protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:12897152 supports or infers identical protein binding, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0042802 identical protein binding | IPI PMID:21984209 Crystal structures of the extracellular domain of LRP6 and i... | KEEP AS NON CORE | Summary: IPI annotation from PMID:21984209 associates LRP6 with identical protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21984209 reports DKK1-induced LRP6 oligomerization in structural studies, but self-association is a regulatory state rather than LRP6's defining coreceptor function. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with regulation of DNA-templated transcription; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports or infers regulation of DNA-templated transcription, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with positive regulation of cytosolic calcium ion concentration; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports or infers positive regulation of cytosolic calcium ion concentration, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0007268 chemical synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with chemical synaptic transmission; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports or infers chemical synaptic transmission, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with neuronal cell body; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0043434 response to peptide hormone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with response to peptide hormone; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports or infers response to peptide hormone, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0098609 cell-cell adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from GO_REF:0000107 associates LRP6 with cell-cell adhesion; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000107 supports or infers cell-cell adhesion, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:A0A0G2K0H3 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. ensembl:ENSRNOP00000071445 SOURCE WEAK OR INFERRED Automated rule, domain, controlled-vocabulary, or electronic source; not independent experimental support. |
| GO:0045121 membrane raft | EXP PMID:23987510 Lypd6 enhances Wnt/Ξ²-catenin signaling by promoting Lrp6 pho... | KEEP AS NON CORE | Summary: EXP annotation from PMID:23987510 associates LRP6 with membrane raft; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:23987510 directly places stimulated LRP6 phosphorylation in raft plasma-membrane domains. This regulated membrane microdomain is valid but secondary to LRP6's defining coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:34896607 Variants in the Wnt co-receptor LRP6 are associated with fam... | UNDECIDED | Summary: IPI annotation from PMID:34896607 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The cached PMID:34896607 record contains no abstract or full text, so the source-specific interaction cannot be verified. Curator deference requires UNDECIDED. |
| GO:0042813 Wnt receptor activity | IMP PMID:34896607 Variants in the Wnt co-receptor LRP6 are associated with fam... | UNDECIDED | Summary: IMP annotation from PMID:34896607 associates LRP6 with Wnt receptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: The cached PMID:34896607 record contains no abstract or full text, so the source-specific functional assay cannot be verified. Curator deference requires UNDECIDED despite LRP6's independently established Wnt-receptor role. |
| GO:0005515 protein binding | IPI PMID:21375506 Mest/Peg1 inhibits Wnt signalling through regulation of LRP6... | UNDECIDED | Summary: IPI annotation from PMID:21375506 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible record for PMID:21375506 does not expose the source-specific IPI evidence for protein binding. Curator deference requires UNDECIDED rather than removing an experimental assertion from incomplete evidence. |
| GO:0005886 plasma membrane | IDA PMID:21375506 Mest/Peg1 inhibits Wnt signalling through regulation of LRP6... | ACCEPT | Summary: IDA annotation from PMID:21375506 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:21375506 reports that MEST blocks LRP6 maturation and plasma-membrane localization; the experiment directly supports the seeded location. |
| GO:0030291 protein serine/threonine kinase inhibitor activity | IDA PMID:19107203 Direct inhibition of GSK3beta by the phosphorylated cytoplas... | ACCEPT | Summary: IDA annotation from PMID:19107203 associates LRP6 with protein serine/threonine kinase inhibitor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:19107203 directly demonstrates that phosphorylated PPPSPxS motifs in the LRP6 cytoplasmic tail inhibit GSK3 beta; this is a mechanistic activity in canonical Wnt signaling. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:14739301 The low density lipoprotein receptor-1, LRP1, interacts with... | KEEP AS NON CORE | Summary: IDA annotation from PMID:14739301 associates LRP6 with positive regulation of transcription by RNA polymerase II; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:14739301 uses a beta-catenin-responsive transcriptional readout while examining LRP-family receptor complexes. The transcription term is a downstream consequence, not a direct LRP6 activity. |
| GO:0005886 plasma membrane | IDA PMID:23572575 Essential roles of grp94 in gut homeostasis via chaperoning ... | ACCEPT | Summary: IDA annotation from PMID:23572575 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:23572575 reports that loss of GRP94 prevents LRP6 export from the ER to the cell surface, directly supporting active plasma-membrane localization. |
