Affinage

LRP6

Low-density lipoprotein receptor-related protein 6 · UniProt O75581

Length
1613 aa
Mass
180.4 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRP6 is a single-pass transmembrane Wnt co-receptor that, upon Wnt binding together with Frizzled, clusters into phosphorylated plasma-membrane signalosomes that recruit Axin and GSK3 to stabilize beta-catenin (PMID:17569865, PMID:20229235). Structurally, the LRP6 ectodomain presents tandem beta-propeller folding units (E1E2 and E3E4) that bind distinct Wnt ligands at separate sites—Wnt3a engaging E3E4 and other Wnts E1E2—while the broad-spectrum antagonist Dkk1 and the antagonist sclerostin (SOST) occupy these surfaces to block signaling (PMID:20093360, PMID:33097721, PMID:19339249); cryo-EM of a Wnt-Frizzled-LRP6 ternary complex shows canonical Wnts engaging the E1E2 funnels through their N-terminal linker domains, with LDLR-domain-mediated LRP6 homodimerization driving a hexameric initiation assembly required for robust pathway activation (PMID:36893265, PMID:24412751). Signalosome activation depends on phosphorylation of conserved cytoplasmic PPSPXS motifs by a battery of kinases including CK1 family, GSK3, GRK5/6, and SIK2, with the activity controlled by adaptors and scaffolds such as TMEM198 and TMEM97 that recruit casein kinases to the receptor (PMID:20229235, PMID:19801552, PMID:21536646, PMID:34615853, PMID:35277657); conversely, CK1-epsilon phosphorylation at Ser1420/Ser1430 and Src/Fer-mediated tyrosine phosphorylation provide negative feedback that limits signalosome formation and surface receptor levels (PMID:16513652, PMID:25391905). Receptor abundance and trafficking are further set by ER chaperones GPR37 and GRP78 that promote LRP6 maturation and protect it from ER-associated degradation (PMID:28341812, PMID:31310747), by the USP46/UAF1/WDR20 deubiquitylase complex that counteracts RNF43/ZNRF3-mediated ubiquitylation at the cell surface (PMID:37798301), and by tyrosine-signal-dependent partitioning between desensitizing clathrin and signaling-promoting caveolar endocytic routes (PMID:25143377). Beyond canonical Wnt signaling, LRP6 acts as a Wnt-independent scaffold for connexin 43 trafficking at cardiac intercalated discs, the loss of which causes lethal arrhythmias (PMID:27250245), regulates LDL receptor internalization through a complex with clathrin and ARH (PMID:22128165), and the LRP6(R611C) hypomorphic mutation drives hepatic lipogenesis and loss of vascular smooth muscle cell differentiation, both rescuable by Wnt3a (PMID:24506864, PMID:26489464). An AD-linked LRP6-Val variant fails to form the Wnt7a-dependent LRP6-Frizzled5 complex and produces age-dependent synaptic defects in knock-in mice (PMID:36638182).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Establishing that LRP6 phosphorylation is the regulatory switch for Wnt signaling required identifying the kinases acting on its cytoplasmic motifs and whether they activate or restrain the pathway.

    Evidence In vitro binding/kinase assays, co-IP, site-directed mutagenesis, and Lef-1 reporter assays for CKI-epsilon on LRP6 Ser1420/1430

    PMID:16513652

    Open questions at the time
    • Did not resolve how this negative feedback is integrated with activating phosphorylation in vivo
    • Stoichiometry and kinetics of multi-site phosphorylation unaddressed
  2. 2007 High

    How LRP6 transduces a Wnt signal at the membrane was unknown; this showed Wnt induces phosphorylated LRP6 aggregates (signalosomes) that recruit Axin to stabilize beta-catenin.

    Evidence Live imaging, detergent solubilization/fractionation, and dominant-negative Dvl in vertebrate cells

    PMID:17569865

    Open questions at the time
    • Molecular architecture of the signalosome not resolved
    • Role of caveolin in aggregate function unclear
  3. 2010 High

    The kinase logic and ligand-binding architecture of LRP6 were defined: multiple proline-directed and CK1-family kinases phosphorylate PPSPXS motifs, and distinct ectodomain regions bind different Wnts and Dkk1.

    Evidence Review synthesis of kinase/mutagenesis studies plus in vitro reconstitution of the Fz8-Wnt3a-LRP6 ternary complex with binding-competition assays

    PMID:20093360 PMID:20229235

    Open questions at the time
    • High-resolution structure of the active complex still lacking at this stage
    • How simultaneous Wnt binding affects signaling output not tested
  4. 2009 High

    Identifying GRK5/6 as direct activating kinases and characterizing the cooperative beta-propeller folding units extended the kinase repertoire and clarified ectodomain modularity.

    Evidence In vitro kinase assays, siRNA depletion, zebrafish epistasis (GRK5/6); recombinant domain folding/ligand-binding assays with Mesd chaperone

    PMID:19339249 PMID:19801552

    Open questions at the time
    • GRK5/6 work single-lab biochemistry combined with in vivo (Medium-rationale domain study)
    • How Mesd-controlled folding is coupled to surface delivery unclear
  5. 2011 High

    Whether kinase recruitment to LRP6 is actively scaffolded was unknown; TMEM198 was shown to bridge casein kinases to LRP6 for activating phosphorylation.

