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FLASH GENE
Symbol LRP5 contributors: shn/npt - updated : 17-05-2018
HGNC name low density lipoprotein receptor-related protein 5
HGNC id 6697
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal extracellular domain binds to Wnt ligands
  • putative signal peptide for protein export
  • four domains consisiting of six YWTD spacer repeats (LY domain)
  • four epidermal growth factor (EGF) repeats with associated spacer domains
  • three LDL-receptor (LDLR)ligand binding domains
  • a single transmembrane spanning domain
  • a proline rich cytoplasmic domain, containing motifs involved in the endocytosis of receptors
  • C-terminal intracellular domain is important for signaling events
    • HOMOLOGY
    interspecies ortholog to Lrp5, Mus musculus
    ortholog to Lrp5, Rattus norvegicus
    ortholog to lrp5, Danio rerio
    intraspecies homolog to low density lipoprotein receptor 1 (LDLR)
    Homologene
    FAMILY
  • LDLR family
    • CATEGORY signaling , receptor
    SUBCELLULAR LOCALIZATION     plasma membrane
    basic FUNCTION
  • playing a role in the WNT signaling pathway probably by acting as a coreceptor together with frizzled for WNT and in lipid metabolism
  • involved in the regulation of bone mass
  • LRP5 signaling is essential for normal morphology, developmental processes and bone health
  • being essential for the development of retinal vasculature, and playing a role in capillary maturation
  • essential for normal cholesterol metabolism and glucose-induced insulin secretion (Fujino et al, 2003)
  • Fz4/Lrp5 signaling could play a role in vascular growth, remodeling, and maintenance in a variety of normal and pathologic contexts beyond the retina (Ye et al, 2009)
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cell to cell transport
    text intercellular transport
    PATHWAY
    metabolism lipid/lipoprotein
    signaling sensory transduction/vision
    WNT signaling pathway
    a component
  • FZD4, LRP5, and TSPAN12 are component of the Norrin-FZD4 complex
  • 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
  • axin and regulates the canonical Wnt signaling pathway (Mao et a, 2001)
  • WNT/frizzled complexes
  • SOST a ligand for LRP5/LRP6 (Semënov et al, 2005)
  • CDH2-axin1-LRP5 interaction negatively regulates Wnt/beta-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass (HAY 2009)
  • CAPRIN2-binding protein
  • MESD is a specialized chaperone for low-density lipoprotein receptor-related protein 5 (LRP5) and LRP6
  • LRP5 physically interacted with GCGR
  • NFIC directly binds to the promoter of low-density lipoprotein receptor-related protein 5 (LRP5) and thereafter transactivates the promoter
  • when RGMB is phosphorylated by the extracellular tyrosine kinase PKDCC, phosphorylated RGMB (p-RGMb) is internalized and carries LRP5 towards intracellular compartments
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) OPPG , HVB2 , OPTA1 , HBMCS , EVR4
    Susceptibility
  • to osteoporosis, idiopathic osteoporosis in males
  • to obesity
    • Variant & Polymorphism SNP , other
  • variant contributing to spinal bone mass, to osteoporosis and size determination
  • SNPs in intron 1 associated with an increased risk of obesity
  • mutation R1036Q associated to osteoporosis in both children and adults
  • polymorphisms associated to idiopathic osteoporosis in men
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    osteoarticularboneostéoporosis
    increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis
    osteoarticularboneostéoporosis
    SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases
    ANIMAL & CELL MODELS
  • mice with Lrp5 disruption develop a low bone mass phenotype and display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis (Kato et al, 2002)
  • mice lacking LRP5 have increased plasma cholesterol levels and a markedly impaired glucose tolerance (Fujino et al, 2003)
  • lithium restored bone metabolism and bone mass near to wild-type levels in Lrp5 deficient mice (Clément-Lacroix et al, 2005)
  • mice lacking LRP5 and apolipoprotein E display severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis (Magoori et al, 2003)
  • Lrp5-/- mice have a leaky and aberrant retinal vasculature (Junge et al, 2009)
  • mice with a loss of LRP5 display underdeveloped intraretinal vasculature associated with endothelial cell (EC) clustering and failed EC migration into deep retinal layers