| GO:0042813 Wnt receptor activity | IDA PMID:11357136 LDL-receptor-related protein 6 is a receptor for Dickkopf pr... | ACCEPT | Summary: IDA annotation from PMID:11357136 associates LRP6 with Wnt receptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11357136 establishes LRP6 as a receptor/coreceptor in Wnt signaling; Wnt receptor activity is a defining molecular role even though this paper focuses on inhibitory DKK ligands. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | ACCEPT | Summary: IDA annotation from PMID:16890161 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:15271658 LDL receptor-related protein LRP6 regulates proliferation an... | ACCEPT | Summary: IDA annotation from PMID:15271658 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:15271658 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:16365045 The low density lipoprotein receptor-related protein 6 inter... | ACCEPT | Summary: IMP annotation from PMID:16365045 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16365045 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0015026 coreceptor activity | NAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | UNDECIDED | Summary: NAS annotation from PMID:24431302 associates LRP6 with coreceptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:24431302 is a review and its accessible abstract does not verify LRP6 coreceptor activity specifically in the planar-cell-polarity extension recorded by GOA. The machine-sourced extension is retained, but the statement-level tuple remains UNDECIDED. |
| GO:0015026 coreceptor activity | IDA PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | ACCEPT | Summary: IDA annotation from PMID:11029007 associates LRP6 with coreceptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports coreceptor activity; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | ACCEPT | Summary: IMP annotation from PMID:11029007 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005515 protein binding | IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/Ξ²-catenin signali... | KEEP AS NON CORE | Summary: IPI annotation from PMID:31073040 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:31073040 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | ACCEPT | Summary: IMP annotation from PMID:20093472 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20093472 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| 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 LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16805831 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. | ACCEPT | Summary: IDA annotation from PMID:11448771 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11448771 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:11742004 Second cysteine-rich domain of Dickkopf-2 activates canonica... | ACCEPT | Summary: IDA annotation from PMID:11742004 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11742004 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| 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 LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:15908424 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:19107203 Direct inhibition of GSK3beta by the phosphorylated cytoplas... | ACCEPT | Summary: IDA annotation from PMID:19107203 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:19107203 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:20093106 The low-density lipoprotein receptor-related protein 10 is a... | ACCEPT | Summary: IDA annotation from PMID:20093106 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20093106 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:16263759 Mesd binds to mature LDL-receptor-related protein-6 and anta... | ACCEPT | Summary: IDA annotation from PMID:16263759 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16263759 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005515 protein binding | IPI PMID:23987510 Lypd6 enhances Wnt/Ξ²-catenin signaling by promoting Lrp6 pho... | KEEP AS NON CORE | Summary: IPI annotation from PMID:23987510 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:23987510 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-209104 | UNDECIDED | Summary: TAS annotation from Reactome:R-NUL-209104 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-NUL-209104 describes phosphorylation of human LRP6 in a receptor complex by frog CKI gamma but does not explicitly establish plasma-membrane localization. The source-specific TAS location remains UNDECIDED. |
| GO:1904948 midbrain dopaminergic neuron differentiation | TAS PMID:22988876 The importance of Wnt signalling for neurodegeneration in Pa... | KEEP AS NON CORE | Summary: TAS annotation from PMID:22988876 associates LRP6 with midbrain dopaminergic neuron differentiation; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22988876 is a review of Wnt signaling in dopaminergic-neuron biology; this developmental outcome is biologically plausible but peripheral to LRP6's defining receptor activity. |