    Evidence Reciprocal co-IP, phosphorylation assays, siRNA, and Xenopus loss-of-function

    PMID:21536646

    Open questions at the time
    • Whether TMEM198 acts within the signalosome or upstream unclear
    • Direct CK1-TMEM198 contact not structurally mapped
  6. 2014 High

    The negative regulatory layer was defined: Src/Fer tyrosine phosphorylation restrains signalosome formation, while a tyrosine-based endocytic signal partitions LRP6 between desensitizing clathrin and signaling caveolar routes; LDLR-domain dimerization was shown to be required for robust activation.

    Evidence cDNA screen, in vitro phosphorylation, knockout MEFs, surface/endocytosis assays, and LDLR-domain mutant interaction studies

    PMID:24412751 PMID:25143377 PMID:25391905

    Open questions at the time
    • Endocytosis and dimerization studies are single-lab (Medium)
    • Cross-talk between tyrosine phosphorylation and trafficking partitioning not fully resolved
  7. 2014 High

    The pathological consequences of attenuated LRP6 activity in metabolism and vasculature were established through the R611C hypomorph, linking LRP6 to lipogenesis and VSMC differentiation via Wnt-rescuable mechanisms.

    Evidence LRP6(R611C) knock-in mice, primary hepatocytes, carotid injury model, and in vivo Wnt3a rescue

    PMID:24506864 PMID:26489464

    Open questions at the time
    • Mechanistic link between receptor hypomorphism and Sp1/IGF1 axis incompletely defined
    • Single-lab models
  8. 2016 High

    A Wnt-independent function for LRP6 was demonstrated: it scaffolds connexin 43 ER-to-Golgi trafficking at cardiac intercalated discs, with loss causing lethal arrhythmias.

    Evidence Co-IP, cardiomyocyte-specific conditional knockout, Cx43 trafficking imaging, and cardiac electrophysiology

    PMID:27250245

    Open questions at the time
    • Structural basis of LRP6-Cx43 interaction not defined
    • Whether this scaffolding generalizes beyond cardiomyocytes unknown
  9. 2017 Medium

    Control of LRP6 biogenesis was extended to ER quality control, with GPR37 (and later GRP78) acting as chaperones protecting LRP6 from ERAD to license Wnt signaling.

    Evidence Co-IP, GPR37 knockdown/knockout, LRP6 maturation/degradation assays (CHIP/VCP), NPC Wnt assays; GRP78 knockdown/ERAD assays in HCC

    PMID:28341812 PMID:31310747

    Open questions at the time
    • Whether GPR37 and GRP78 act sequentially or redundantly unknown
    • Single-lab studies
  10. 2020 High

    High-resolution structure and proximity proteomics refined the activation mechanism: the Wnt-Frizzled-LRP6 initiation complex engages E1E2 via Wnt linker domains, and rapid Wnt-induced recruitment of ESCRT/endosomal machinery including TFG supports signaling.

    Evidence Cryo-EM with chimeric Wnt engineering and peptide antagonists; APEX2 proximity labeling with MS and Xenopus validation; SOST-E1E2 crystal structure

    PMID:33097721 PMID:33299006 PMID:36893265

    Open questions at the time
    • How endosomal recruitment couples mechanistically to beta-catenin stabilization not fully resolved
    • TFG study single-lab (Medium)
  11. 2023 High

    The ubiquitin/deubiquitin balance setting surface LRP6 levels was defined, with USP46/UAF1/WDR20 counteracting RNF43/ZNRF3, and a disease-linked LRP6-Val variant was shown to disrupt Wnt7a-dependent receptor complex assembly and synaptic maintenance.

    Evidence Ubiquitylation assays, co-IP, multi-organism genetics, and organoid assays (USP46); CRISPR knock-in mice, LRP6-Frizzled5 co-IP, and synaptic/AD-model analysis (LRP6-Val)

    PMID:36638182 PMID:37798301

    Open questions at the time
    • How Wnt promotes USP46-LRP6 association mechanistically unresolved
    • Causal chain from LRP6-Val synapse loss to AD pathology not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LRP6's distinct roles—canonical Wnt signalosome receptor, Wnt-independent trafficking scaffold, LDLR endocytic partner, oxPL/CXCR4-binding ectodomain—are physically and spatially segregated within a single receptor remains unresolved.
  • No unified structural model integrating Wnt-dependent and Wnt-independent functions
  • Tissue-specific determinants of which LRP6 function dominates undefined
  • Several non-canonical interactions rest on single-lab co-IP evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2
Partners
AXIN1DKK1FZD8GJA1GPR37PTK7SOSTUSP46
Complex memberships
LRP6-LDLR-clathrin-ARH complexUSP46/UAF1/WDR20 deubiquitylase complexWnt-Frizzled-LRP6 signalosome

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Wnt treatment induces plasma membrane-associated LRP6 aggregates (signalosomes) that are phosphorylated and form ribosome-sized multiprotein complexes. Dishevelled (Dvl) is required for LRP6 phosphorylation and aggregation, and phospho-LRP6 aggregates contain caveolin but no common vesicular traffic markers. Phospho-LRP6 promotes Axin recruitment and beta-catenin stabilization. Live imaging of vertebrate cells, detergent solubilization, biochemical fractionation, dominant-negative Dvl experiments Science High 17569865
2010 LRP6 is phosphorylated at multiple conserved PPSPXS motifs by both proline-directed kinases (GSK3, PKA, Pftk1, GRK5/6) and non-proline-directed kinases (CK1 family). This phosphorylation is induced by Wnt ligand binding and by mitosis, and phospho-LRP6 promotes Axin and GSK3 recruitment to stabilize beta-catenin. Review synthesizing in vitro kinase assays, mutagenesis, and cell-based signaling assays from multiple studies Cellular and Molecular Life Sciences High 20229235
2010 In vitro reconstitution of the Fz8 CRD·Wnt3a·LRP6 signaling complex established that Wnt3a binds to LRP6 E3E4 (third and fourth beta-propeller domains), while Wnt9b binds to a distinct region (E1E2). Wnt3a and Wnt9b can bind LRP6 simultaneously. Dkk1 binds both E1E2 and E3E4 and competes with both Wnts, providing a mechanism for broad-spectrum Wnt inhibition. Insect cell expression/purification of soluble LRP6 extracellular domain fragments, binding affinity measurements, in vitro reconstitution of ternary complex Journal of Biological Chemistry High 20093360
2006 LRP6 is required for anthrax toxin internalization and lethality. LRP6 interacts at the cell surface with PA receptors TEM8/ATR and/or CMG2 to form a multicomponent complex that enables toxin endocytosis. Downregulation of LRP6 or expression of a dominant-negative LRP6 truncation, or antibodies against LRP6 extracellular domain, protected cells from anthrax toxin. siRNA knockdown, dominant-negative LRP6 expression, antibody blocking, fluorescence microscopy, biochemical co-immunoprecipitation Cell Medium 16564009
2007 NEGATIVE RESULT: LRP5 and LRP6 are NOT required for protective antigen (PA)-mediated internalization or lethality of anthrax lethal toxin. Uptake was unaltered in cells and mice with targeted deletions of Lrp5 or Lrp6, and siRNA knockdown of LRP5/6 did not impair PA-mediated uptake in ANTXR-expressing CHO cells. Cells and mice with targeted Lrp5/Lrp6 deletions, siRNA knockdown, cytotoxicity assay PLoS Pathogens Medium 17335347
2009 GRK5 and GRK6, membrane-associated kinases classically known for GPCR desensitization, directly phosphorylate the PPPSP motifs on LRP6 and activate Wnt/LRP6 signaling. Depletion of GRK5 markedly reduces Wnt3A-stimulated LRP6 phosphorylation in cells. In zebrafish, functional knockdown of GRK5 reduces Wnt signaling similarly to LRP6 knockdown. In vitro kinase assay, cell-based phosphorylation assays, siRNA depletion, zebrafish knockdown with beta-catenin/target gene readout Journal of Biological Chemistry High 19801552
2006 CKI-epsilon binds to LRP5 and LRP6 in vitro and in vivo and phosphorylates LRP6 at Ser1420 and Ser1430, which negatively regulates Wnt signaling. Mutation of these sites to alanine makes LRP6 a more potent activator of beta-catenin/Lef-1 and strengthens its interaction with Axin, suggesting a negative feedback mechanism. In vitro binding and kinase assays, co-immunoprecipitation, site-directed mutagenesis of LRP6, Lef-1 reporter assays Journal of Biological Chemistry High 16513652
2011 TMEM198, a seven-transmembrane protein, associates with LRP6 and recruits casein kinase family proteins via its cytoplasmic domain to phosphorylate LRP6 at key activation residues. TMEM198 is required for Wnt signaling and CK1-induced LRP6 phosphorylation in mammalian cells and for Wnt-mediated neural crest formation in Xenopus. Co-immunoprecipitation, LRP6 phosphorylation assays, siRNA knockdown in mammalian cells, Xenopus loss-of-function experiments Molecular and Cellular Biology High 21536646
2014 Tyrosine kinases Src and Fer directly phosphorylate LRP6 at conserved tyrosine residues adjacent to PPSPXS motifs, negatively regulating Wnt/LRP6 signaling. Src reduces cell surface LRP6 levels and disrupts LRP6 signalosome formation. MEF cells lacking Src/Fer show enhanced Wnt signaling. CK1γ inhibits Fer-induced LRP6 tyrosine phosphorylation, suggesting CK1γ de-represses inhibitory tyrosine phosphorylation. Cell culture cDNA expression screen, co-immunoprecipitation, in vitro phosphorylation assays, MEF knockout cells, cell surface LRP6 measurements, signalosome imaging EMBO Reports High 25391905
2014 LRP6 endocytosis is regulated by a tyrosine-based signal in its cytoplasmic tail. LRP6 with defective tyrosine signal has increased cell surface distribution, increased localization to caveolae, increased phosphorylation, and enhanced Wnt/beta-catenin signaling. Clathrin-mediated endocytosis of LRP6 desensitizes signaling, while caveolae-mediated endocytosis promotes it. Wnt3a treatment redistributes LRP6 to lipid rafts. LRP6 tyrosine mutant analysis, cell surface distribution assays, caveolae inhibitor treatments, phosphorylation assays, Wnt reporter assays Journal of Biological Chemistry Medium 25143377
