Affinage

LRP5

Low-density lipoprotein receptor-related protein 5 · UniProt O75197

Length
1615 aa
Mass
179.1 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRP5 is a single-pass transmembrane LDL-receptor-family protein that functions as a Wnt co-receptor to activate canonical Wnt/β-catenin signaling, a role central to bone accrual and tissue development (PMID:11719191, PMID:9790987). Upon Wnt or Norrin engagement of a ternary complex with Frizzled receptors—to which LRP5 binds directly through its ectodomain (PMID:24186977, PMID:25902418)—its cytoplasmic PPPSPxS motifs are phosphorylated and recruit Frat1 and Axin to the membrane in a Dishevelled-dependent manner, sequestering Axin and inhibiting GSK3-mediated β-catenin destruction (PMID:15699046, PMID:21887268). LRP5 is phosphorylated less efficiently than its paralog LRP6 because of an intervening 'gap4' region, but phosphorylated LRP5 binds Axin directly without GSK3 as a bridge (PMID:21887268). Its extracellular YWTD-EGF β-propeller repeats are docking sites for the secreted antagonists sclerostin and DKK1, which bind distinct repeats non-competitively; high-bone-mass (HBM) mutations such as G171V reduce inhibitor binding and Mesd-dependent surface trafficking to elevate osteoblast-lineage Wnt output (PMID:15778503, PMID:15143163, PMID:18521528). LRP5 acts redundantly with LRP6 in gastrulation, limb and intestinal development, but has paralog-selective functions including β-catenin-driven fatty-acid β-oxidation in osteoblasts and Wnt-independent control of glucose uptake (PMID:15537447, PMID:15142971, PMID:21866564, PMID:25802278, PMID:26711269). Beyond canonical Wnt signaling, LRP5 suppresses gut serotonin synthesis via Tph1 inhibition to promote bone formation (PMID:20392224), directly binds TGF-β receptors to drive Smad2/3-dependent renal fibrosis (PMID:32345960), and supports endothelial retinal vascularization (PMID:27031698). Loss-of-function LRP5 mutations underlie osteoporosis-pseudoglioma (OPPG), consistent with reduced bone formation and elevated serotonin in patients (PMID:20392224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1998 Medium

    Established LRP5 as a single-pass LDL-receptor-family transmembrane protein and asked which domain carried biological activity, localizing mitogenic function to the ectodomain.

    Evidence cDNA cloning from human osteoblasts and domain-deletion transfection with proliferation assay in NIH 3T3 cells

    PMID:9790987

    Open questions at the time
    • Did not identify the Wnt co-receptor function
    • Mechanism of ectodomain mitogenic activity unresolved
  2. 2001 High

    Defined LRP5 as a functional Wnt co-receptor required for bone accrual, connecting Wnt/β-catenin signaling to skeletal biology.

    Evidence In situ expression, in vitro Wnt signaling assay, and dominant-negative LRP5 in mouse calvarial explants

    PMID:11719191

    Open questions at the time
    • Intracellular signaling steps not yet mapped
    • Did not address LRP6 redundancy
  3. 2004 High

    Resolved how LRP5 and LRP6 collaborate in vivo, showing genetic redundancy in gastrulation, limb, and bone development.

    Evidence Compound Lrp5/Lrp6 mutant mice with embryological staging, DXA, and micro-CT

    PMID:15142971 PMID:15537447

    Open questions at the time
    • Tissue-specific division of labor between paralogs unresolved
    • Molecular basis of differential signaling not addressed
  4. 2004 High

    Explained the gain-of-function HBM G171V mutation by linking it to disrupted Mesd chaperone binding, reduced surface receptor, and DKK1-resistance dependent on the third YWTD repeat.

    Evidence Co-IP, surface biotinylation, domain mutagenesis, and paracrine vs autocrine Wnt reporter assays

    PMID:15143163

    Open questions at the time
    • Did not test all HBM mutants
    • In vivo confirmation of autocrine paradigm lacking
  5. 2005 Medium

    Mapped the cytoplasmic signaling output of LRP5, showing Frat1/Axin recruitment to the membrane and Dishevelled-dependent regulation upstream of GSK3 inhibition.

    Evidence Yeast two-hybrid, co-IP, dominant-negative Dishevelled, and TCF reporter assay

    PMID:15699046

    Open questions at the time
    • Quantitative contribution of Frat1 vs Axin unclear
    • Phosphorylation requirements not addressed here
  6. 2005 High

    Identified sclerostin as a direct YWTD-EGF-binding antagonist of LRP5, establishing a druggable extracellular regulatory node for bone.

    Evidence Co-IP/binding assays, domain-deletion mapping, and Wnt luciferase reporter with LRP5 overexpression rescue

    PMID:15778503

    Open questions at the time
    • Relationship to DKK1 binding not yet defined
    • Structural details of the interaction absent
  7. 2008 Medium

    Clarified that DKK1 and sclerostin act independently and that HBM mutants resist both, explaining the molecular logic of inhibitor regulation.