| GO:0017147 Wnt-protein binding | IPI PMID:20093360 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex r... | ACCEPT | Summary: IPI annotation from PMID:20093360 associates LRP6 with Wnt-protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20093360 supports Wnt-protein binding; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005515 protein binding | IPI PMID:20093360 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex r... | KEEP AS NON CORE | Summary: IPI annotation from PMID:20093360 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20093360 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| 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 LRP6 with Wnt-protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22988876 supports Wnt-protein binding; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | TAS PMID:22988876 The importance of Wnt signalling for neurodegeneration in Pa... | ACCEPT | Summary: TAS annotation from PMID:22988876 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22988876 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | IDA PMID:20093360 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex r... | ACCEPT | Summary: IDA annotation from PMID:20093360 associates LRP6 with Wnt-Frizzled-LRP5/6 complex; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20093360 supports Wnt-Frizzled-LRP5/6 complex; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| 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 LRP6 with Wnt-Frizzled-LRP5/6 complex; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22988876 supports Wnt-Frizzled-LRP5/6 complex; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| 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 LRP6 with Wnt signalosome; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:24115276 supports Wnt signalosome; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0071542 dopaminergic neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation from GO_REF:0000024 associates LRP6 with dopaminergic neuron differentiation; evidence specificity, source support, and core relevance were reviewed. Reason: GO_REF:0000024 supports or infers dopaminergic neuron differentiation, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O88572 SUPPORTS TRANSFER |
| GO:1990909 Wnt signalosome | IDA PMID:22899650 LRRK2 functions as a Wnt signaling scaffold, bridging cytoso... | ACCEPT | Summary: IDA annotation from PMID:22899650 associates LRP6 with Wnt signalosome; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22899650 directly places LRP6 in a Wnt signalosome assembled with LRRK2 and cytosolic pathway components, supporting this core signaling-complex annotation. |
| GO:0072659 protein localization to plasma membrane | IPI PMID:22899650 LRRK2 functions as a Wnt signaling scaffold, bridging cytoso... | KEEP AS NON CORE | Summary: IPI annotation from PMID:22899650 associates LRP6 with protein localization to plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:22899650 supports LRRK2-dependent recruitment/localization of Wnt pathway components at the plasma membrane; this trafficking event is valid but non-core for LRP6. |
| GO:0005515 protein binding | IPI PMID:11357136 LDL-receptor-related protein 6 is a receptor for Dickkopf pr... | KEEP AS NON CORE | Summary: IPI annotation from PMID:11357136 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11357136 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0016055 Wnt signaling pathway | IDA PMID:11357136 LDL-receptor-related protein 6 is a receptor for Dickkopf pr... | ACCEPT | Summary: IDA annotation from PMID:11357136 associates LRP6 with Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11357136 supports Wnt signaling pathway in LRP6 biology, and the annotation is retained at an appropriate level of specificity. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:17239604 The vacuolar-ATPase inhibitor bafilomycin and mutant VPS35 i... | ACCEPT | Summary: IDA annotation from PMID:17239604 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:17239604 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005515 protein binding | IPI PMID:11433302 Novel mechanism of Wnt signalling inhibition mediated by Dic... | KEEP AS NON CORE | Summary: IPI annotation from PMID:11433302 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11433302 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | IPI PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | ACCEPT | Summary: IPI annotation from PMID:11029007 associates LRP6 with Wnt-Frizzled-LRP5/6 complex; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports Wnt-Frizzled-LRP5/6 complex; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:1990851 Wnt-Frizzled-LRP5/6 complex | IPI PMID:11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. | ACCEPT | Summary: IPI annotation from PMID:11448771 associates LRP6 with Wnt-Frizzled-LRP5/6 complex; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11448771 supports Wnt-Frizzled-LRP5/6 complex; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0031410 cytoplasmic vesicle | IDA PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | UNDECIDED | Summary: IDA annotation from PMID:20093472 associates LRP6 with cytoplasmic vesicle; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible PMID:20093472 abstract establishes a prorenin-receptor/V-ATPase requirement for Wnt signaling but does not expose the seeded LRP6 cytoplasmic-vesicle localization experiment. Cached full text is unavailable, so curator deference requires UNDECIDED. |
| GO:0005515 protein binding | IPI PMID:20093472 Requirement of prorenin receptor and vacuolar H+-ATPase-medi... | UNDECIDED | Summary: IPI annotation from PMID:20093472 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible PMID:20093472 abstract identifies the prorenin receptor as a component of the Wnt receptor complex but does not expose a direct LRP6 interaction assay. Cached full text is unavailable, so the generic IPI remains UNDECIDED. |
| GO:0031901 early endosome membrane | TAS Reactome:R-HSA-5368596 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-5368596 associates LRP6 with early endosome membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-5368596 supports early endosome membrane in LRP6 biology, and the annotation is retained at an appropriate level of specificity. |
