Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Orphanet Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
FLASH GENE
Symbol LRP6 contributors: mct - updated : 02-06-2015
HGNC name low density lipoprotein receptor-related protein 6
HGNC id 6698
Corresponding disease
CADO coronary artey disease with osteoporosis
OLD3 Oligodontia 3
Location 12p13.2      Physical location : 12.268.962 - 12.419.811
Synonym symbol(s) FLJ90062, FLJ90421, ADCAD2
DNA
TYPE functioning gene
STRUCTURE 150.85 kb     23 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
text structure
  • GN box in the promoter of LRP6
  • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    23 - 10088 180 1613 - 2010 20053636
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularvessel   highly Homo sapiens
    Endocrineparathyroid   highly
    Hearing/Equilibriumearinnercochlea highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularsmoothvessel predominantly Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text coexpressed with LRP5 during embryogenesis and in adult tissues
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a putative peptide signal
  • four epidermal growth factor (EGF) repeats with associated spacer domains
  • three LDL-receptor (LDLR) repeats consisting of YWTD repeats (LY domain)
  • a single transmembrane spanning domain
  • a cytoplasmic domain containing motifs
  • five PPPSP motifs in the cytosplasmic tail phosphorylated by GSK3 and casein kinase I and subsequent recruitment of the scaffold protein Axin, contributing in a combinatorial fashion to activate the canonical Wnt-beta catenin pathway
  • a large extracellular domain (ECD) to which Wnt-proteins are known to bind
  • secondary structure modular structure of four beta-propeller domains interconnected by an EGF-like domain followed by three LDLR type A ligand-binding domains
    mono polymer complex
    HOMOLOGY
    interspecies homolog to murine Lrp6 (97.89 pc)
    homolog to rattus Lrp6 (98.51 pc)
    intraspecies homolog to low density lipoprotein receptor 6 (LDLR)
    Homologene
    FAMILY
  • LDL receptor-related family
  • CATEGORY protooncogene , receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm
    text
  • single pass type I membrane protein
  • LRP6 and LDLR colocalized both on the cell surface and within the cytoplasm
  • basic FUNCTION
  • required for canonical Wntsignaling
  • probably acting as a coreceptor
  • involved in endocytosis of receptors
  • upon phosphorylation by CSNK1G1, recruiting Axin
  • interacting with DKK1 and blocking LRP6-mediated Wnt/beta catenin signaling via LRP6 removal via Kremen proteins-mediated endocytosis
  • enabling anthrax toxin internalization by interacting at the cell surface with protective antigen receptors TEM8/ATR and/or CMG2
  • can stabilize CTNNB1 by stimulating degradation of Axin, a scaffold protein required for CTNNB1 degradation, and also independently of Axin degradation by directly inhibiting GSK3 phosphorylation of CTNNB1
  • play a role in cell-cycle activity in response to Wnt stimulation
  • single-span transmembrane coreceptor that is essential for transmission of canonical Wnt signaling
  • critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and loss of this function contributes to development of early atherosclerosis
  • negatively regulates cellular proliferation in response to PDGF signaling
  • critical modulator of receptor-mediated LDL endocytosis and variation in LRP6 may contribute to high serum LDL level
  • functions as a critical scaffolding protein that promotes formation of a complex between LDLR and endocytic machinery and triggers their endocytosis
  • LRP6-mediated LDL uptake is a clathrin but not a caveolin-dependent process
  • may regulate multiple signaling pathways in mesenchyme-derived cells that play critical roles in bone mineralization, arterial wall functions, and microvascular wall functions
  • coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK1
  • LRP6 in osteoblasts is essential for osteoblastic differentiation during bone remodeling and the anabolic effects of PTH
  • functions as a co-receptor in the canonical Wnt/CTNNB1 signaling cascade
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS immunity/defense
    PATHWAY
    metabolism
    signaling signal transduction
    Wnt signaling of a ternary complex with KREMEN1/2 and DKK1
    a component
  • essential component of the Wnt7 receptor complex (LRP6/FZD5)
  • component of cell-surface receptors for Wnt proteins
  • LRP6 forms a complex with PDGFRB and promotes its degradation