    Evidence Co-IP competition assays and Wnt reporter assays with six HBM-LRP5 mutants

    PMID:18521528

    Open questions at the time
    • Binding stoichiometry not quantified
    • Single-lab observation
  8. 2010 High

    Proposed a Wnt-independent, gut-mediated mechanism for LRP5's bone effect through Tph1 suppression and serotonin signaling.

    Evidence Intestine-specific Lrp5 KO, microarray, serum serotonin in mice and OPPG patients, plus pharmacological rescue

    PMID:20392224

    Open questions at the time
    • Mechanism debated by later studies
    • Molecular link between LRP5 and Tph1 transcription unresolved
  9. 2011 High

    Explained why LRP5 signals less robustly than LRP6 by attributing the difference to phosphorylation efficiency governed by a 'gap4' region, not Axin affinity.

    Evidence Chimeric domain swaps, in vitro phosphorylation, Axin co-IP, and Wnt reporter assays

    PMID:21887268

    Open questions at the time
    • Kinases responsible not fully defined
    • In vivo relevance of gap4 untested
  10. 2013 High

    Provided structural basis for ligand-induced ternary complex formation, showing Norrin bridges Fz4 and LRP5/6 via separate binding sites.

    Evidence X-ray crystallography, co-IP, and cell-based signaling with mutant Norrin

    PMID:24186977

    Open questions at the time
    • Direct LRP5-Norrin contacts not crystallographically resolved
    • Conformational changes on LRP5 unknown
  11. 2015 High

    Extended the structural model showing Norrin mimics Wnt for Frizzled recognition and defined a GAG-binding interface across the complex.

    Evidence X-ray crystallography, SAXS, mutagenesis, and signaling assays

    PMID:26158506

    Open questions at the time
    • LRP5/6 binding patch inferred, not co-crystallized
    • Role of GAGs in vivo untested
  12. 2014 High

    Identified paralog-selective and Wnt-independent disease roles, placing LRP5 upstream of TGF-β in pulmonary fibrosis.

    Evidence Lrp5 KO mice, bleomycin and adeno-TGF-β models, bone marrow transplantation, and β-catenin inhibition

    PMID:24921217

    Open questions at the time
    • Cell-autonomous vs systemic contributions only partly dissected
    • Direct molecular target downstream unresolved at this stage
  13. 2015 High

    Demonstrated paralog-specific metabolic functions, with LRP5 (not LRP6) driving β-catenin-dependent fatty-acid oxidation in osteoblasts and Wnt-independent glucose uptake in mammary cells.

    Evidence Conditional Lrp5 KO and HBM knock-in mice with metabolic phenotyping; shRNA knockdown with metabolic and ROS assays

    PMID:25802278 PMID:26711269

    Open questions at the time
    • Molecular basis of LRP5/LRP6 functional divergence unclear
    • Direct effectors of glucose-uptake function unidentified
  14. 2015 Medium

    Revealed that direct LRP5/6-Frizzled binding restrains non-canonical Wnt signaling and suppresses tumor cell migration.

    Evidence Co-IP, recombinant LRP6 ectodomain rescue, migration assays, and in vivo metastasis model

    PMID:25902418

    Open questions at the time
    • LRP5-specific contribution not isolated from LRP6
    • Mechanism of non-canonical suppression incomplete
  15. 2016 High

    Established endothelial LRP5 as necessary and sufficient for retinal vascular development in an LRP6-independent manner.

    Evidence Endothelium-specific Lrp5 KO (Flk1-Cre) and endothelial LRP5 re-expression rescue in global KO mice

    PMID:27031698

    Open questions at the time
    • Downstream endothelial Wnt targets not fully mapped
    • Ligand driving this signaling not defined here
  16. 2018 High

    Refined the bone signaling model by genetically dissociating Wnt1 anabolism and sclerostin action from sole LRP5 dependence.

    Evidence Conditional Wnt1-overexpression x Lrp5 KO and Sost x Lrp5 double-KO mice with LRP6-blocking antibodies

    PMID:23901037 PMID:30404864

    Open questions at the time
    • Relative LRP5 vs LRP6 contributions context-dependent
    • Mechanism of partial LRP5 dependence unresolved
  17. 2018 Medium

    Uncovered ligand-independent and cancer-associated LRP5 activation modes via FZD oligomerization and a JAM3-LRP5-PDK1/AKT axis sustaining leukemia-initiating cells.

    Evidence Co-IP of FZD-LRP5/6 with dominant negatives and reporter in HepG2; JAM3-LRP5 co-IP with AML KO models and pathway readouts

    PMID:29584620 PMID:30361437

    Open questions at the time
    • Physiological triggers of ligand-independent oligomerization unclear
    • Direct JAM3-LRP5 binding interface unmapped
  18. 2020 High

    Defined a Wnt-independent profibrotic mechanism whereby LRP5 directly binds and stabilizes TGF-β receptors to activate Smad2/3 in kidney.

