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FLASH GENE
Symbol NOS3 contributors: mct - updated : 03-02-2015
HGNC name nitric oxide synthase 3 (endothelial cell)
HGNC id 7876
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminal oxygenase domain, involved in dimerization
  • FAD binding domain
    • mono polymer homomer , dimer
    HOMOLOGY
    interspecies homolog to murine Nos3
    Homologene
    FAMILY NOS family
    CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus
    text
  • myristoylated membrane anchor
  • translocation to mitochondria is regulated by the phosphorylation of NOS3 at Ser(617) and Ser(1179) by AKT1 and this is enhanced when AKT1 becomes nitrated at Tyr(350)
    • basic FUNCTION
  • catalyzing the synthesis of NO from l-arginine
  • plays an important role in adiponectin synthesis in adipocytes by increasing mitochondrial biogenesis and enhancing mitochondrial function
  • novel and important role of NOS3 in chondrocyte proliferation and endochondral bone growth and loss of NOS3 results in premature cell cycle exit and prehypertrophic chondrocyte differentiation during cartilage development
  • NOS3 and ADH5 play an important role in endothelial cell–mediated postnatal angiogenesis and vascular tone
  • is a pressure-dependent regulator of intraocular pressure
  • role for NOS3 in bone growth and metabolism and therefore its contribution may at least in part occur during early skeletal development
  • both NOS3 in the mother and the conceptus contribute to uteroplacental vascular changes and increased uterine arterial blood flow in normal pregnancy
  • enzyme responsible for synthesis of nitric-oxide (NO) in the vasculature
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
    INTERACTION
    DNA
    RNA
    small molecule metal binding,
    calcium Ca2+
    protein
  • binding the heme moiety of soluble guanylate cyclase forming a metal-nitrosyl adduct that is activated to catalyze the conversion of GTP to LGMP
  • RPA1, repressor of NOS3 associated with the development of coronary artery
  • calmodulin
  • PRKCZ binds and phosphorylates MAPK7, thereby decreasing NOS3 protein stability and contributing to early events of atherosclerosis
  • controls the expression of the angiogenesis inhibitor thrombospondin 2
  • JNK2 is a physiological kinase responsible for NOS3-Ser(116) phosphorylation and regulates NO production
  • GIT1 plays an important role in NOS3 function, in both normal and abnormal pathophysiologic states
  • GIT1 might regulate NOS3 activity in sinusoidal endothelial cells
  • activation of NOS3 promotes SRC-dependent CAV1-Tyr-14 phosphorylation and NOS3/CAV1 binding, that is, NOS3 feedback inhibition
  • VEGFA-mediated NOS3 phosphorylation on Ser1177 regulates angioblast and embryonic endothelial cells (EEC) division, which underlies the formation of blood vessels and vascular networks
  • UBIAD1 is a nonmitochondrial COQ10-forming enzyme with specific cardiovascular protective function via the modulation of NOS3 activity
  • HRAS mediates VEGFA-induced activation of endothelial nitric-oxide synthase (NOS3) and migratory response of human endothelial cells
  • neuronal NOS1 and endothelial NOS3 are constitutive calcium-dependent forms of the enzyme that regulate neural and vascular function respectively
    • cell & other
    REGULATION
    Other regulated by SMAD2
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in squamous hyperplasia, dysplasia and squamous cell carcinoma of the head and neck
    constitutional   LOH    
    in atherosclerotic plaques
    Susceptibility
  • coronary spasm
  • placental abruption
  • putative susceptibility factor for late onset Alzheimer disease
  • to embryonic spina bifida
  • myocardial infarction, coronary spasm and preeclampsia
  • to Fabry disease with severe phenotype
  • to hypertension, pregnancy-induced
  • to hypertension resistant to conventional therapy
  • to limb deficiency defects in the presence of maternal smoking
  • to coronary artery disease (CAD)
  • to altered vascular function
    • Variant & Polymorphism SNP , other
  • G894T not likely to be involved in atherosclerosis
  • E298D variant in hypertension in pregnancy and in lower age at end stage renal disease in PKD1
  • Glu 298 ASP in fabry disease with severe phenotype
  • SNP increasing the risk of limb deficiency defects in the presence of maternal smoking
  • G894T associated to embryonic spina bifida
  • intron 4-VNTR and T-786C mutation enhance the inflammatory process in patients with chronic coronary artery disease
  • polymorphism 894G>T associated with increased CAD risk
  • subjects carrying the rs753482-C genotype express a novel stable truncated form of NOS3 with altered enzymatic activity that influences endothelial function, and associated with altered vascular function
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinflammatory 
    both SRC and NOS3 inhibition may be important therapeutic targets to prevent or limit vascular inflammation
    ANIMAL & CELL MODELS
  • mice deficient in endothelial NO synthase (Nos3-/-) show reduced VEGFA-induced mobilization of bone marrow progenitor cells to sites of injury