  • interacting with FAM123B (fusion of FAM123B to the cytoplasmic domain of LRP6 induces LRP6 phosphorylation and stimulates robust Wnt/beta catenin signalling)
  • instead of inducing FZD4 dimerization, NDP induces the formation of a ternary complex with FZD4 and LRP5/6 by binding to their respective extracellular domains
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • high specificity receptor for DKK1, DKK2
  • receptor for DKK3, DKK4
  • interacting with FZD5
  • interacting with DKK1 (antagonizes LRP6 function)
  • IGFBP4 physically interacted with FZD8, and a Wnt co-receptor, LRP6, and inhibited the binding of WNT3A to FZD8 and LRP6
  • interacting with GRK5, GRK6 (GRK5/6 are novel kinases for the single transmembrane receptor LRP6 during Wnt signaling)
  • CAPRIN2-binding protein
  • MESD is a specialized chaperone for low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6
  • interacting with MEST (MEST inhibited maturation of LRP6 by controlling the glycosylation of LRP6)
  • LGR5 interacts and forms a supercomplex with the Wnt coreceptors LRP6 and FZD5 which is rapidly internalized and then degraded
  • is indispensable for proper LDLR internalization
  • DAB2 selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis
  • LRRK2 can interact with the intracellular domain of LRP6 in cells and that this binding is likely to be direct, via the LRRK2-RocCOR domain
  • interacts closely with PDGFRB and TGFBR1 at the cell membrane, suggesting that it may have roles in pathways other than WNT/CTNNB
  • LRP6 is required for parathyroid hormone (PTH)-stimulated signaling pathways in osteoblasts
  • TGM2 binds directly to the extracellular domain of LRP6, which is also able to act as a substrate for TGM2-mediated protein cross-linking
  • PTK7 and LRP6 proteins physically interact, suggesting that PTK7 stabilization of LRP6 protein reciprocally regulates both canonical and noncanonical Wnt activities in the embryo
  • DKK4 interaction with LRP6 modulates WNT function during Meibomian gland (MG) development, with a novel limitation of DKK4 action by proteolytic cleavage
  • LRP6 promotes TNBC cell migration and invasion by regulating the expression and func)tion of S100A4 via the WNT/CTNNB1 signaling pathway
  • LRP6 is an essential WNT co-receptor of the WNT/CTNNB1 signaling pathway
  • NDN binds to the GN box in the promoter of LRP6 to attenuate LRP6 transcription and inhibit the Wnt signaling pathway in colorectal cancer
  • cell & other
    REGULATION
    induced by phosphorylation
    an intracellular conformational switch (from an inactive dimer to an active monomer)
    WNT3A (WNT3A acts in parallel to induce the caveolin-dependent internalization of low-density-lipoprotein receptor-related protein 6 (LRP6), as well as the phosphorylation of LRP6 and the recruitment of Axin to LRP6 on the cell surface membrane)
    repressed by a novel feedback mechanism by which Wnt, acting through beta-catenin, negatively regulates LRP6 at the mRNA level
    DKK1 (DKK1 induces the internalization of LRP6 to suppress its phosphorylation in the lipid raft and allows subsequent recycling of LRP6 so that it can be reused for signaling)
    Other modulated by MESDC2
    phosphorylation of LRP6 regulated by WNT3A-mediated formation of PIP5K1A, PIP5K1B, PIP5K1C
    ASSOCIATED DISORDERS
    corresponding disease(s) CADO , OLD3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in leukemia, by hypermethylation
    tumoral     --low  
    sufficient to inhibit breast cancer tumorigenesis
    constitutional     --over  
    colocalizes with PDGFRB and is expressed abundantly in atherosclerotic lesions (
    constitutional       loss of function
    in hyperlipidemia
    Susceptibility to premature coronary artery disease
    Variant & Polymorphism other
  • LRP6R611C mutation with a dominant-negative effects on the inhibition of PDGFRB, linked to a form of premature coronary artery disease
  • Candidate gene
  • plausible candidate genes for SHFM
  • Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductivebreast
    potential therapeutic target in breast cancer, and introduce Mesd (LRP6 antagonist) as a promising antitumor agent for treating breast cancer subtypes with Wnt activation at the cell surface
    metabolismlipid 
    potential target for development of novel therapeutics in hyperlipidemia
    ANIMAL & CELL MODELS
  • in Lrp6 mutant mice, the mechanism of birth defect prevention by Folic acid supplementation (reduction of neural tube defects occurrence by amelioration versus increased embryonic loss) can vary not only with the genes associated with increased risk, but also with the type of mutation within those genes (i.e. loss or gain of function )