| GO:0005576 extracellular region | TAS Reactome:R-NUL-1458871 | MARK AS OVER ANNOTATED | Summary: TAS annotation from Reactome:R-NUL-1458871 associates LRP6 with extracellular region; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-NUL-1458871 describes soluble human LRP6 ectodomain constructs in conditioned medium, not native secretion of full-length LRP6. Extracellular exposure is real, but annotating the intact type-I membrane receptor to extracellular region overstates the construct evidence. |
| GO:0005769 early endosome | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | KEEP AS NON CORE | Summary: IDA annotation from PMID:16890161 associates LRP6 with early endosome; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. |
| GO:0005794 Golgi apparatus | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | UNDECIDED | Summary: IDA annotation from PMID:16890161 associates LRP6 with Golgi apparatus; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 directly studies LRP6 internalization, but the accessible abstract does not expose the seeded Golgi colocalization result and cached full text is unavailable. Curator deference requires UNDECIDED. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-201677 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-201677 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-201677 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-1458902 | UNDECIDED | Summary: TAS annotation from Reactome:R-NUL-1458902 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-NUL-1458902 describes phosphorylation of LRP6 by Xenopus CK1 gamma but does not state a plasma-membrane localization assertion. The independently secure location does not verify this source-specific TAS tuple, so it remains UNDECIDED. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5368596 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-5368596 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-5368596 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005515 protein binding | IPI PMID:16815997 The role of microtubule actin cross-linking factor 1 (MACF1)... | KEEP AS NON CORE | Summary: IPI annotation from PMID:16815997 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16815997 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:12857724 Functional characterization of WNT7A signaling in PC12 cells... | KEEP AS NON CORE | Summary: IDA annotation from PMID:12857724 associates LRP6 with positive regulation of transcription by RNA polymerase II; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:12857724 directly reports beta-catenin stabilization and TCF-reporter activation through an FZD5-LRP6 receptor complex. Transcriptional regulation is a downstream readout and therefore non-core. |
| GO:0005109 frizzled binding | IPI PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | ACCEPT | Summary: IPI annotation from PMID:11029007 associates LRP6 with frizzled binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports frizzled binding; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0014029 neural crest formation | IDA PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | KEEP AS NON CORE | Summary: IDA annotation from PMID:11029007 associates LRP6 with neural crest formation; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports or infers neural crest formation, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:12121999 A novel set of Wnt-Frizzled fusion proteins identifies recep... | ACCEPT | Summary: IDA annotation from PMID:12121999 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:12121999 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| 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 LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:18762581 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:17804805 R-Spondin1 regulates Wnt signaling by inhibiting internaliza... | KEEP AS NON CORE | Summary: IPI annotation from PMID:17804805 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:17804805 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0005886 plasma membrane | IDA PMID:17569865 Wnt induces LRP6 signalosomes and promotes dishevelled-depen... | ACCEPT | Summary: IDA annotation from PMID:17569865 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:17569865 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005901 caveola | IDA PMID:17569865 Wnt induces LRP6 signalosomes and promotes dishevelled-depen... | UNDECIDED | Summary: IDA annotation from PMID:17569865 associates LRP6 with caveola; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:17569865 directly supports LRP6 signalosome formation, but the accessible abstract does not expose the seeded caveolar colocalization assay and cached full text is unavailable. Curator deference requires UNDECIDED. |
| GO:0009986 cell surface | IDA PMID:12897152 A novel mechanism for Wnt activation of canonical signaling ... | UNDECIDED | Summary: IDA annotation from PMID:12897152 associates LRP6 with cell surface; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible record for PMID:12897152 does not expose the source-specific IDA evidence for cell surface. Curator deference requires UNDECIDED rather than removing an experimental assertion from incomplete evidence. |
