Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
UniProtKB entry O75197 (LRP5_HUMAN), low-density lipoprotein receptor-related protein 5
LDL-receptor-related proteins in Wnt signal transduction.
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The paper establishes mammalian LRP6, not LRP5, as a Wnt coreceptor and mentions LRP5 only as a homolog of Drosophila Arrow.
"Here we report that LRP6 functions as a
co-receptor for Wnt signal transduction."
Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.
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LRP5 acts synergistically with Wnt rather than activating canonical signaling on its own in fibroblasts.
"LRP-5, when expressed in fibroblast cells, showed
no effect on the canonical Wnt signaling pathway by itself, but acted
synergistically with Wnt."
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Wnt promotes membrane recruitment of Axin and its interaction with the LRP5 intracellular domain.
"Addition of
Wnt caused the translocation of Axin to the membrane and enhanced the
interaction between Axin and LRP-5."
Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.
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The accessible paper specifically identifies LRP6 as the DKK1-binding component of the receptor complex.
"Dkk-1 specifically
inhibits canonical Wnt signalling by binding to the LRP6 component of the
receptor complex."
A novel set of Wnt-Frizzled fusion proteins identifies receptor components that activate beta -catenin-dependent signaling.
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In the reported 293T fusion-protein assay, several Wnt-FZD constructs activated a reporter with LRP6 but not LRP5.
"In 293T cells, coexpression of several Wnt-Fz
fusion proteins with LRP6, but not LRP5, significantly activated a
Wnt-responsive promoter, Optimized TOPFlash."
Functional characterization of WNT7A signaling in PC12 cells: interaction with A FZD5 x LRP6 receptor complex and modulation by Dickkopf proteins.
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WNT7A signaling in rat PC12 cells was assigned to an FZD5-LRP6 receptor complex, with no LRP5 experiment described in the abstract.
"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."
Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.
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Human LRP5 variants segregate with familial exudative vitreoretinopathy, linking LRP5-dependent Wnt signaling to ocular vascularization.
"Here, we describe mutations in a second gene at the EVR1 locus,
low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor."
Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.
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Norrin activates classical Wnt signaling through FZD4 and an LRP-dependent coreceptor component during ocular and inner-ear vascular development.
"the high efficiency with which Norrin induces Fz4- and Lrp-dependent
activation of the classical Wnt pathway"
Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5.
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Homozygous LRP5 variants were identified in three consanguineous families with autosomal-recessive FEVR.
"Sequencing of LRP5 shows, in all
three families, homozygous mutations R570Q, R752G, and E1367K."
SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.
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Sclerostin binds the extracellular domains of LRP5 and LRP6 and disrupts formation of the Wnt-induced Frizzled-LRP complex.
"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."
Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells.
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Ectopic LRP5 expression in PC12 cells exposed inhibition of Wnt signaling by APOE2 and APOE3, with APOE4 remaining the strongest inhibitor.
"expression of LRP5 unmasked an inhibition by ApoE2 and ApoE3"
Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells.
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Activating and inactivating LRP5 variants drive opposite osteoblast-versus-adipocyte differentiation outcomes in human mesenchymal stem cells.
"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)."
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Wild-type and activating-mutant LRP5 supported ectopic mineralized bone formation in a mouse implantation assay.
"Similarly,
hMSC-LRP5(WT) and hMSC-LRP5(T253) but not hMSC-LRP5(T244) formed ectopic
mineralized bone when implanted subcutaneously with hydroxyapatite/tricalcium
phosphate in SCID/NOD mice."
Moderate reduction of Norrin signaling activity associated with the causative missense mutations identified in patients with familial exudative vitreoretinopathy.
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Disease-associated LRP5 missense variants reduced Norrin-dependent reporter signaling in a functional assay.
"single missense mutations in LRP5 and FZD4 caused a
moderate level of reduction (ranging from 26 to 48, 36% on average)"
An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling.
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A tumor-associated internally deleted LRP5 product supported ligand-dependent beta-catenin transcription and resisted DKK1 inhibition.
"WNT3 ligand and the internally truncated LRP5 receptor strongly activated
transcription, and the internally truncated LRP5 receptor was insensitive to
inhibition by DKK1."
Evidence against a human cell-specific role for LRP6 in anthrax toxin entry.
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LRP5 knockdown alone or with LRP6 did not alter anthrax lethal-toxin entry in human HeLa cells.
"We show here that efficient
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."
LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children.
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Common LRP5 variants did not predispose to premature adrenarche but showed associations with cholesterol and blood-pressure traits in a small pediatric cohort.
"Genetic variation in LRP5 did not predispose to PA but was
associated with metabolic characteristics, especially lipid profile, in healthy
prepubertal children."
Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation.