    Evidence Lrp5 KO obstructive nephropathy, tubular LRP5 overexpression, LRP5-TβRI/II co-IP, and Smad2/3 translocation assays

    PMID:32345960

    Open questions at the time
    • Domain-level TβR binding site not finely mapped
    • Cross-talk with canonical Wnt in fibrosis unresolved
  19. 2022 Medium

    Identified additional non-Wnt LRP5 partnerships, including a B7-1-Hsp90ab1-LRP5 complex in podocyte injury and AKT/P21-mediated cardiomyocyte proliferation.

    Evidence LC-MS/MS, docking/mutagenesis, co-IP, and disease mouse models for podocytes; cardiac-specific KO with AKT/P21 analysis

    PMID:35429093 PMID:35710882

    Open questions at the time
    • Generality of these complexes beyond disease models unclear
    • Single-lab observations
  20. 2023 Medium

    Demonstrated that SELENOP directly binds LRP5/6 to augment canonical Wnt signaling in colorectal cancer.

    Evidence Protein interaction mapping, Selenop KO adenoma model, and organoid Wnt rescue

    PMID:37166989

    Open questions at the time
    • Binding interface and stoichiometry undefined
    • LRP5 vs LRP6 selectivity not resolved
  21. 2019 High

    Provided targetable structural insight by showing VHH antibodies block Wnt3/3a binding at the LRP5/6 third β-propeller to inhibit β-catenin signaling.

    Evidence VHH selection, structural analysis, Wnt reporter, and Rnf43/Znrf3-mutant organoid differentiation

    PMID:30664649

    Open questions at the time
    • LRP5-specific affinity vs LRP6 not separated
    • In vivo efficacy not addressed
  22. 2025 Medium

    Defined post-transcriptional control of LRP5 abundance by butyrate-driven ZFP36-mediated mRNA decay to limit Wnt-dependent cancer stemness.

    Evidence RNA-seq, H3K9ac ChIP, ZFP36 manipulation, mRNA stability assays, and tumor models