| GO:0014033 neural crest cell differentiation | IDA PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | KEEP AS NON CORE | Summary: IDA annotation from PMID:11029007 associates LRP6 with neural crest cell differentiation; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports or infers neural crest cell differentiation, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0017147 Wnt-protein binding | IPI PMID:11029007 LDL-receptor-related proteins in Wnt signal transduction. | ACCEPT | Summary: IPI annotation from PMID:11029007 associates LRP6 with Wnt-protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:11029007 supports Wnt-protein binding; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0017147 Wnt-protein binding | IPI PMID:12897152 A novel mechanism for Wnt activation of canonical signaling ... | UNDECIDED | Summary: IPI annotation from PMID:12897152 associates LRP6 with Wnt-protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible record for PMID:12897152 does not expose the source-specific IPI evidence for Wnt-protein binding. Curator deference requires UNDECIDED rather than removing an experimental assertion from incomplete evidence. |
| GO:0019210 kinase inhibitor activity | IMP PMID:16365045 The low density lipoprotein receptor-related protein 6 inter... | MODIFY | Summary: IMP annotation from PMID:16365045 associates LRP6 with kinase inhibitor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16365045 directly shows that LRP6 binds and attenuates the serine/threonine kinase GSK3 beta. Current GO:0030291 protein serine/threonine kinase inhibitor activity is the more precise replacement for generic kinase inhibitor activity. Proposed replacements: protein serine/threonine kinase inhibitor activity |
| 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 LRP6 with toxin transmembrane transporter activity; evidence specificity, source support, and core relevance were reviewed. Reason: This assertion is explicitly negated: PMID:18350154 shows that efficient LRP6 knockdown does not affect anthrax-toxin entry or pore formation in human HeLa cells, so the NOT annotation is correct. Supporting Evidence: PMID:18350154 These data argue against a specific requirement for either LRP6 or LRP5 in anthrax toxin entry. |
| GO:0019534 toxin transmembrane transporter activity | IMP PMID:16564009 The LDL receptor-related protein LRP6 mediates internalizati... | MARK AS OVER ANNOTATED | Summary: IMP annotation from PMID:16564009 associates LRP6 with toxin transmembrane transporter activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16564009 reports that LRP6 is required for anthrax-toxin uptake and lethality in its tested mammalian-cell contexts, but a receptor requirement for entry does not establish that LRP6 itself transports toxin across a membrane. The experimental observation is retained while the transporter-activity interpretation is marked as over-annotated; this context-specific positive result does not negate the later human-HeLa NOT assertion in PMID:18350154. |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | IMP PMID:15271658 LDL receptor-related protein LRP6 regulates proliferation an... | KEEP AS NON CORE | Summary: IMP annotation from PMID:15271658 associates LRP6 with negative regulation of smooth muscle cell apoptotic process; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:15271658 links LRP6-dependent canonical Wnt signaling to survival of vascular smooth-muscle cells. The anti-apoptotic outcome is supported but is tissue- and context-specific rather than core. |
| GO:0042803 protein homodimerization activity | IPI PMID:12897152 A novel mechanism for Wnt activation of canonical signaling ... | KEEP AS NON CORE | Summary: IPI annotation from PMID:12897152 associates LRP6 with protein homodimerization activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:12897152 supports or infers protein homodimerization activity, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0045787 positive regulation of cell cycle | IMP PMID:15271658 LDL receptor-related protein LRP6 regulates proliferation an... | KEEP AS NON CORE | Summary: IMP annotation from PMID:15271658 associates LRP6 with positive regulation of cell cycle; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:15271658 supports or infers positive regulation of cell cycle, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0005515 protein binding | IPI PMID:18721193 LRP5 in premature adrenarche and in metabolic characteristic... | UNDECIDED | Summary: IPI annotation from PMID:18721193 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: The accessible PMID:18721193 record concerns LRP5 genetic associations and does not expose an LRP6 interaction assay. Cached full text is unavailable, so the curator-made LRP6 IPI remains UNDECIDED rather than being overruled. |
| GO:0045893 positive regulation of DNA-templated transcription | IMP PMID:18215320 Ror2 modulates the canonical Wnt signaling in lung epithelia... | KEEP AS NON CORE | Summary: IMP annotation from PMID:18215320 associates LRP6 with positive regulation of DNA-templated transcription; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:18215320 supports or infers positive regulation of DNA-templated transcription, but this is a broad, downstream, or context-dependent consequence rather than LRP6's defining molecular function. |