2010 Dkk1 stabilizes LRP6 protein with prolonged half-life and causes LRP6 accumulation at the cell surface and in endosomes, in contrast to its expected role as a Wnt inhibitor that promotes LRP6 internalization. Kremen2 co-expression abrogated Dkk1-induced LRP6 accumulation. Wnt3A treatment induces LRP6 down-regulation through caveolae-mediated endocytosis, and Dkk1 blocks this Wnt3A-induced LRP6 down-regulation. Conditioned medium/recombinant protein treatment, protein half-life assay, cell surface biotinylation, co-expression of Kremen2, caveolae endocytosis inhibitor PLoS ONE Medium 20543981
2011 LRP6 forms a complex with LDL receptor (LDLR), clathrin, and ARH, and undergoes clathrin-mediated internalization after LDL stimulation. LRP6 knockdown severely impairs LDLR internalization and LDL uptake. The LRP6(R611C) mutation impairs LRP6 complex formation with LDLR/clathrin/ARH, and reduces LDLR and LRP6 internalization and LDL uptake. LRP6 overexpression and knockdown in CHO cells (LDLR-deficient and wild-type), co-immunoprecipitation of LRP6-LDLR-clathrin-ARH complex, LDL binding/uptake assays Journal of Biological Chemistry Medium 22128165
2013 Crystal structure of a Drosophila WntD N-terminal domain fragment at 2.1 Å resolution reveals conformational plasticity compared to Xenopus Wnt8. Structure-based mutational analysis of mouse Wnt3a shows that the linker between N- and C-terminal domains is required for LRP6 binding. X-ray crystallography, structure-based mutagenesis of Wnt3a, LRP6 binding assays Structure High 23791946
2023 Cryo-EM structure of an affinity-matured XWnt8-Frizzled8-LRP6 ternary initiation complex reveals that canonical Wnts engage LRP6 E1E2 domain funnels through their N-termini and linker domains. Chimeric Wnts with modular linker grafts transferred LRP6 domain specificity between Wnts and enabled non-canonical Wnt5a to signal through the canonical pathway. Synthetic peptides comprising the linker domain acted as Wnt-specific antagonists. Cryo-EM structure determination, chimeric Wnt engineering, cell-based signaling assays, synthetic peptide antagonism PNAS High 36893265
2020 Crystal structure of the LRP6 E1E2-sclerostin (SOST) complex reveals two tandem interaction sites: the known LRP6 E1 domain interaction and an unexpected additional binding site between the C-terminus of SOST and the LRP6 E2 domain. The E2 interaction was confirmed by in vitro binding and cell-based signaling assays, and validated in vivo in Xenopus laevis embryos. X-ray crystallography, in vitro binding assays, cell-based Wnt signaling assays, Xenopus embryo functional validation Nature Communications High 33097721
2009 LRP6 beta-propeller (BP) domains 1+2 form one cooperative folding unit and BP3+4 form another. BP12 and BP34 each independently bind Wnt3a, Dkk1, and the chaperone Mesd. Mesd blocks binding of both Wnt3a and Dkk1 to LRP6, enabling it to function as a Wnt signaling modulator. Recombinant LRP6 domain expression, folding/secretion assays with Mesd co-expression, ligand binding competition assays Journal of Biological Chemistry Medium 19339249
2013 Caveolin-1 (Cav-1) interacts with LRP6 in prostate cancer cells, and this interaction stimulates Wnt-β-catenin signaling and aerobic glycolysis. Cav-1 and LRP6 exert their effects on Akt and glycolytic activities (HK2, Glut3) by stimulating IGF-IR/IR signaling. LRP6 knockdown or Cav-1 knockdown reduces Akt-mTORC1 signaling and aerobic glycolysis. Co-immunoprecipitation, gene knockdown, chemical inhibition of Akt, glycolysis assays in prostate cancer cells Cancer Research Medium 23302227
2016 LRP6 acts as a scaffold protein at cardiac intercalated discs, binding connexin 43 (Cx43) independently of Wnt/beta-catenin signaling. LRP6 deficiency impairs Cx43 trafficking from the ER to the Golgi apparatus, leading to lysosomal degradation of Cx43 and disruption of gap junction formation. Cardiac-specific Lrp6-knockout mice show reduced Cx43 gap junction plaques and lethal arrhythmias without abnormality in Wnt signaling. Co-immunoprecipitation, cardiomyocyte-specific conditional knockout, immunofluorescence of Cx43 localization, ER-to-Golgi trafficking assays, cardiac electrophysiology Nature Communications High 27250245
2014 The LRP6(R611C) mutation triggers hepatic de novo lipogenesis, lipid/cholesterol biosynthesis, and apoB secretion through Sp1-dependent activation of IGF1, AKT, and both mTORC1 and mTORC2. In vivo administration of recombinant Wnt3a to LRP6(R611C) mice normalized lipogenic enzyme expression and restored plasma TG and LDL levels. LRP6(R611C) knock-in mouse model, primary hepatocyte culture, IGF1R antagonist/rapamycin/Wnt3a treatments, in vivo Wnt3a rescue Cell Metabolism High 24506864
2015 Impaired LRP6 activity in LRP6(R611C) mice promotes loss of VSMC differentiation through enhanced non-canonical Wnt signaling, leading to diminished TCF7L2 and increased Sp1-dependent activation of PDGF signaling. Wnt3a administration improved LRP6 activity, led to TCF7L2-dependent VSMC differentiation, and rescued post-carotid-injury neointima formation. LRP6(R611C) knock-in mice, high-fat diet/LDLR-KO crosses, carotid injury model, Wnt3a in vivo administration, TCF7L2 and PDGF signaling analysis Cell Reports High 26489464
2013 PTK7 physically interacts with LRP6 and stabilizes LRP6 protein levels, thereby maintaining high LRP6 to promote canonical Wnt/beta-catenin signaling. PTK7 morpholino depletion in Xenopus reduces LRP6 protein levels and inhibits Wnt/beta-catenin activity while phenocopying LRP6 depletion. High LRP6 levels maintained by PTK7 negatively regulate Wnt/PCP activity. Co-immunoprecipitation, morpholino knockdown in Xenopus, western blot for LRP6 protein levels, Wnt reporter assays Development Medium 24353057
2017 GPR37, a Parkinson's disease-associated receptor, functions as an ER chaperone for LRP6, promoting maturation of LRP6's N-terminal beta-propellers. GPR37 protects LRP6 from ER-associated degradation (ERAD) via CHIP and VCP. GPR37 is required for Wnt/beta-catenin signaling and for Wnt-dependent neurogenesis in neural progenitor cells. Co-immunoprecipitation, GPR37 knockdown/knockout, LRP6 protein maturation and degradation assays (CHIP/VCP), neural progenitor cell Wnt signaling assays EMBO Reports Medium 28341812
2020 LRP6 deficiency in cardiomyocytes increases cell cycle activity and induces a regenerative response after myocardial infarction. The pro-proliferative effect of Lrp6 deficiency is mediated through the ING5/P21 signaling pathway. Lineage tracing showed newly formed cardiomyocytes derive from resident cardiomyocytes. AAV9-mediated miRNA knockdown of Lrp6 promoted cardiac repair in vivo. Cardiomyocyte-specific conditional knockout, genetic lineage tracing, ING5/P21 pathway analysis, AAV9 gene therapy in mice, hiPSC-derived cardiomyocyte assays Cell Research Medium 32973339
2014 LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation. Wnt ligand stimulation induces conformational change of Frizzled-LRP6 complex leading to hexamer formation with a core LDLR domain-mediated LRP6 homodimer stabilized by two Wnt3a-Frz8 pairs (Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a). Co-immunoprecipitation, Wnt reporter assays, LDLR domain mutant analysis, protein interaction studies Cellular Signalling Medium 24412751
2015 N-cadherin restrains PTH-induced Lrp6/PTHR1 interaction. Ablation of N-cadherin gene in osteogenic cells increased Lrp6/PTHR1 interaction in response to PTH, enhancing PKA signaling and PKA-dependent beta-catenin C-terminus phosphorylation (which promotes transcriptional activity). Beta-catenin C-terminus phosphorylation was abolished by Lrp6 knockdown. Conditional Cdh2-deletion mice showed accentuated PTH anabolic effect on bone. Cdh2 conditional knockout in osteogenic cells, co-immunoprecipitation of Lrp6/PTHR1, LRP6 knockdown, PKA and beta-catenin phosphorylation assays, in vivo PTH bone mass measurements Journal of Bone and Mineral Research Medium 25088803
2019 VSTM2A, a secreted protein, directly binds to LRP6 (E1-4 domain via its IgV domain) at the cell membrane, suppresses LRP6 phosphorylation in a time- and dose-dependent manner, and induces LRP6 endocytosis and lysosome-mediated degradation, thereby inactivating Wnt signaling in colorectal cancer cells. Mass spectrometry identification, co-immunoprecipitation, deletion/mutation mapping, LRP6 phosphorylation assays, lysosome inhibitor experiments, LRP6 endocytosis assays Theranostics Medium 31588233
2018 Oxidized phospholipids (oxPLs) are direct ligands of LRP6 (but not the closely related LRP5). oxPL-LRP6 binding induces LRP6 endocytosis through a clathrin-mediated pathway in bone marrow mesenchymal stromal cells, decreasing osteogenic factor responses and diminishing osteoblast differentiation. LRP6 binding assays with purified oxPLs, LRP6 vs LRP5 specificity assays, clathrin inhibitor experiments, osteoblast differentiation assays Bone Research Medium 30038821
2012 Cripto-1 binds to LRP5 and LRP6 co-receptors, facilitating Wnt3a binding to LRP5 and LRP6, and enhances Wnt3a/beta-catenin signaling including cytoplasmic beta-catenin stabilization and TCF transcriptional activation. Wnt3a also increases Cripto-1-stimulated migration, invasion, and colony formation in mammary epithelial cells. Co-immunoprecipitation of Cripto-1 with LRP5/LRP6, beta-catenin stabilization assays, TCF reporter assays, migration/invasion assays Cellular Signalling Medium 23022962
2019 GRP78 chaperones LRP6 folding and maturation in the ER. GRP78 knockdown leads to LRP6 misfolding and ER-associated degradation (ERAD), reducing mature LRP6 levels and inhibiting Wnt/HOXB9 signaling in hepatocellular carcinoma cells. GRP78 knockdown, LRP6 protein maturation/ERAD assays, Wnt signaling pathway analysis, HCC invasion/metastasis assays Experimental Cell Research Medium 31310747
2023 The deubiquitylase complex USP46/UAF1/WDR20 deubiquitylates LRP6. Wnt signaling promotes association between the USP46 complex and cell-surface LRP6. USP46 knockdown decreases steady-state LRP6 levels and increases ubiquitylated LRP6. USP46 complex overexpression blocks LRP6 ubiquitylation by the ubiquitin ligases RNF43 and ZNFR3. USP46 is essential for Wnt-dependent intestinal organoid viability. Co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, CRISPR knockout in cells and zebrafish/Xenopus, size exclusion chromatography, intestinal organoid assays Nature Communications High 37798301