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CAPRIN2 binds LRP5/6, promotes receptor phosphorylation, and strengthens Axin recruitment in canonical Wnt signaling.
"Moreover, Caprin-2 facilitates LRP5/6 phosphorylation by
glycogen synthase kinase 3, and thus enhances the interaction between Axin and
LRP5/6."
Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia.
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Individuals carrying damaging LRP5 variants had low bone density and a high prevalence of abnormal glucose metabolism, while lipid findings were inconclusive.
"We found high prevalence of osteoporosis and abnormal glucose
metabolism in subjects with LRP5 mutation(s). Further studies are needed to
establish the role of LRP5 in glucose and lipid metabolism."
Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6.
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The purified signaling complex contained mouse FZD8, WNT3A, and human LRP6; LRP5 was not reconstituted.
"reconstitute in vitro the Fz8 CRD.Wnt3a.LRP6 signaling complex."
Association of LPR5 polymorphism with bone mass density and cholesterol level in population of Chinese Han.
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The LRP5 rs3736228 risk allele was associated with reduced bone mineral density and higher total cholesterol in a Chinese Han cohort.
"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."
APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
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APCDD1 interacts with WNT3A and LRP5 in vitro and inhibits canonical Wnt signaling upstream of beta-catenin.
"We show that APCDD1 is a membrane-bound glycoprotein that is
abundantly expressed in human hair follicles, and can interact in vitro with
WNT3A and LRP5-two essential components of Wnt signalling."
Low-density lipoprotein receptor-related protein 5 polymorphisms are associated with bone mineral density in Greek postmenopausal women: an interaction with calcium intake.
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One common LRP5 variant showed a calcium-intake-dependent association with spinal bone mineral density.
"These findings demonstrate that both rs4988321 polymorphism and its interaction
with calcium intake are associated with BMD"
Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function.
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The paper identifies LRP4, not LRP5, as a direct sclerostin-binding facilitator in bone cells.
"Biochemical assays with recombinant proteins
confirmed that sclerostin LRP4 interaction is direct."
The importance of Wnt signalling for neurodegeneration in Parkinson's disease.
The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
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The review describes LRP5 and LRP6 jointly as canonical Wnt coreceptors that relay Wnt-FZD binding across the plasma membrane.
"The binding of Wnt ligands to the combination of FZD and LRP5/6 proteins allows the extracellular signal to be relayed across the plasma membrane, leading to the activation of intracellular signaling."
Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's disease.
Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis.
LRP5 variants may contribute to ADPKD.
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Three candidate ADPKD-associated LRP5 variants significantly reduced canonical Wnt reporter activation.
"luciferase activity assays presented for three LRP5 variants
significant decreased signal activation of canonical Wnt signaling."
Architecture of the human interactome defines protein communities and disease networks.
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BioPlex 2.0 reports affinity-purification mass-spectrometry candidate co-associations rather than necessarily direct binary interactions.
"With more than 56,000 candidate interactions"
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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BioPlex 3.0 comprises cell-line-specific affinity-purification mass-spectrometry interaction networks.
"mass spectrometry, we have created two proteome-scale, cell-line-specific"
Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity.
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The cloned human LRP5/LR3 product is a 1,615-residue LDL-receptor-family protein with a large modular ectodomain.
"The cDNA was
isolated from a human osteoblast cDNA library and encoded a 1,615 amino acids
protein designated as LR3."
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Full-length or ectodomain LRP5/LR3 increased proliferation in transfected NIH 3T3 cells, whereas the intracellular domain did not.
"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."
Phosphorylation of LRP5/6 cytoplasmic domain by membrane-associated GSK3beta
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Reactome models phosphorylation of five intracellular LRP5/6 motifs as promoting Axin interaction and Wnt signaling.
"Individual phosphorylation of each of these motifs promotes interaction with AXIN and stimulates WNT signaling as assessed by activation of a TCF/beta-catenin responsive reporter (Tamai et al, 2004; Zeng et al, 2005; MacDonald et al, 2008)."
misspliced mutants of LRP5 support enhanced beta-catenin-dependent signaling
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Reactome models an internally deleted LRP5 product as activating beta-catenin-dependent transcription and resisting DKK1 inhibition.
"Expression of the internally deleted LRP5 protein results in elevated levels of the active, unphosphorylated beta-catenin, enhanced expression of the both WNT-dependent reporter genes and the endogenous WNT-target gene MYC, and is required for cellular proliferation (Bjorklund et al, 2007a, b; Bjorklund et al, 2009)."
frog CK1gamma phosphorylates LRP5/6
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The Reactome summary describes Xenopus CK1gamma phosphorylation of LRP6, not human LRP5.
"Xenopus tropicalis Casein kinase 1 gamma was identified in a screen for proteins that covalently modify LRP6."