    PMID:40038255

    Open questions at the time
    • Generality across tissues untested
    • Single-lab observation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LRP5 achieves its many paralog-selective and Wnt-independent functions through a single ectodomain/cytoplasmic architecture, and what distinguishes LRP5 from LRP6 mechanistically across tissues, remains unresolved.
  • No unified structural explanation for LRP5 vs LRP6 functional divergence
  • Direct effectors of several Wnt-independent functions unidentified
  • In vivo relevance of ligand-independent oligomerization unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
AXINDISHEVELLEDDKK1FRAT1FZD4PCSK9SOSTTGFBR1
Complex memberships
B7-1–Hsp90ab1–LRP5 complexNorrin–Fz4–LRP5 ternary complexWnt signalosome (FZD–LRP5/6–Dishevelled)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 LRP5 is expressed by osteoblasts and can transduce Wnt signaling via the canonical (β-catenin) pathway in vitro; a mutant secreted form of LRP5 reduces bone thickness in mouse calvarial explant cultures, establishing LRP5 as a functional Wnt co-receptor required for bone accrual. In situ expression analysis, in vitro Wnt signaling assay, mouse calvarial explant culture with dominant-negative LRP5 Cell High 11719191
1998 LRP5 (originally cloned as LR3) is a single-pass transmembrane LDL receptor family protein with extracellular YWTD/EGF repeat domains; its ectodomain alone is sufficient for mitogenic activity in NIH 3T3 cells, whereas the intracellular domain has no proliferative effect. cDNA cloning from human osteoblast library, transfection of full-length, ectodomain-only, and intracellular-domain-only constructs into NIH 3T3 cells with proliferation assay Biochemical and biophysical research communications Medium 9790987
2005 Sclerostin binds directly to the first two YWTD-EGF repeat domains of LRP5 (and LRP6) and antagonizes canonical Wnt signaling; overexpression of LRP5 reverses sclerostin-mediated inhibition. Canonical Wnt ligand does not appear to compete with sclerostin for binding to LRP5. Co-immunoprecipitation/binding assay in HEK293T and MC3T3 cells, domain-deletion mapping, luciferase Wnt reporter assay The Journal of biological chemistry High 15778503
2004 The high-bone-mass G171V mutation in LRP5 disrupts LRP5 interaction with the chaperone Mesd, reducing LRP5 cell-surface levels. The third YWTD repeat (not the first) is required for DKK1-mediated antagonism of LRP5. In an autocrine Wnt paradigm, the G171V mutation does not reduce Wnt signaling despite fewer surface receptors, explaining its gain-of-function phenotype. Co-immunoprecipitation, cell-surface biotinylation, domain-deletion mutagenesis, Wnt reporter assays (paracrine vs. autocrine paradigm) Molecular and cellular biology High 15143163
2008 DKK1 and sclerostin independently (not synergistically) regulate LRP5 signaling; DKK1 can displace sclerostin from pre-formed sclerostin–LRP5 complexes, and neither inhibitor efficiently inhibits any of six tested HBM-LRP5 mutants. Co-immunoprecipitation competition assays, Wnt luciferase reporter assays with HBM-LRP5 mutants Calcified tissue international Medium 18521528
2005 The cytoplasmic domain of LRP5 interacts with Frat1; Wnt3a or constitutively active truncated LRP5 (LRP5C) induces Frat1 recruitment to the cell membrane. Dishevelled positively regulates LRP5/Frat1 interaction. Axin co-immunoprecipitates with Frat1 and LRP5 at the membrane, linking LRP5 to Axin degradation and GSK3 inhibition upstream of β-catenin. Yeast two-hybrid screen, co-immunoprecipitation, dominant-negative Dishevelled overexpression, TCF-1 luciferase reporter assay The Journal of biological chemistry Medium 15699046
2011 LRP5 and LRP6 differ in their in vivo phosphorylation efficiency rather than in Axin-binding affinity: in vitro phosphorylated LRP5C and LRP6C bind Axin similarly, but LRP5C receives much less phosphorylation in cells. A 'gap4' region between the two most C-terminal PPPSPxS motifs accounts for much of the difference; alterations in gap4 enhance LRP5 PPPSPxS phosphorylation to LRP6 levels. Phosphorylated LRP5/6 binds Axin directly without requiring GSK3 as a bridge. Chimeric receptor domain swaps, in vitro phosphorylation assay, Axin co-immunoprecipitation, luciferase Wnt reporter assay PloS one High 21887268
2013 Norrin forms a dimeric cystine-knot structure and contains separate binding sites for Frizzled 4 and for LRP5 (or LRP6); Norrin induces a ternary signaling complex with Fz4 and LRP5/6 by binding their respective extracellular domains rather than inducing Fz4 dimerization. X-ray crystallography, functional co-immunoprecipitation, cell-based signaling assays with mutant Norrin Genes & development High 24186977
2015 Crystal structure and SAXS of Norrin–Fz4CRD complex reveal that Norrin mimics Wnt for Frizzled recognition; distinct patches on Norrin mediate Fz4 and putative LRP5/6 binding, and a GAG binding site spans both Norrin and Fz4CRD. X-ray crystallography, small-angle X-ray scattering, site-directed mutagenesis, cell-based signaling assays eLife High 26158506
2004 Lrp5 and Lrp6 are genetically redundant co-receptors for Wnt signaling in bone and limb development; compound Lrp5/Lrp6 mutant mice show dose-dependent reductions in BMD and limb defects not seen with either single mutant alone. Generation of compound Lrp5/Lrp6 mutant mice, DXA, micro-CT skeletal analysis Journal of bone and mineral research High 15537447
2004 Lrp5 and Lrp6 are functionally redundant Wnt co-receptors essential for gastrulation; double-homozygous null mice fail to establish a primitive streak, and Lrp5(+/−);Lrp6(−/−) embryos show selective loss of paraxial mesoderm and expansion of anterior structures, consistent with a Wnt–Fgf pathway link. Compound Lrp5/Lrp6 knockout mouse analysis, embryological staging, gene expression analysis Development (Cambridge, England) High 15142971
