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FLASH GENE
Symbol LRP2 contributors: mct - updated : 07-03-2015
HGNC name low density lipoprotein-related protein 2
HGNC id 6694
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
  • LRP2 and CUBN may be important in human maternal-fetal transfer, and they increase across gestation to facilitate this function
  • 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)
  • to diabetes-associated end stage renal disease
  • Variant & Polymorphism SNP
  • clusters of rare DRVs associated with ASD
  • LRP2 rare variant associated with diabetes-associated end stage renal disease
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
    knockout mice, lacking LRP2, lose 25 (OH) D3 in the urine and develop severe bone disease