2020 Proximity labeling (APEX2 fused to Lrp6) revealed that endosomal proteins, ESCRT machinery components, and Trk-fused gene (TFG) are recruited near LRP6 within 5 min of Wnt3a treatment. TFG depletion (siRNA or CRISPR) significantly reduced Wnt/beta-catenin signaling in cell culture, and TFG is required for Wnt-dependent embryonic patterning in Xenopus. APEX2 proximity biotinylation, mass spectrometry, siRNA knockdown, CRISPR knockout, Xenopus in vivo patterning assays Scientific Reports Medium 33299006
2021 TMEM97 interacts with the LRP6 intracellular domain and enhances LRP6-mediated Wnt signaling in a CK1delta/epsilon-dependent manner. TMEM97 binding to LRP6 facilitates recruitment of CK1delta/epsilon to the LRP6 complex, resulting in LRP6 phosphorylation at Ser1490 and beta-catenin stabilization. TMEM97 knockout attenuates Wnt/beta-catenin signaling via reduced LRP6 phosphorylation. Co-immunoprecipitation, LRP6 phosphorylation assays, TMEM97 knockout in breast cancer cells, Wnt target gene expression analysis, xenograft tumor model Cell Death & Disease Medium 34615853
2022 SIK2, phosphorylated by CK1alpha, directly phosphorylates LRP6 in a SIK2 kinase activity-dependent manner, activating Wnt/beta-catenin signaling and maintaining breast cancer stemness. SIK2-mediated Wnt/beta-catenin activation induces IDH1 expression, causing metabolic reprogramming in breast cancer cells. SIK2 inhibitors block LRP6 phosphorylation and beta-catenin accumulation. Kinase activity assays, LRP6 phosphorylation assays, SIK2 knockdown/inhibitor treatment, BCSC proportion assays, IDH1 expression analysis Oncogene Medium 35277657
2019 LRP6 ectodomain (LRP6N) directly binds CXCR4 and competitively prevents SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced breast cancer metastasis to lung in vivo. LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis. A secreted form of LRP6N was detected in serum of mice and humans. Direct binding assays (LRP6N to CXCR4), competitive binding assays, LRP6 knockdown, in vivo breast cancer metastasis model, serum LRP6N detection Clinical Cancer Research Medium 31010839
2015 Calcipotriol (vitamin D analogue) inhibits Wnt/beta-catenin signaling in PDAC cells through a novel mechanism: transcriptional upregulation of LDLRAP1 (LDL receptor adaptor protein 1), which decreases LRP6 protein levels. Changes in LRP6 or LDLRAP1 expression directly alter Wnt reporter activity. Cell-based Wnt reporter assays, LRP6 protein level analysis with calcipotriol, LDLRAP1 overexpression/knockdown experiments, PDAC cell growth assays Molecular Cancer Research Low 26224368
2013 Syndecan-4 (SDC4) and fibronectin inhibit Wnt/beta-catenin signaling at the cell membrane level through regulation of LRP6. Epistatic and biochemical experiments placed this inhibition at the LRP6 level. SDC4 modulates the ability of R-spondin 3 to potentiate Wnt/beta-catenin signaling through LRP6. Gain- and loss-of-function in mammalian cell lines and Xenopus embryos, epistasis analysis, co-immunoprecipitation International Journal of Biochemistry & Cell Biology Low 24275095
2024 ATP6AP2 promotes LRP6/beta-catenin and N-cadherin/beta-catenin protein complex distribution at the cell membrane in osteoblasts, preventing their degradation. ATP6AP2 conditional knockout in osteoblast-lineage cells reduced LRP6 and N-cadherin levels in BMSCs and OBs (but not osteocytes), impairing beta-catenin signaling and trabecular bone formation. Conditional knockout mice, proteomic analysis, cell surface fractionation, co-immunoprecipitation, beta-catenin signaling assays Bone Research Medium 38811544
2023 The AD-linked LRP6-Val variant has reduced Wnt signaling. Wnt7a stimulates formation of the LRP6-Frizzled-5 complex, but this complex does not form when LRP6-Val is present. Lrp6-val knock-in mice develop normally but neurons do not respond to Wnt7a, exhibit age-dependent structural and functional synaptic defects, and show exacerbated synapse loss around amyloid plaques in an AD mouse model. CRISPR knock-in mice, LRP6-Frizzled-5 co-immunoprecipitation assays, Wnt7a signaling assays in neurons, synapse structural/functional analysis, NL-G-F AD model crossing Science Advances High 36638182
2008 LRP6 forms a complex with anthrax toxin receptors (ATRs/ANTXRs) at the cell surface. This ATR-LRP6 interaction is bidirectional: ATRs control LRP6 protein levels (RNAi against ATRs decreased LRP6 levels and reduced Wnt signaling), while LRP6 plays a role in anthrax toxin endocytosis (toxin binding triggers LRP6 tyrosine phosphorylation, redistribution into detergent-resistant domains, and LRP6 endocytosis; LRP6 RNAi strongly delayed toxin endocytosis). Co-immunoprecipitation, siRNA against ATRs and LRP6, Wnt signaling reporter assays, LRP6 tyrosine phosphorylation analysis, detergent-resistant domain fractionation, toxin endocytosis assays Cellular Microbiology Medium 18717822
2022 Ninjurin1 (Ninj1) forms an assembly with LRP6 through its extracellular N-terminal domain and recruits Frizzled2 and downstream signaling mediators, resulting in ligand-independent activation of the LRP6/beta-catenin signaling pathway in lung cancer cells. Co-immunoprecipitation, domain mapping of Ninj1-LRP6 interaction, Wnt reporter assays, functional gain/loss of Ninj1 expression Journal of Experimental & Clinical Cancer Research Low 35395804