2010 Lrp5 enhances bone formation by inhibiting, in duodenal enterochromaffin cells, expression of tryptophan hydroxylase 1 (Tph1), the rate-limiting enzyme in gut serotonin synthesis; elevated circulating serotonin inhibits osteoblast proliferation via Htr1b/CREB. This Wnt-independent, gut-mediated mechanism accounts for LRP5's effect on bone formation. Conditional gene deletion (intestine-specific Lrp5 KO), microarray, serum serotonin measurement in Lrp5−/− mice and OPPG patients, pharmacological serotonin normalization rescue experiment Annals of the New York Academy of Sciences High 20392224
2017 Conditional mammary-specific Lrp5 deletion (WAP-Cre×Lrp5FL/FL) during lactation increases serotonin concentrations in both mammary gland and systemic circulation, establishing that mammary-derived Lrp5 regulates local and circulating serotonin levels without affecting milk yield or alveolar morphology. Conditional knockout (WAP-Cre×Lrp5FL/FL) mouse model, serotonin measurement in gland and serum, alveolar morphology assessment Scientific reports Medium 29123193
2015 LRP5 regulates fatty acid β-oxidation in osteoblasts via a Wnt/β-catenin axis that is not shared by LRP6; osteoblast/osteocyte-specific Lrp5 knockout mice show increased body fat and reduced energy expenditure, and HBM-Lrp5 mice are leaner with lower triglyceride levels. Downstream β-catenin activation by Lrp5 (not Lrp6) induces key FAO enzyme expression. Osteoblast/osteocyte-conditional Lrp5 KO mice, HBM-Lrp5 knock-in mice, metabolic phenotyping, gene expression analysis Molecular and cellular biology High 25802278
2015 LRP5 (and LRP6) directly bind Frizzled receptors through the LRP6 ectodomain; this direct LRP5/6–Frizzled interaction prevents Frizzled-mediated non-canonical Wnt pathway activation and suppresses non-canonical pathway-dependent tumour cell migration and metastasis in vitro and in vivo. Co-immunoprecipitation, recombinant LRP6 ectodomain protein rescue experiment, tumour cell migration assay, in vivo metastasis model Nature communications Medium 25902418
2018 FZD–LRP5/6 homo- and hetero-oligomerization on the cell surface, independently of Wnt ligands, recruits Dishevelled into the LRP5/6 signalosome and drives ligand-independent β-catenin signaling; specific FZDs expressed in hepatoma cells promote LRP5/β-catenin activation without Wnt. Co-immunoprecipitation of FZD–LRP5/6 complexes, dominant-negative constructs, luciferase β-catenin reporter assay in HepG2 cells The Journal of biological chemistry Medium 30361437
2014 Lrp5 promotes pulmonary fibrosis through β-catenin signaling upstream of TGF-β production; Lrp5-null mice are protected from bleomycin-induced fibrosis with reduced TGF-β1 production by alveolar type 2 cells and leukocytes. Lrp5-null mice are not protected from fibrosis induced by exogenous active TGF-β, placing Lrp5 upstream of TGF-β. Lrp5 knockout mouse model, bleomycin and adeno-TGF-β fibrosis models, bone marrow transplantation, β-catenin inhibitor treatment, cytokine measurement American journal of respiratory and critical care medicine High 24921217
2018 Wnt1 promotes bone formation independently of LRP5; loss of LRP5 does not reduce the bone-anabolic effect of conditional Wnt1 overexpression in osteoblasts, demonstrating that Wnt1's bone-forming activity can proceed without this co-receptor. Conditional osteoblast-specific Wnt1 overexpression crossed with Lrp5-knockout mice, bone mass and histomorphometry analysis Science translational medicine High 30404864
2014 Sclerostin-induced bone loss is partially dependent on LRP5 and fully dependent on Wnt1-class LRP6 signaling; Sost deficiency bone gain is blunted but not abolished in Lrp5−/− mice, and is completely reversed by selective blockade of Wnt1-class LRP6 activity. Sost−/−;Lrp5−/− double-knockout mice, LRP6-blocking monoclonal antibodies with Wnt-class selectivity, micro-CT and histomorphometry Journal of bone and mineral research High 23901037
2020 LRP5 promotes tubulointerstitial fibrosis via a Wnt-independent mechanism: LRP5 directly co-immunoprecipitates with TGF-β receptors I and II through its extracellular domain, stabilizes TβRs at the membrane, enhances TGF-β1-induced TβR internalization, and activates Smad2/3 nuclear translocation. Lrp5 knockout in obstructive nephropathy mouse model, LRP5 overexpression in tubular epithelial cells, co-immunoprecipitation of LRP5–TβRI/II, Smad2/3 nuclear translocation assay Signal transduction and targeted therapy High 32345960
2012 LRP5 regulates lung microvascular and alveolar development by controlling Tie2 expression in endothelial cells; LRP5 knockdown decreases Tie2 levels and inhibits vascular/alveolar growth when Ang1 is dominant, while high LRP5 and Tie2 expression under Ang2-dominated conditions suppress angiogenesis. LRP5 siRNA knockdown in cultured endothelial cells and neonatal mouse lungs, Tie2 expression assay, in vivo hyperoxia and pneumonectomy models PloS one Medium 22848540
2016 Endothelium-derived LRP5 is both necessary and sufficient for retinal vascular development; endothelium-specific deletion of LRP5 (using Flk1-Cre) recapitulates the hypovascularization of Lrp5−/− retinas, and endothelial LRP5 restoration in Lrp5−/− mice rescues retinal vascular defects. Retinal vascularization depends on LRP5 in a dosage-dependent manner and does not depend on LRP6. Endothelium-specific Lrp5 conditional KO (Flk1-Cre), rescue by endothelial-specific LRP5 re-expression in global Lrp5−/− mice, retinal vascular phenotype analysis PloS one High 27031698
2012 Lrp5 and Lrp6 are functionally redundant in intestinal epithelium; single-gene gut-specific knockouts (villin-Cre) are viable with normal intestines, but double Lrp5/Lrp6 gut-knockout pups die within 1 day of birth with absent proliferation, premature differentiation, and reduced cyclin D1 in intestinal epithelium. Villin-Cre conditional double-knockout mice, immunohistochemistry for proliferation/differentiation markers and cyclin D1 Journal of cellular biochemistry High 21866564
