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FLASH GENE
Symbol LRP4 contributors: mct/npt/pgu - updated : 12-01-2016
HGNC name low density lipoprotein receptor-related protein 4
HGNC id 6696
EXPRESSION
Type
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularheart   highly
Digestiveintestinesmall intestine  moderately
 intestinelarge intestinecolon highly
Endocrinethyroid   predominantly
Hearing/Equilibriumearinnercochlea moderately
Nervousbrainforebraincerebral cortex highly Homo sapiens
 brainlimbic systemhippocampus   Homo sapiens
 brainhindbraincerebellum   Homo sapiens
 nerve   highlyHomo sapiens
Olfactory (smell)olfactory bulb     Homo sapiens
Skeleton      Homo sapiens
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularstriatumskeletal  
cells
SystemCellPubmedSpeciesStageRna symbol
Skeletonosteoblast Homo sapiens
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • eight LDL-receptor class A domains
  • two calcium binding type EGF-like motif
  • twenty LDL-receptor class B repeats
  • a extracellular beta-propeller structured domain required for the sclerostin facilitator activity
  • an EGF-like motifs
  • a cytoplasmic domain having important signaling and/or anchoring functions in certain tissues but not at neuromuscular synapses
    • conjugated GlycoP
    isoforms Precursor a 17 aa signal peptide of 1.9 kda and a 1888 aa mature peptide of 210.1 kda
    HOMOLOGY
    interspecies homolog to rattus Lrp4 (96.4 pc)
    homolog to murine Lrp4 (96.6 pc)
    intraspecies homolog to low density lipoprotein receptor 4 (LDLR)
    Homologene
    FAMILY
  • LDLR family
    • CATEGORY receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
    text type II membrane anchored protein
    basic FUNCTION
  • acting as a potential cell surface endocytic receptor which binds and internalizes extracellular ligands for degradation by lysosomes
  • receptor for Agrin, which forms a complex with MUSK, and mediates MUSK activation by Agrin
  • can binds ligands that are structurally akin to AGRN and associates with other receptor tyrosine kinases, like MUSK, in these tissues
  • important for control and modification of Wnt signaling by its antagonistic effect on LRP6-mediated activation of WNT signaling
  • multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling
  • specifically facilitates the previously described inhibitory action of sclerostin on WNT1/CTNNB signaling
  • functions as a direct muscle-derived retrograde signal for early steps in presynaptic differentiation
  • acts bi-directionally and coordinates synapse formation by binding Agrin, activating MUSK and stimulating postsynaptic differentiation
  • LRP4 and MUSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for ACHR clustering
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism
    signaling
    a component
  • LRP4 and MUSK can interact and form a complex
    • INTERACTION
    DNA
    RNA
    small molecule metal binding, nucleotide,
  • Ca2+
    • protein
  • AGRN receptor
  • sclerostin (SOST) interaction partner (interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone)
  • AGRN binds LRP4 and stimulates further MUSK phosphorylation, stabilizing nascent synapses
  • cis-acting ligand for MUSK, whereas AGRN functions as an allosteric and paracrine regulator to promote association between LRP4 and MUSK
  • interplay between LRP4 and SOSTDC1 in inhibiting Wnt/CTNNB1 signaling, providing an insight into how modulation of Wnt/CTNNB1 signaling controls cellular processes important for skin placode formation
  • ligand for MUSK, and binding affinity for MUSK is potentiated by agrin, a neuronally derived heparan-sulfate proteoglycan 9)
  • MESD binds to the intracellular form of LRP4 and promotes its glycosylation and cell-surface expression
  • COLQ binds directly to LRP4 but not to MUSK and COLQ interacts indirectly with MUSK through LRP4
  • LRP4 is a major receptor of COLQ
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) SDTY7 , SOST2 , CMS17
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    associated with bone overgrowth and impaired sclerostin facilitator function
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • polysyndactyly caused by two recessive mutations in the mouse Lrp4 gene
  • syndactyly caused by mutations in the bovine Lrp4 gene
  • Lrp4 mutant mice displayed a delay in placode initiation and changes in distribution and number of mammary precursor cells leading to abnormal morphology, number and position of mammary placodes
  • Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis
  • Lrp4 null mutations in mice result in limb development defects and in perinatal death due to a lack of neuromuscular junction formation