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FLASH GENE
Symbol NFAT5 contributors: mct/npt/pgu - updated : 20-03-2014
HGNC name nuclear factor of activated T-cells 5, tonicity-responsive
HGNC id 7774
Location 16q22.1      Physical location : 69.598.996 - 69.738.553
Synonym name
  • NFAT-like protein 1
  • TonE-binding protein
  • glutamine rich protein H65
  • nuclear factor of activated T-cells 5
  • osmotic response element-binding protein
  • tonicity-responsive enhancer binding protein
  • T cell transcription factor NFAT5
  • transcription factor associated with hypertonicity
  • Synonym symbol(s) TONEBP, TONE-BP, KIAA0827, EVI94, NFATL1, OREBP, NFATZ, NF-AT5
    DNA
    TYPE functioning gene
    STRUCTURE 138.70 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Physical map
    LOC339065 16q22.1 similar to putative membrane-bound dipeptidase-2 DDX28 16q22.2 DEAD (Asp-Glu-Ala-Asp) box polypeptide 28 FLJ20399 16q22.1 hypothetical protein FLJ20399 NFATC3 16q22.1 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 3 FLJ21918 16q22.1 hypothetical protein FLJ21918 LYPLA3 16q22.1 lysophospholipase 3 (lysosomal phospholipase A2) SLC7A6 16q22.1 solute carrier family 7 (cationic amino acid transporter, y+ system), member 6 FLJ13291 16q22.1 hypothetical protein FLJ13291 FLJ10640 16q22.1 hypothetical protein FLJ10640 FLJ22593 16q22.1 hypothetical protein FLJ22593 SMPD3 16q22.2 sphingomyelin phosphodiesterase 3, neutral membrane (neutral sphingomyelinase II) ZFP90 16q22.1 zinc finger protein 90 homolog (mouse) CDH3 16q22.1 cadherin 3, type 1, P-cadherin (placental) CDH1 16q22.1 cadherin 1, type 1, E-cadherin (epithelial) FLJ12331 16q22.1 hypothetical protein FLJ12331 HAS3 16q22.1 hyaluronan synthase 3 FLJ20400 16q22.1 CTF8, chromosome transmission fidelity factor 8 homolog (S. cerevisiae) CIRH1A 16q22.1 cirrhosis, autosomal recessive 1A (cirhin) SNTB2 16q22-q23 syntrophin, beta 2 (dystrophin-associated protein A1, 59kDa, basic component 2) VPS4A 16q23.1 vacuolar protein sorting 4A (yeast) COG8 16q22.1 component of oligomeric golgi complex 8 PDF 16q22.1 peptide deformylase-like protein CGI-37 16q22.1 comparative gene identification transcript 37 MGC23911 16q22.1 hypothetical protein MGC23911 TERF2 16q22.1 telomeric repeat binding factor 2 CYB5-M 16q22.1 cytochrome b5 outer mitochondrial membrane precursor NFAT5 16q22.1 nuclear factor of activated T-cells 5, tonicity-responsive NQO1 16q12-q22 NAD(P)H dehydrogenase, quinone 1 NOB1P 16q22.3 likely ortholog of mouse nin one binding protein LOC388285 16 hypothetical gene supported by U89867; NM_007363 WWP2 16q22.1 Nedd-4-like ubiquitin-protein ligase LOC348174 16q22.1 secretory protein LOC348174 LOC390737 16 similar to MGC9515 protein LOC283970 16q22.1 hypothetical protein LOC283970 PDPR 16q22.1 pyruvate dehydrogenase phosphatase regulatory subunit MGC34761 16q22.1 hypothetical protein MGC34761 LOC388286 16 hypothetical gene supported by AF395444; NM_014006 MTR3 16q22.1 homolog of yeast mRNA transport regulator 3 AARS 16q22.1 alanyl-tRNA synthetase DDX19 16q22.1 DEAD (Asp-Glu-Ala-As) box polypeptide 19 FLJ11126 16q22.1 hypothetical protein FLJ11126 SIAT4B 16q22.3 sialyltransferase 4B (beta-galactoside alpha-2,3-sialyltransferase) FUK 16q22.1 fucokinase COG4 16q22.3 component of oligomeric golgi complex 4 SF3B3 16q22.1 splicing factor 3b, subunit 3, 130kDa MGC34647 16q22.1 hypothetical protein MGC34647 LOC92154 16q22.1 hypothetical protein BC002770 FLJ10305 16q22.1 hypothetical protein FLJ10305 HYDIN 16q22.2 hydrocephalus inducing LOC388287 16 similar to hydrocephalus-inducing protein FLJ14665 16q22.2 hypothetical protein FLJ14665
    RNA
    TRANSCRIPTS type messenger
    text five alternative splicing transcripts
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    15 - 14185 - 1455 - 2000 11060450
    also called variant 4/isoform a
    14 - 14123 165.8 1531 - 2000 11060450
    also called variant 3/isoform c
    15 - 14177 - 1484 - 2000 11060450
    also called variant 2/isoform b
    16 - 14239 - 1455 - 2011 22071693
  • also called variant 1/isoform a
  • contribute about half of all endogenous expression of human NFAT5 isoforms in the isotonic state
  • is indeed myristoylated and palmitoylated on its transport to the plasmalemma via the endoplasmic reticulum and the Golgi
  • 15 - 14174 - 1548 - 2000 11060450
    also called variant 6/isoform d
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveintestinelarge intestinecolon  
    Lymphoid/Immunethymus     Homo sapiens
    Nervousbrain   highly
    Reproductivefemale systemplacenta  highly
     male systemprostate   
    Urinarykidneyrenal medulla  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • IP-TIG domain
  • a DNA-binding domain related to both the NFAT and NFKB families