2018 JAM3 directly associates with LRP5 to activate the PDK1/AKT pathway, which suppresses GSK3β and activates β-catenin/CCND1 signaling to maintain leukemia-initiating cell self-renewal; JAM3-LRP5 interaction is required for LIC maintenance but not normal HSC function. Co-immunoprecipitation of JAM3 with LRP5, JAM3 knockout in AML mouse model, serial transplantation, JAM3 knockdown in human leukemia cells, pathway component analysis (pAKT, GSK3β, β-catenin, CCND1) The Journal of clinical investigation Medium 29584620
2015 LRP5 loss in macrophages reduces intracellular cholesterol ester accumulation (lipid uptake); LRP5 forms a complex with PCSK9 in lipid-loaded macrophages; in the absence of LRP5, PCSK9 release is reduced, implicating LRP5 in PCSK9 secretion from macrophages. LRP5 and PCSK9 siRNA silencing in primary human macrophages, cholesterol ester accumulation assay, co-immunoprecipitation of LRP5–PCSK9 Cardiovascular research Medium 32991689
2022 B7-1 activates podocyte β-catenin signaling through a B7-1–Hsp90ab1–LRP5 complex; Hsp90ab1 residue K69 is the key binding site for B7-1 transmission to LRP5/β-catenin; B7-1 is also a downstream target of β-catenin, forming a feedforward loop mediating podocyte injury. LC-MS/MS identification of Hsp90ab1, molecular docking and mutant analysis (K69 site), co-immunoprecipitation of B7-1–Hsp90ab1–LRP5 complex, B7-1 transgenic and adriamycin nephropathy mouse models, transcriptomic analysis Cell death and differentiation Medium 35710882
2015 LRP5 has a Wnt-independent role in glucose uptake in mammary epithelial cells; Lrp5 knockdown decreases glucose uptake, lactate secretion, and oxygen consumption and induces mitochondrial ROS accumulation and p38α activation; this function is not shared by LRP6. Lrp5 and Lrp6 shRNA knockdown in mammary epithelial cells, glucose uptake assay, lactate and oxygen consumption measurement, ROS and p38α activation assays Molecular and cellular biology High 26711269
2015 Lrp5 is required for cranial neural crest cell (CNCC) migration in zebrafish; lrp5 knockdown and CRISPR/Cas9 editing do not impair CNCC induction but reduce proliferation of premigratory CNCCs and cause cells to cluster at ectopic positions, resulting in craniofacial skeleton malformations. Morpholino knockdown, transient CRISPR/Cas9 editing in zebrafish, in situ hybridization, cell migration tracking PloS one Medium 26121341
2010 Both Sp1 and KLF15 transcription factors bind to the LRP5 promoter region (−72 to −53 bp) and are required for its basal transcriptional activity, as demonstrated by chromatin immunoprecipitation and transactivation assays in Drosophila SL2 cells. Luciferase reporter deletion analysis, chromatin immunoprecipitation, transactivation in Drosophila SL2 cells (lacking endogenous Sp1/KLF) BMC genetics Medium 20141633
2022 LRP5 regulates neonatal cardiomyocyte proliferation and heart regeneration via the AKT/P21 pathway: LRP5 deficiency accelerates AKT protein degradation, elevating the CDK inhibitor P21 and reducing cardiomyocyte proliferation; cardiac-specific Lrp5 deletion impairs neonatal cardiac regeneration after injury. Cardiac-specific Lrp5 conditional knockout mice, neonatal apex resection model, LRP5 overexpression, AKT/P21 pathway analysis by Western blot Journal of cellular and molecular medicine Medium 35429093
2023 Selenoprotein P (SELENOP) directly interacts with LRP5/6 through protein-protein interactions and uses this interaction to augment canonical WNT signaling activity; disruption of SELENOP–LRP5/6 binding reduces WNT target gene expression in colorectal cancer organoids. Protein-protein interaction mapping, Selenop knockout in APC-deletion mouse adenoma model, organoid WNT signaling rescue, WNT target gene expression analysis The Journal of clinical investigation Medium 37166989
2019 Anti-LRP5/6 VHH single-domain antibodies bind the third β-propeller (P3E3P4E4) region of LRP6 (and LRP5) with nanomolar affinity, sterically blocking Wnt3/3a binding; these VHHs strongly inhibit Wnt3/3a-induced β-catenin signaling and drive terminal differentiation of Wnt-hypersensitive Rnf43/Znrf3-mutant intestinal organoids. CIS display VHH selection, structural analysis of VHH–LRP5/6 interaction, luciferase Wnt reporter assay, intestinal organoid growth assay Nature communications High 30664649
2020 Co-deletion of Lrp5 and Lrp6 selectively in bone (Dmp1-Cre) nearly completely abrogates the bone-anabolic response to sclerostin monoclonal antibody, establishing that both LRP5 and LRP6 are required in osteoblast-lineage cells for sclerostin antibody action. Dmp1-Cre conditional Lrp5f/f;Lrp6f/f double-knockout mice, sclerostin mAb treatment, DXA, micro-CT, pQCT, bone histomorphometry Bone High 33164872
2007 MDA PCa 2b prostate cancer cells induce new bone formation through Wnt canonical signaling and this effect requires the osteoblast Wnt co-receptor Lrp5; in calvaria from Lrp5−/− mice, MDA PCa 2b cells fail to induce bone formation. DKK1 blocks osteoblast proliferation and new bone formation by MDA PCa 2b cells. Co-culture of prostate cancer cells with primary mouse osteoblasts and Lrp5−/− bone organ cultures, DKK1 functional blocking experiment Oncogene Medium 17700537
2025 Butyrate decreases LRP5 mRNA stability by elevating histone H3K9 acetylation of the ZFP36 locus, transcriptionally activating the RNA-binding protein ZFP36, which then binds AU-rich elements in LRP5 transcript and accelerates its decay, thereby blocking Wnt/β-catenin activation and cancer stemness. RNA-seq, HDAC inhibitor assays, H3K9 acetylation ChIP, ZFP36 overexpression/knockdown, LRP5 mRNA stability assay, syngeneic and orthotopic tumor models Signal transduction and targeted therapy Medium 40038255