| GO:0060070 canonical Wnt signaling pathway | IMP PMID:18215320 Ror2 modulates the canonical Wnt signaling in lung epithelia... | ACCEPT | Summary: IMP annotation from PMID:18215320 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:18215320 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005102 signaling receptor binding | IPI PMID:14739301 The low density lipoprotein receptor-1, LRP1, interacts with... | MODIFY | Summary: IPI annotation from PMID:14739301 associates LRP6 with signaling receptor binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:14739301 specifically reports interaction between an LRP6 extracellular fragment and human Frizzled-1. Current GO:0005109 frizzled binding is more informative than generic signaling receptor binding. Proposed replacements: frizzled binding |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:14739301 The low density lipoprotein receptor-1, LRP1, interacts with... | ACCEPT | Summary: IDA annotation from PMID:14739301 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:14739301 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:20137080 Helicobacter pylori-induced activation of beta-catenin invol... | ACCEPT | Summary: IDA annotation from PMID:20137080 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20137080 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005886 plasma membrane | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | ACCEPT | Summary: IDA annotation from PMID:16890161 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005901 caveola | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | KEEP AS NON CORE | Summary: IDA annotation from PMID:16890161 associates LRP6 with caveola; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. |
| GO:0031410 cytoplasmic vesicle | IDA PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | KEEP AS NON CORE | Summary: IDA annotation from PMID:16890161 associates LRP6 with cytoplasmic vesicle; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 supports a trafficking or context-specific localization of LRP6; it is biologically relevant but secondary to its defining cell-surface coreceptor role. |
| GO:0071397 cellular response to cholesterol | IMP PMID:16890161 Caveolin is necessary for Wnt-3a-dependent internalization o... | KEEP AS NON CORE | Summary: IMP annotation from PMID:16890161 associates LRP6 with cellular response to cholesterol; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16890161 studies cholesterol-sensitive caveolin-dependent LRP6 internalization. The cholesterol response is a specialized trafficking context rather than LRP6's defining coreceptor activity. |
| GO:0005515 protein binding | IPI PMID:20059949 Cell cycle control of wnt receptor activation. | KEEP AS NON CORE | Summary: IPI annotation from PMID:20059949 associates LRP6 with protein binding; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20059949 supports or curates an LRP6 interaction, but generic protein binding is uninformative and does not represent LRP6's defining Wnt-coreceptor activity. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:20059949 Cell cycle control of wnt receptor activation. | ACCEPT | Summary: IDA annotation from PMID:20059949 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:20059949 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:16543246 Mouse cristin/R-spondin family proteins are novel ligands fo... | ACCEPT | Summary: IDA annotation from PMID:16543246 associates LRP6 with canonical Wnt signaling pathway; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16543246 supports canonical Wnt signaling pathway; this is part of LRP6's defining ligand-dependent canonical Wnt coreceptor mechanism. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1504186 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-1504186 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-1504186 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3769397 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-3769397 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-3769397 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3769401 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-3769401 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-3769401 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641236 | UNDECIDED | Summary: TAS annotation from Reactome:R-HSA-4641236 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-4641236 describes USP8-dependent FZD recycling and does not mention LRP6. Plasma-membrane localization of LRP6 is independently secure, but this source-specific TAS tuple is unsupported and remains UNDECIDED. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641249 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-4641249 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-4641249 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641253 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-4641253 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-4641253 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5340587 | UNDECIDED | Summary: TAS annotation from Reactome:R-HSA-5340587 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-5340587 describes RNF43-mutant effects on FZD abundance and Wnt signaling without identifying LRP6. The source-specific LRP6 plasma-membrane TAS tuple therefore remains UNDECIDED. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5368586 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-5368586 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-5368586 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0031901 early endosome membrane | TAS Reactome:R-HSA-5368586 | ACCEPT | Summary: TAS annotation from Reactome:R-HSA-5368586 associates LRP6 with early endosome membrane; evidence specificity, source support, and core relevance were reviewed. Reason: Reactome:R-HSA-5368586 supports early endosome membrane in LRP6 biology, and the annotation is retained at an appropriate level of specificity. |
| GO:0005041 low-density lipoprotein particle receptor activity | IDA PMID:16263759 Mesd binds to mature LDL-receptor-related protein-6 and anta... | UNDECIDED | Summary: IDA annotation from PMID:16263759 associates LRP6 with low-density lipoprotein particle receptor activity; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16263759 demonstrates high-affinity MESD binding to cell-surface LRP6 and explicitly states that LRP6 is not a constitutively active endocytosis receptor; its accessible abstract does not establish low-density-lipoprotein-particle receptor activity. Cached full text is unavailable, so curator deference requires UNDECIDED rather than removal. |