  • the motif-Y143 is in a region (AAs 132
  • 156) previously characterized as an auxiliary export domain (AED), necessary for export from the nucleus under normotonic and hypotonic conditions
    mono polymer homomer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • NFAT/Rel family
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus
    text present in both the cytoplasm and the nucleus under normotonic conditions
    basic FUNCTION
  • playing a central role as a tonicity-responsive transcription factor required for kidney homeostasis and function
  • only known mammalian transcription factor that regulates hypertonic stress-induced gene transcription
  • initiating loss of nucleosome(s) by an NFAT5-independent mechanism, but significantly potentiated in the presence of NFAT5
  • importance of Ser-155 and Ser-158 in the nucleocytoplasmic trafficking of NFAT5 and CSNK1A1 can plays a major role in regulating this process
  • protects cells from osmotic stress
  • role of NFAT5 and CD24 in the homeostasis of T cells under osmostress
  • novel regulator of smooth muscle cell phenotypic modulation
  • is a novel regulator of mammalian anti-pathogen responses
  • role of NFAT5 in cardiac differentiation of stem cells (PMID;
  • regulator of Wnt signaling, and NFAT5 regulation of intestinal cell differentiation may be through inhibition of Wnt/CTNNB signaling
  • has specific functions during T-cell development independent of its role as an osmoprotective transcription factor
  • the specific participation of NFAT5 downstream from the pre-TCR also lends support to the notion that this receptor controls distinct outcomes that are, for the most part, functionally independent
  • transcription factor that protects the kidney from hypertonic stress and also is activated by hypoxia
  • NFAT5 is part of a protective mechanism that limits renal damage induced by ischemia-reperfusion injury (IRI)
  • arterial wall stress controls NFAT5 activity in vascular smooth muscle cells
  • CELLULAR PROCESS nucleotide, transcription
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • PLCG1 is part of the protein complex that associates with NFAT5 at its DNA binding site
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with PLCG1 (when NaCl is elevated, NFAT5 becomes phosphorylated at Y143, resulting in binding of PLCG1 to that site, which contributes to NFAT5 transcriptional activity, transactivating activity, and nuclear localization)
  • interacting with NUP88 (up-regulated in response to hypertonic stress and acts to retain NFAT5 in the nucleus, activating transcription of critical osmoprotective genes)
  • is necessary for the regulation of AQP1 expression in the inner medulla of the kidney under hypertonic conditions
  • CD24 is a novel NFAT5 target induced by hypertonicity, and required to sustain T cell expansion under osmostress (NFAT5 bound to the CD24 promoter in response to hypertonicity facilitated the local derepression of chromatin and enhanced the expression of CD24 mRNA and protein)
  • WWTR1 modulates cellular responses to hyperosmotic stress through fine-tuning of NFAT5 activity via tyrosine phosphorylation
  • is necessary for the transcriptional regulation of AQP4 expression and for local astrocyte swelling with accompanying restriction of the neuropil extracellular space
  • interaction between CIDEC and NFAT5, and CIDEC not only modulates lipid droplet (LD) homeostasis but also modulates the response to osmotic stress via a physical interaction with NFAT5 at the LD surface
  • is a target of the IKBKB/NFKB pathway in thymocytes and as a downstream effector of the prosurvival role of the pre-T-cell receptor
  • HIF1A positively regulates the induction of NFAT5 and HSPA4 by placental hypoxia
  • cell & other
    REGULATION
    Other extensively regulated by phosphatases, including PTPN6, whose inhibition by high NaCl increases phosphorylation of NFAT5 at Y143, contributing to the nuclear localization and activation of NFAT5
    regulated by the IKBKB pathway in thymocytes and acts as a survival factor downstream from the pre-TCR, independent of its osmoprotective function
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    significantly higher in the preeclamptic compared to normal placentas
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyimmunodeficiency 
    long terminal repeat site NFAT5 interaction may thus present a novel therapeutic target to suppress HIV-1 replication and progression of AIDS
    ANIMAL & CELL MODELS
  • TonEBP mutant mice display marked decrement in the expression of AQP1 in the inner medulla
  • Nfat5-deficient mice present severe atrophy of the renal medulla, systemic hypernatremia, and a reduced thymocyte compartment and mature T-cell lymphopenia