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Wnt induces LRP6 signalosomes and promotes dishevelled-dependent LRP6 phosphorylation. Science (New York, N.Y.) 758 17569865
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
2010 Reconstitution of a frizzled8.Wnt3a.LRP6 signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6. The Journal of biological chemistry 180 20093360
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
2019 Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function. Circulation research 158 30582454
2010 Regulation of Lrp6 phosphorylation. Cellular and molecular life sciences : CMLS 157 20229235
2016 β-Catenin-Independent Roles of Wnt/LRP6 Signaling. Trends in cell biology 155 27568239
2021 LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. Frontiers in cell and developmental biology 135 34026761
2009 Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion. Development (Cambridge, England) 133 19700620
2009 The Wnt co-receptor Lrp6 is required for normal mouse mammary gland development. PloS one 117 19503830
2006 The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Cell 108 16564009
2014 MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. Journal of translational medicine 100 25240815
2014 The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue. Cell metabolism 95 24506864
2014 Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells. Journal of cellular biochemistry 87 24905570
2010 Dkk1 stabilizes Wnt co-receptor LRP6: implication for Wnt ligand-induced LRP6 down-regulation. PloS one 78 20543981
2013 structural Studies of Wnts and identification of an LRP6 binding site. Structure (London, England : 1993) 74 23791946
2004 LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells. American journal of physiology. Heart and circulatory physiology 74 15271658
2013 Caveolin-1-LRP6 signaling module stimulates aerobic glycolysis in prostate cancer. Cancer research 73 23302227
2004 LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution. Oncogene 71 15516984
2015 Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis. Nutrients 70 26046396
2020 LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration. Cell research 69 32973339
2014 MicroRNA-183 suppresses retinoblastoma cell growth, invasion and migration by targeting LRP6. The FEBS journal 68 24289859
2012 Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion. PloS one 66 22570728
2021 ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway. Theranostics 64 33391525
2013 PTK7 modulates Wnt signaling activity via LRP6. Development (Cambridge, England) 63 24353057
2015 Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease. Cell reports 62 26489464
2011 LRP6 protein regulates low density lipoprotein (LDL) receptor-mediated LDL uptake. The Journal of biological chemistry 61 22128165
2016 Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. Genetics in medicine : official journal of the American College of Medical Genetics 60 26963285
2014 miR-202 suppresses cell proliferation in human hepatocellular carcinoma by downregulating LRP6 post-transcriptionally. FEBS letters 60 24704686
2008 Ocular coloboma and dorsoventral neuroretinal patterning defects in Lrp6 mutant eyes. Developmental dynamics : an official publication of the American Association of Anatomists 58 18985738
2017 Role of Wnt Co-Receptor LRP6 in Triple Negative Breast Cancer Cell Migration and Invasion. Journal of cellular biochemistry 57 28247948
2015 Deletion of LRP5 and LRP6 in dendritic cells enhances antitumor immunity. Oncoimmunology 57 27141399
2020 Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains. Nature communications 56 33097721
2009 G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway. The Journal of biological chemistry 56 19801552
2019 A Role for the WNT Co-Receptor LRP6 in Pathogenesis and Therapy of Epithelial Cancers. Cancers 55 31412666
2021 Effect and Mechanism of LRP6 on Cardiac Myocyte Ferroptosis in Myocardial Infarction. Oxidative medicine and cellular longevity 52 34712388
2012 Lrp5 and Lrp6 play compensatory roles in mouse intestinal development. Journal of cellular biochemistry 50 21866564
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
2019 LRP6 regulates Rab7-mediated autophagy through the Wnt/β-catenin pathway to modulate trophoblast cell migration and invasion. Journal of cellular biochemistry 45 31544984
2016 Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer. Cancer letters 45 27919787
2020 Exosomal circFBLIM1 Promotes Hepatocellular Carcinoma Progression and Glycolysis by Regulating the miR-338/LRP6 Axis. Cancer biotherapy & radiopharmaceuticals 44 32907351
2018 Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor. Frontiers in synaptic neuroscience 44 30425633
2015 Rare LRP6 variants identified in spina bifida patients. Human mutation 44 25546815
2021 Regulation of the Low-Density Lipoprotein Receptor-Related Protein LRP6 and Its Association With Disease: Wnt/β-Catenin Signaling and Beyond. Frontiers in cell and developmental biology 43 34589484
2012 Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors. Cellular signalling 43 23022962
2018 MiR-183 inhibits osteosarcoma cell growth and invasion by regulating LRP6-Wnt/β-catenin signaling pathway. Biochemical and biophysical research communications 41 29402412
2020 Circular RNA circ-LRP6 facilitates Myc-driven tumorigenesis in esophageal squamous cell cancer. Bioengineered 40 32867570
2015 Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer. Molecular cancer research : MCR 40 26224368
2010 Generation of Lrp6 conditional gene-targeting mouse line for modeling and dissecting multiple birth defects/congenital anomalies. Developmental dynamics : an official publication of the American Association of Anatomists 40 19653321
2011 Transmembrane protein 198 promotes LRP6 phosphorylation and Wnt signaling activation. Molecular and cellular biology 39 21536646
2006 Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation. The Journal of biological chemistry 39 16513652
