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FLASH GENE
Symbol SMPD3 contributors: mct/npt - updated : 06-05-2019
HGNC name sphingomyelin phosphodiesterase 3, neutral membrane (neutral sphingomyelinase II)
HGNC id 14240
Location 16q22.1      Physical location : 68.392.231 - 68.482.409
Synonym name
  • neutral sphingomyelinase 2
  • nSMase-2
  • neutral sphingomyelin phosphodiesterase 3
    • Synonym symbol(s) NSMASE2, FLJ22593, MGC138443
    EC.number 3.1.4.12
    DNA
    TYPE functioning gene
    STRUCTURE 90.18 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • promoter is activated by BMP2 and is directly regulated by the RUNX2 transcription factor (Chae 2009)
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 5269 - 655 - 2018 29337691
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly
    Lymphoid/Immunethymus   highly
    Nervousbrainbasal nucleistriatum highly Homo sapiens
    Respiratorylung   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone    Homo sapiens
    Connectivecartilage    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveodontoblast Homo sapiens
    Nervousneuron Homo sapiens
    not specificchondrocyte Homo sapiens
    Skeletonosteoblast Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two putative N-terminal hydrophobic membrane-anchoring domains
  • a collagen-like linker region
  • a C-terminal catalytic domain
    • HOMOLOGY
    Homologene
    FAMILY
  • neutral sphingomyelinase family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    basic FUNCTION
  • catalyzing the hydrolysis of sphingomyelin to form ceramide and phosphocholine
  • may be acting as a regulator of postnatal development
    • and participating in bone and dentin mineralization
  • acting as a bona fide SMPD2 in cells, and is implicated in the regulation of cell growth and cell signaling (Marchesini 2003)
  • membrane-bound enzyme that cleaves sphingomyelin to generate several bioactive metabolites
  • its expression in odontoblasts is required for tooth mineralization
  • critical role of ceramide generated by SMPD3 in stem cell ciliogenesis and differentiation
  • is the major sphingomyelinase activated in response to pro-inflammatory cytokines and during oxidative stress
  • is a redox-sensitive enzyme, whose basal activity is influenced by thioredoxin-mediated changes in its oligomeric state
  • key regulator of skeletal development
  • SMPD3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development
  • key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication
  • important function of SMPD3 in the striatum
  • plays a significant role in extracellular matrix (ECM) mineralization and chondrocyte apoptosis during fracture healing
  • SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with EED (with EED are recruited to the TNFRSF1A•NSMAF•RACK1-complex in a timeframe concurrent with activation of SMPD3 (Philipp 2010)
  • binds to EED through its C-terminal catalytic domain, but not through its N terminus (Philipp 2010)
  • IL1B regulates FOXO1 activity through a novel SMPD3-dependent pathway
    • cell & other
    REGULATION
    activated by exclusively by the 55-kDa receptor TNF receptor 1 (TNFRSF1A) (Philipp 2009)
    Other regulated by PRKCD (PRKCD is a regulator of SMPD3 and a point of cross-talk between the PKC and sphingolipid pathways) (Clarke 2008)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    responsible for developmental defects of bone (Kim 2008)
    tumoral somatic mutation      
    implicate the ceramide pathway in human leukemias (Kim 2008)
    constitutional     --over  
    may increase cellular ceramide levels, leading to enhanced cell death and arrested cell proliferation (Zhu 2010)
    constitutional       loss of function
    perturbs neuronal proteostasis and causes progressive cognitive impairment
    tumoral       loss of function
    plays a role in the survival or proliferation ofiver cancer stem-like cells (CSCs), leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis
    constitutional       gain of function
    is required for the development of infection-induced diaphragm calpain activation and muscle weakness
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • SMPD3 deficiency is the pathogenetic basis of a novel form of chondrodysplasia
    • Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinfectious 
    therapies that inhibit SMPD3 in patients may prevent infection-induced skeletal muscle dysfunction
    ANIMAL & CELL MODELS
  • Smpd3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism