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FLASH GENE
Symbol LRP2 contributors: mct - updated : 07-03-2013
HGNC name low density lipoprotein-related protein 2
HGNC id 6694
Corresponding disease
FOAR facio-oculo-acoustico-renal syndrome
Location 2q31.1      Physical location : 169.983.619 - 170.219.122
Synonym name
  • calcium sensor protein
  • Heymann nephritis antigen homolog
  • megalin
  • glycoprotein 330
  • Synonym symbol(s) DBS, GP330
    EC.number 3.1.1.3
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head
    STRUCTURE 235.58 kb     79 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Physical map
    CMYA3 2q31.1 cardiomyopathy associated 3 LOC90643 2q31.1 similar to Meningioma-expressed antigen 6/11 (MEA6) (MEA11) B3GALT1 2q24.3 UDP-Gal:betaGlcNAc beta 1,3-galactosyltransferase, polypeptide 1 STK39 2q24.3 serine threonine kinase 39 (STE20/SPS1 homolog, yeast) LOC253782 2q31.1 hypothetical protein LOC253782 NOSTRIN 2q31.1 nitric oxide synthase trafficker AD024 IGRP 2q24-q31 nitric oxide synthase trafficker ABCB11 2q24.1 ATP-binding cassette, sub-family B (MDR/TAP), member 11 DHRS9 2q31.1 dehydrogenase/reductase (SDR family) member 9 LRP2 2q31-q32.1 low density lipoprotein-related protein 2 DKFZp762I194 2q31.1 hypothetical protein DKFZp762I194 SARCOSIN 2q31.1 hypothetical protein DKFZp762I194 FLJ21901 2q31 hypothetical protein FLJ21901 PPIG 2q31.1 peptidyl-prolyl isomerase G (cyclophilin G) LOC129881 2q31.1 hypothetical LOC129881 MGC22679 2q31.1 hypothetical protein MGC22679 LOC389057 2 similar to hypothetical protein MGC22679 AF357534 2q31.1 thioredoxin 1 pseudogene 7 LOC391459 2 LOC391459 SSB 2q31.1 Sjogren syndrome antigen B (autoantigen LA) HSPC133 2q31.1 HSPC133 protein LOC344287 2q31.1 similar to hypothetical protein A130030D10 KIAA2024 2q31.1 similar to F10G7.10.p MYO3B 2q31.1-q31.2 myosin IIIB LOC389058 2 similar to zinc finger protein Sp5 LOC285140 2q31.1 eukaryotic translation initiation factor 2 beta-like pseudogene LOC389059 2 LOC389059 LOC285141 2q31.1 similar to CG14853-PB GAD1 2q31 glutamate decarboxylase 1 (brain, 67kDa) GORASP2 2p24.3-q21.3 golgi reassembly stacking protein 2, 55kDa
    regionally located . knochout mice, lacking LRP2, lose 25 (OH) D3 in the urine and develop severe bone disease
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    79 - 15735 522 4655 - 1995 7657789
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Hearing/Equilibriumearinner   
    Nervousbrain     Homo sapiens
     plexus choroid     Homo sapiens
    Reproductivefemale systemplacenta  highly
    Urinarykidneytubuleconvoluted tubuleproximal tubulehighly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialabsorptive excretorydigestive epithelium (mucosa)  
    Epithelialbarrier/liningneuroepithelium  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    Nervousastrocyte Homo sapiens
    Nervousependymal cell Homo sapiens
    Nervousoligodendrocyte Homo sapiens
    Reproductiveepithelial cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text forebrain and renal proximal tubule development
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • 36 extracellular binding LDLR class A repeats, 37 LDLR class B, 16
  • growth factor repeats
  • one EGF-like motif
  • a transmembrane segment (1TM)
  • a short cytoplasmic tail, with internalization signals
  • four SH3 binding domains
  • one SH2 binding domain
  • internal NHERF binding domain in the C-terminus
  • HOMOLOGY
    interspecies homolog to murine Lrp2
    Homologene
    FAMILY LDLR receptor superfamily
    CATEGORY receptor , transport
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • colocalizing with cubilin (CUBN) in the kidney proximal tubule
  • apical membrane
    basic FUNCTION
  • multifunctional clearance receptor, with endocytic function, endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins
  • possessing broad ligand specificity and mediating the uptake and lysosomal degradation of macromolecules
  • including lipoproteins, proteases and protease inhibitors and in vivo the Ca2+ sensing in the parathyroids, renal uptake of 25 (OH) D3 and activation of CYP25D1A, of renal uptake of retinol bound to RBP
  • acting as a new regulatory component of the SHH signaling pathway
  • endocytic receptor on the apical membranes of proximal tubule cells, involved in the reabsorption of albumin(essential process for overall body homeostasis)
  • large, multiligand endocytic receptor and member of the low-density lipoprotein-receptor family, able to bind and mediate cellular uptake of folate binding proteins
  • promoting both the protection of normally functioning cells at low/physiological albumin concentrations and programmed cell death at high concentrations more typical of disease states
  • mediating SEPP1 uptake by the kidney proximal tubule, a tissue requiring a high selenium supply to support synthesis of GPX3
  • receptor for albumin in astrocytes and is required for the synthesis of the neurotrophic factor oleic acid
  • with CUBN, are multifunctional endocytotic receptors expressed in many absorptive epithelia
  • plays a critical role in the endocytosis of albumin and other filtered low-molecular-weight proteins
  • plays a critical role in the reabsorption (endocytosis) of glomerular-filtered proteins including albumin and low-molecular-weight proteins
  • potentially prevents urinary SEPP1 loss and participates in brain Se/SePP1 uptake
  • has an important role in Abeta-mediated neurotoxicity, and therefore may be involved in the neurodegenerative processes that occur in Alzheimer disease
  • LRP8, and LRP2 mediate tissue-specific SEPP1 uptake
  • prevents urinary SEPP1 loss and participates in brain Selenium/SEPP1 uptake
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism
    signaling
  • hypothalamic CLU-LRP2 axis is a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling
  • a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
    calcium Ca2+
    protein
  • clusterin and other ligands
  • internalization of cubulin-bound ligand
  • LRP2BP
  • interaction with GIPC1/synectin required for LRP2 function
  • binds AKT1 (anchoring AKT1 in the luminal plasma membrane), and determining the survival or death of renal proximal tubule cells
  • escorted by LDLRAP1 to and through endosomes
  • interacting with SHH (having a role in cell signaling by interaction with sonic hedgehog)
  • LRP2 binds BMP4, leading to its internalization and catabolism, and reduced levels of LRP2 are associated with elevated BMP4 and disruption of normal brain development
  • MYH9 is functionally linked to megalin by interaction with DAB2 and is likely involved in megalin-mediated endocytosis in proximal tubule cells
  • could also interact with APP in neurons, and with APBB1
  • SLC9A3R1 bound to an internal PDZ binding motif in megalin (LRP2)
  • Vitamin D binding protein is one of megalin endocytic ligands
  • can bind ApoE as well as a large variety of additional ligands
  • cell & other
    REGULATION
    repressed by lipopolysaccharide-mediated upregulation of TNF which is involved in suppressing megalin gene expression partially via ERK1/2 pathway
    ASSOCIATED DISORDERS
    corresponding disease(s) FOAR
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    major autoantigen in rhumatoid arthritis
    constitutional     --low  
    in diabetic nephropathy, involved in the development of proteinuria/albuminuria
    Susceptibility
  • to diabetic and metabolic syndrome-related nephropathies
  • to autism spectrum disorder (ASD)
  • Variant & Polymorphism SNP
  • clusters of rare DRVs associated with ASD
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
    knockout mice, lacking LRP2, lose 25 (OH) D3 in the urine and develop severe bone disease