2023 Structure of the Wnt-Frizzled-LRP6 initiation complex reveals the basis for coreceptor discrimination. Proceedings of the National Academy of Sciences of the United States of America 38 36893265
2016 LRP6 acts as a scaffold protein in cardiac gap junction assembly. Nature communications 38 27250245
2010 Functional interactions between the LRP6 WNT co-receptor and folate supplementation. Human molecular genetics 38 20843827
2008 Radiographic osteoarthritis at three joint sites and FRZB, LRP5, and LRP6 polymorphisms in two population-based cohorts. Osteoarthritis and cartilage 38 18406176
2010 Delayed dopaminergic neuron differentiation in Lrp6 mutant mice. Developmental dynamics : an official publication of the American Association of Anatomists 36 19795519
2009 A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol. Arteriosclerosis, thrombosis, and vascular biology 36 19667113
2008 Functional interactions between anthrax toxin receptors and the WNT signalling protein LRP6. Cellular microbiology 36 18717822
2014 Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/β-catenin signalling. EMBO reports 35 25391905
2015 N-cadherin restrains PTH activation of Lrp6/β-catenin signaling and osteoanabolic action. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 25088803
2019 VSTM2A suppresses colorectal cancer and antagonizes Wnt signaling receptor LRP6. Theranostics 33 31588233
2018 Oxidized phospholipids are ligands for LRP6. Bone research 33 30038821
2017 Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP6. EMBO reports 33 28341812
2020 In-silico identification of new inhibitors for Low-density lipoprotein receptor-related protein6 (LRP6). Journal of biomolecular structure & dynamics 32 33351722
2019 GRP78 activates the Wnt/HOXB9 pathway to promote invasion and metastasis of hepatocellular carcinoma by chaperoning LRP6. Experimental cell research 32 31310747
2017 Wnt co-receptors Lrp5 and Lrp6 differentially mediate Wnt3a signaling in osteoblasts. PloS one 32 29176883
2017 LRP6 promotes invasion and metastasis of colorectal cancer through cytoskeleton dynamics. Oncotarget 32 29312635
2014 LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation. Cellular signalling 32 24412751
2007 LRP5 and LRP6 are not required for protective antigen-mediated internalization or lethality of anthrax lethal toxin. PLoS pathogens 32 17335347
2020 Wnt-inducible Lrp6-APEX2 interacting proteins identify ESCRT machinery and Trk-fused gene as components of the Wnt signaling pathway. Scientific reports 30 33299006
2014 Tyrosine-based signal mediates LRP6 receptor endocytosis and desensitization of Wnt/β-catenin pathway signaling. The Journal of biological chemistry 30 25143377
2023 A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer's disease. Science advances 29 36638182
2020 Lrp6 Dynamic Expression in Tooth Development and Mutations in Oligodontia. Journal of dental research 29 33164649
2017 Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases. The pharmacogenomics journal 29 28696417
2010 Genetic interaction between Lrp6 and Wnt5a during mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 29 19795512
2021 Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer. Cell death & disease 28 34615853
2018 C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis. Cancer letters 28 30583072
2009 Cooperative folding and ligand-binding properties of LRP6 beta-propeller domains. The Journal of biological chemistry 28 19339249
2022 LRP6 Receptor Plays Essential Functions in Development and Human Diseases. Genes 27 35052459
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
2015 Reduced LRP6 expression and increase in the interaction of GSK3β with p53 contribute to podocyte apoptosis in diabetes mellitus and are prevented by green tea. The Journal of nutritional biochemistry 27 25655048
2024 The inhibition of YTHDF3/m6A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer. International journal of biological sciences 26 38250152
2022 Chlorogenic Acid Inhibits Epithelial-Mesenchymal Transition and Invasion of Breast Cancer by Down-Regulating LRP6. The Journal of pharmacology and experimental therapeutics 26 36456194
2019 LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung. Clinical cancer research : an official journal of the American Association for Cancer Research 26 31010839
2013 Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3. The international journal of biochemistry & cell biology 26 24275095
2022 SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. Oncogene 25 35277657
2022 Anti-β2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts. Cells 24 35455968
2022 circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis. International journal of oncology 23 35211755
2021 Synergistic Mutations of LRP6 and WNT10A in Familial Tooth Agenesis. Journal of personalized medicine 23 34834569
2014 Functional analysis LRP6 novel mutations in patients with coronary artery disease. PloS one 23 24427284
2005 Genetic interaction between Wnt7a and Lrp6 during patterning of dorsal and posterior structures of the mouse limb. Developmental dynamics : an official publication of the American Association of Anatomists 23 15880584
2002 Cloning and expression of Xenopus Lrp5 and Lrp6 genes. Mechanisms of development 23 12204281
2024 ATP6AP2, a regulator of LRP6/β-catenin protein trafficking, promotes Wnt/β-catenin signaling and bone formation in a cell type dependent manner. Bone research 22 38811544
2023 The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling. Nature communications 22 37798301
2020 High bone mass from mutation of low-density lipoprotein receptor-related protein 6 (LRP6). Bone 22 32730923
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
2022 Ninjurin1 drives lung tumor formation and progression by potentiating Wnt/β-Catenin signaling through Frizzled2-LRP6 assembly. Journal of experimental & clinical cancer research : CR 21 35395804
2020 Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3β. Redox biology 21 32905882

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