| GO:0005886 plasma membrane | IDA PMID:16263759 Mesd binds to mature LDL-receptor-related protein-6 and anta... | ACCEPT | Summary: IDA annotation from PMID:16263759 associates LRP6 with plasma membrane; evidence specificity, source support, and core relevance were reviewed. Reason: PMID:16263759 supports plasma-membrane localization, which is intrinsic to LRP6's architecture as a cell-surface Wnt coreceptor. |
| GO:0097110 scaffold protein binding | IPI PMID:16341017 A dual-kinase mechanism for Wnt co-receptor phosphorylation ... | NEW | Summary: Added the specific molecular function for binding the AXIN scaffold through the phosphorylated LRP6 cytoplasmic tail. Reason: GO:0097110 captures the core AXIN-binding step more informatively than the existing generic protein-binding rows. It is distinct from LRP6's Wnt/Frizzled coreceptor activities and from direct inhibition of GSK3. Supporting Evidence: PMID:16341017 phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with |
| GO:1904701 Wnt-Frizzled-LRP5/6 complex assembly | IDA PMID:11448771 Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. | NEW | Summary: Added the receptor-complex assembly process directly demonstrated by Wnt-induced Frizzled-LRP6 association and its disruption by DKK1. Reason: Existing rows record LRP6 as part of the Wnt-Frizzled-LRP5/6 complex but do not capture the experimentally supported assembly process. Supporting Evidence: PMID:11448771 RESULTS: We report that Dkk-1 is a high-affinity ligand for LRP6 and inhibits Wnt signaling by preventing Fz-LRP6 complex formation induced by Wnt. Dkk-1 binds neither Wnt nor Fz, nor does it affect Wnt-Fz interaction. Dkk-1 function in head induction and Wnt signaling inhibition strictly correlates with its ability to bind LRP6 and to disrupt the Fz-LRP6 association. LRP6 function and Dkk-1 inhibition appear to be specific for the Wnt/Fz beta-catenin pathway. |
| GO:1904887 Wnt signalosome assembly | IDA PMID:17569865 Wnt induces LRP6 signalosomes and promotes dishevelled-depen... | NEW | Summary: Added the Wnt-induced assembly of phosphorylated LRP6 signalosomes that recruit AXIN. Reason: Existing rows record membership in the Wnt signalosome but not LRP6's direct participation in its ligand-induced assembly. Supporting Evidence: PMID:17569865 quickly induces plasma membrane-associated LRP6 aggregates. LRP6 aggregates are phosphorylated and can be detergent-solubilized as ribosome-sized multiprotein complexes. Phospho-LRP6 aggregates contain Wnt-pathway components but no common vesicular traffic markers except caveolin. The scaffold protein Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation. We propose that Wnts induce coclustering of receptors and Dvl in LRP6-signalosomes, which in turn triggers LRP6 phosphorylation to promote Axin recruitment and beta-catenin |
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Download this section (compressed HTML)Q: Which NCBI RefSeq LRP6 models a-j are translated in human tissues, and do any product-specific sequences alter surface delivery, ligand binding, or the PPPSP-dependent signalosome mechanism relative to UniProtKB O75581/RefSeq b?
Q: What is the full-length architecture of a human Wnt-Frizzled-LRP6 signalosome, and how does extracellular complex geometry control phosphorylation and AXIN recruitment by the cytoplasmic tail?
Q: In endogenous human signaling, how much beta-catenin stabilization is caused by direct GSK3 inhibition by phosphorylated LRP6 motifs versus AXIN-GSK3 recruitment or sequestration?
Q: Which human tissues depend specifically on LRP6 rather than LRP5, and which disease variants perturb ligand binding, receptor trafficking, signalosome assembly, or direct GSK3 inhibition?
Experiment: Combine long-read RNA sequencing, targeted junction assays, ribosome profiling, and isoform-unique targeted proteomics across human Wnt-responsive tissues. Express only sequence-verified products at matched levels in an LRP6-null human background and compare maturation, plasma-membrane abundance, Wnt/Frizzled complex assembly, tail phosphorylation, and beta-catenin signaling.
Hypothesis: Only a subset of NCBI RefSeq LRP6 models a-j produces stable cell-surface protein, with the O75581/RefSeq-b product accounting for the established core Wnt-coreceptor activity.
Type: isoform-resolved transcriptomics, proteomics, and functional rescue
Experiment: Reconstitute full-length human LRP6 with defined human Wnt and Frizzled partners in nanodiscs and matched human cells, then combine cryo-EM or cryo-electron tomography with cross-linking mass spectrometry, phosphosite mapping, and single-particle clustering measurements. Include fragment-only constructs as controls rather than treating them as full-receptor structures.
Hypothesis: Defined Wnt and Frizzled combinations impose distinct full-length LRP6 conformations that couple extracellular receptor assembly to cytoplasmic-tail phosphorylation and signalosome formation.
Type: full-length membrane-complex structural and phosphoproteomic analysis
Experiment: Introduce endogenous separation-of-function edits in individual PPPSP motifs, quantify AXIN/GSK3 recruitment and GSK3 substrate phosphorylation in real time, and measure beta-catenin stabilization in human cells. Compare intact LRP6 with recruitment-defective and inhibitor-defective tails while verifying equal surface abundance and Wnt-Frizzled complex formation.