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 1701 11719191
2005 Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. The Journal of biological chemistry 1070 15778503
2012 Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harbor perspectives in biology 512 23209147
2004 Decreased BMD and limb deformities in mice carrying mutations in both Lrp5 and Lrp6. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 283 15537447
2004 The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development (Cambridge, England) 234 15142971
2008 Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 202 18349089
1997 RfaH and the ops element, components of a novel system controlling bacterial transcription elongation. Molecular microbiology 164 9426123
2009 Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 161 19072724
2015 Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast. Molecular and cellular biology 139 25802278
2004 Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. International journal of cancer 137 14735475
2021 LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. Frontiers in cell and developmental biology 135 34026761
2004 The LRP5 high-bone-mass G171V mutation disrupts LRP5 interaction with Mesd. Molecular and cellular biology 135 15143163
2008 The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. Calcified tissue international 115 18521528
2015 Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. eLife 109 26158506
2013 Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex. Genes & development 103 24186977
2014 Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine 100 24921217
2004 LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. Journal of human genetics 97 14727154
2018 Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Science translational medicine 74 30404864
2009 The emerging role of serotonin (5-hydroxytryptamine) in the skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5). Bone 74 19591966
2009 Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clinical endocrinology 74 19673927
2021 PCSK9 and LRP5 in macrophage lipid internalization and inflammation. Cardiovascular research 73 32991689
2005 LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint bone spine 72 15850991
2014 Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 68 24677211
2018 Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway. The Journal of biological chemistry 66 30361437
2014 Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 64 23901037
2005 LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women. Bone 63 15777745
2005 Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. The Journal of biological chemistry 62 15699046
2015 LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis. Nature communications 59 25902418
2012 Retinal expression of Wnt-pathway mediated genes in low-density lipoprotein receptor-related protein 5 (Lrp5) knockout mice. PloS one 59 22272305
2011 Dissecting molecular differences between Wnt coreceptors LRP5 and LRP6. PloS one 59 21887268
1998 Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. Biochemical and biophysical research communications 58 9790987
2018 JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling. The Journal of clinical investigation 57 29584620
2015 Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity. Oncoimmunology 57 27141399
2005 LRP5 gene polymorphisms and idiopathic osteoporosis in men. Bone 56 16168727
2007 Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. Oncogene 55 17700537
1988 A unique deoxyguanosine triphosphatase is responsible for the optA1 phenotype of Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America 55 2833745
2005 Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton. Trends in molecular medicine 53 15760771
2017 Lrp5/β-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis. American journal of respiratory cell and molecular biology 52 27668462
2009 The internally truncated LRP5 receptor presents a therapeutic target in breast cancer. PloS one 52 19158955
2012 Lrp5 and Lrp6 play compensatory roles in mouse intestinal development. Journal of cellular biochemistry 50 21866564
2010 Lrp5 and bone formation : A serotonin-dependent pathway. Annals of the New York Academy of Sciences 50 20392224
2020 Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 49 33118644
2015 New Insights into Wnt-Lrp5/6-β-Catenin Signaling in Mechanotransduction. Frontiers in endocrinology 49 25653639
2015 Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 49 26244290
2019 Anti-LRP5/6 VHHs promote differentiation of Wnt-hypersensitive intestinal stem cells. Nature communications 47 30664649
2015 LRP5 deficiency down-regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice. Journal of cellular and molecular medicine 44 25656427
2016 NINJA-OPS: Fast Accurate Marker Gene Alignment Using Concatenated Ribosomes. PLoS computational biology 41 26820746
2017 LRP5: From bedside to bench to bone. Bone 38 28341377
2008 Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts. Osteoarthritis and cartilage 38 18406176
2003 Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Human genetics 37 12700977
2021 Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone. Bone research 36 34230453
2008 Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis. BMC medical genetics 35 18588671
2017 Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy. Investigative ophthalmology & visual science 34 29181528
2017 Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. PloS one 32 29176883
2014 Polymorphism of LRP5 gene and emphysema severity are associated with osteoporosis in Japanese patients with or at risk for COPD. Respirology (Carlton, Vic.) 32 25392953
2012 LRP5 regulates development of lung microvessels and alveoli through the angiopoietin-Tie2 pathway. PloS one 32 22848540