Hypothesis: AXIN recruitment and direct GSK3 inhibition are separable phospho-tail functions whose relative importance changes with signaling dose and duration.
Type: endogenous phosphosite editing and quantitative signaling kinetics
Experiment: Engineer representative extracellular, transmembrane-proximal, and tail variants into isogenic human retinal, dental, bone, and vascular models. Measure surface delivery, ligand and Frizzled binding, signalosome assembly, and beta-catenin output with matched LRP5 knockout and rescue conditions; do not use LRP4 or LRP5L as functional substitutes.
Hypothesis: LRP6 disease alleles cause tissue-specific phenotypes through distinct defects in receptor trafficking, extracellular ligand/coreceptor assembly, or phospho-tail signaling, modulated by LRP5 compensation.
Type: isogenic variant phenotyping in tissue-relevant human models
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: It is unknown whether the additional NCBI RefSeq LRP6 transcript/protein models designated a-j produce stable products with functions that differ from the UniProtKB O75581/RefSeq isoform-b model reviewed here.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: UniProtKB O75581 has no ALTERNATIVE PRODUCTS or VAR_SEQ record and maps to RefSeq isoform b, whereas current NCBI records enumerate additional predicted models. None of the reviewed functional studies establishes an isoform-specific activity for those non-b products, and the GSK3A isoform study PMID:30824926 supplies no LRP6 isoform evidence.
Significance: Assigning core receptor functions to untested transcript models could obscure product-specific trafficking, extracellular architecture, or cytoplasmic-tail differences.
What would resolve it: Establish transcript abundance and translation with isoform-resolved long-read RNA sequencing and proteogenomics, then compare cell-surface delivery and Wnt signaling of sequence-verified products against the O75581/RefSeq-b product.
Gap: The architecture and conformational transitions of full-length, membrane-embedded human LRP6 in an activated Wnt-Frizzled signalosome remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Existing structures define isolated human LRP6 extracellular E1E2 or E3E4 fragments and fragment complexes with DKK1 or Kremen1. They do not establish the structure of intact LRP6, its transmembrane segment, cytoplasmic tail, or a complete membrane receptor signalosome.
Significance: Full-length structural information is needed to connect extracellular ligand/coreceptor geometry to tail phosphorylation, oligomerization, AXIN recruitment, and antagonist action.
What would resolve it: Determine structures of endogenous or near-endogenous full-length human LRP6 with defined Wnt and Frizzled partners in a membrane environment, supported by cross-linking mass spectrometry and phosphosite-resolved conformational assays.
Provenance (the field's own admissions):
Gap: The relative contribution of direct GSK3 inhibition by phosphorylated LRP6 motifs versus recruitment and sequestration of AXIN-GSK3 in endogenous human signalosomes is not quantitatively resolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Phosphorylated PPPSPxS peptides directly inhibit GSK3 in vitro, and separate experiments show phosphorylation-dependent AXIN engagement and recruitment. The direct inhibition evidence includes synthetic peptides and Xenopus assays, so it does not by itself establish the dominant mechanism in every human tissue.
Significance: Resolving these mechanisms is necessary to model how a non-enzymatic receptor tail suppresses beta-catenin destruction without incorrectly assigning LRP6 an autonomous catalytic activity.
What would resolve it: Use endogenous phosphosite editing, quantitative GSK3 activity reporters, and time-resolved AXIN/GSK3 recruitment in human cells to compare intact LRP6 with separation-of-function tails that preserve recruitment but disrupt inhibitory phosphomotifs, or vice versa.
Provenance (the field's own admissions):
Gap: The tissue-specific division of labor between human LRP6 and LRP5, and the mechanistic effects of many LRP6 disease variants, remain incompletely resolved.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: LRP6-specific human evidence supports the core receptor mechanism, but many studies report LRP5/6 jointly or use Xenopus, mouse, zebrafish, PC12, NIH3T3, or other heterologous systems. LRP4- and LRP5L-specific findings are not transferable to LRP6, and disease-associated variants do not by themselves define normal LRP6 function; PMID:34896607 lacks locally accessible functional text.
Significance: Tissue-specific redundancy and variant mechanisms determine which phenotypes reflect altered ligand binding, receptor trafficking, signalosome assembly, or paralog compensation.
What would resolve it: Compare endogenous LRP6 variant alleles in human tissue-relevant models with matched LRP5 loss or rescue, and test ligand binding, surface abundance, phospho-tail signaling, and signalosome assembly without extrapolating from LRP4 or LRP5L.
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