2007 LRP5 and LRP6 are not required for protective antigen-mediated internalization or lethality of anthrax lethal toxin. PLoS pathogens 32 17335347
2021 LRP5 Promotes Gastric Cancer via Activating Canonical Wnt/β-Catenin and Glycolysis Pathways. The American journal of pathology 31 34896072
2020 A novel role of LRP5 in tubulointerstitial fibrosis through activating TGF-β/Smad signaling. Signal transduction and targeted therapy 31 32345960
2025 Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness. Signal transduction and targeted therapy 30 40038255
2015 LRP5 variants may contribute to ADPKD. European journal of human genetics : EJHG 30 25920554
2015 The Wnt Co-Receptor Lrp5 Is Required for Cranial Neural Crest Cell Migration in Zebrafish. PloS one 29 26121341
2012 Potential role for therapies targeting DKK1, LRP5, and serotonin in the treatment of osteoporosis. Current osteoporosis reports 28 22210558
2022 B7-1 mediates podocyte injury and glomerulosclerosis through communication with Hsp90ab1-LRP5-β-catenin pathway. Cell death and differentiation 27 35710882
2018 The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 27 30474181
2009 LRP5 Polymorphisms and response to risedronate treatment in osteoporotic men. Calcified tissue international 27 19148563
2016 Critical Endothelial Regulation by LRP5 during Retinal Vascular Development. PloS one 26 27031698
2016 LRP5/canonical Wnt signalling and healing of ischemic myocardium. Basic research in cardiology 25 27704249
2012 LRP5 and bone mass regulation: Where are we now? BoneKEy reports 25 23951413
2010 Low-density lipoprotein receptor-related protein 5 (LRP5) expression in human osteoarthritic chondrocytes. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 25 19810105
2014 Cholesterol modulates LRP5 expression in the vessel wall. Atherosclerosis 24 24929284
2005 LRP5/6 in Wnt signaling and tumorigenesis. Future oncology (London, England) 24 16556044
2017 Characterization of mammary-specific disruptions for Tph1 and Lrp5 during murine lactation. Scientific reports 23 29123193
2015 LRP5 and plasma cholesterol levels modulate the canonical Wnt pathway in peripheral blood leukocytes. Immunology and cell biology 23 25748163
2015 LRP5 associates with specific subsets of macrophages: Molecular and functional effects. Journal of molecular and cellular cardiology 23 26666179
2002 Cloning and expression of Xenopus Lrp5 and Lrp6 genes. Mechanisms of development 23 12204281
2019 Lrp5 and Lrp6 are required for maintaining self-renewal and differentiation of hematopoietic stem cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 30668923
2014 Common polymorphism in the LRP5 gene may increase the risk of bone fracture and osteoporosis. BioMed research international 22 25580429
2022 WNT5A Interacts With FZD5 and LRP5 to Regulate Proliferation and Self-Renewal of Endometrial Mesenchymal Stem-Like Cells. Frontiers in cell and developmental biology 21 35295855
2012 Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses. Seminars in cancer biology 21 22257681
2021 Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20 33831261
2016 MiR-9-5p, miR-675-5p and miR-138-5p Damages the Strontium and LRP5-Mediated Skeletal Cell Proliferation, Differentiation, and Adhesion. International journal of molecular sciences 20 26891291
2015 Protective effects of electroacupuncture at LR3 on cardiac hypertrophy and apoptosis in hypertensive rats. Acupuncture in medicine : journal of the British Medical Acupuncture Society 20 26566622
2015 Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells. Molecular and cellular biology 20 26711269
2022 LRP5 promotes cancer stem cell traits and chemoresistance in colorectal cancer. Journal of cellular and molecular medicine 19 34997691
2014 Osteoblast-specific Krm2 overexpression and Lrp5 deficiency have different effects on fracture healing in mice. PloS one 19 25061805
2005 Parameters of LRP5 from a structural and molecular perspective. Critical reviews in eukaryotic gene expression 19 16390319
2022 Mutations in LRP5 and BMP4 are associated with mesiodens, tooth agenesis, root malformation, and oral exostoses. Clinical genetics 18 35754005
2019 LRP5, Bone Density, and Mechanical Stress: A Case Report and Literature Review. Frontiers in endocrinology 18 30972028
2023 SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions. The Journal of clinical investigation 17 37166989
2020 Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2S252W/+ ) mouse model. Developmental dynamics : an official publication of the American Association of Anatomists 16 32822074
2020 Co-deletion of Lrp5 and Lrp6 in the skeleton severely diminishes bone gain from sclerostin antibody administration. Bone 15 33164872
2017 Interaction between LRP5 and periostin gene polymorphisms on serum periostin levels and cortical bone microstructure. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 15 29038835
2010 Low-density lipoprotein receptor-related protein 5 (LRP5) variation in fracture prone children. Bone 15 20045498
2010 Novel LRP5 gene mutation in a patient with osteoporosis-pseudoglioma syndrome. Joint bone spine 15 20096619
2010 Sp1 and KLF15 regulate basal transcription of the human LRP5 gene. BMC genetics 15 20141633
2022 LRP5 regulates cardiomyocyte proliferation and neonatal heart regeneration by the AKT/P21 pathway. Journal of cellular and molecular medicine 14 35429093
2021 WNT-FRIZZLED-LRP5/6 Signaling Mediates Posterior Fate and Proliferation during Planarian Regeneration. Genes 14 33467529
2019 LRP5 in age-related changes in vascular and alveolar morphogenesis in the lung. Aging 14 30612120
2018 Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism. Bone 14 30409757

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