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FLASH GENE
Symbol STAT3 contributors: mct/shn - updated : 27-07-2016
HGNC name signal transducer and activator of transcription 3 (acute-phase response factor)
HGNC id 11364
Corresponding disease
HIES hyper IgE syndrome 2
Location 17q21.2      Physical location : 40.465.342 - 40.540.513
Synonym name
  • acute phase response factor
  • DNA-binding protein APRF
  • signal transducer and activator of transcription 3
  • Synonym symbol(s) APRF, FLJ20882, MGC16063, HIES
    DNA
    TYPE functioning gene
    STRUCTURE 75.17 kb     24 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    MAPPING cloned Y linked N status confirmed
    Map cen - D17S1793 - D17S1801 - STAT3 - D17S932 - D17S1789 - qter
    Physical map
    LOC201181 17q21.31 similar to hypothetical protein A930006D11 LOC390796 17 similar to hypothetical protein A930006D11 LGP2 17q21.2 similar to hypothetical protein A930006D11 GCN5L2 17q21 GCN5 general control of amino-acid synthesis 5-like 2 (yeast) HspB9 17q21.31 small heat shock protein B9 RAB5C 17q21 RAB5C, member RAS oncogene family KCNH4 17q21.31 potassium voltage-gated channel, subfamily H (eag-related), member 4 HCRT 17q21 hypocretin (orexin) neuropeptide precursor LGP1 17q21.2 hypocretin (orexin) neuropeptide precursor STAT5B 17q11.2 signal transducer and activator of transcription 5B STAT5A 17q11.2 signal transducer and activator of transcription 5A MGC16063 17q21.31 hypothetical protein MGC16063 STAT3 17q21 signal transducer and activator of transcription 3 (acute-phase response factor) PTRF 17q21.2 polymerase I and transcript release factor ATP6V0A1 17q21.3 ATPase, H+ transporting, lysosomal V0 subunit a isoform 1
    RNA
    TRANSCRIPTS type messenger
    text four isoforms alpha, truncated beta and gamma, delta, differentially expressed during granulocytic differentiation
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    24 - 4978 88.1 770 - 2008 18172861
    also called STAT3 alpha or variant 1/isoform 1
    24 splicing 4819 83.2 722 - 2011 22006329
  • also called STAT3B, STAT3 beta or variant 3/isoform 3
  • uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain
  • lacks the 55-AA C-terminal transactivation domain (TAD), replaced by seven unique amino acids
  • can act as a dominant-negative regulator of transcription and promote apoptosis
  • protein whose unique biological functions contribute to the complex biology of STAT3
  • 24 - 4953 - 769 - 2008 18172861
    alsos called STAT3 delta or variant 2/isoform 2
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Mus musculusAdult
    Digestiveliver   highly Mus musculusAdult
    Lymphoid/Immunespleen   lowly Mus musculusAdult
    Nervousbrain   lowly Homo sapiensAdult
    Reproductivemale systemtestis  moderately Mus musculusAdult
    Respiratorylung   lowly Mus musculusAdult
    Urinarykidney   moderately Mus musculusAdult
    cell lineage granulocytic lineage
    cell lines transformed cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text neural development
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminus conserved domain
  • the coiled coil domain
  • the DNA binding domain, a linker region
  • a SRC homology domain 2 (SH2), a critical site of tyrosine phosphorylation and the carboxy-terminal transactivation domain
  • mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Stat3, Mus musculus
    ortholog to Stat3, Rattus norvegicus
    ortholog to stat3, Danio rerio
    ortholog to STAT3, Pan troglodytes
    intraspecies homolog to p91
    Homologene
    FAMILY
  • transcription factor STAT family
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,nucleus,chromatin/chromosome
    text located in the cytoplasm and translocated to the nucleus after tyrosine phosphorylation (activation), present in plasma membrane rafts
  • present in the mitochondria of cultured cells and primary tissues, including the liver and heart
  • basic FUNCTION
  • mediating granulocytic differentiation
  • playing a critical role in the maintenance of an undifferentiated ES phenotype
  • crucial functions in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure
  • essential for normal glucose homeostasis
  • playing a role in glial and neural differentiation and in leptin mediated energy balance
  • negative regulator of granulopoiesis, possibly through induced expression of the signaling inhibitor, SOCS3
  • required for ALK-mediated lymphomagenesis
  • playing a critical role for the preservation of postpartum myocardial angiogenesis and function
  • a critical role for mouse Stat3beta in the control of systemic inflammation
  • critical roles in the development and regulation of innate immunity
  • plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury
  • a key regulator of reactive astrocytes in the healing process after spinal cord injury
  • required for de novo epithelial carcinogenesis
  • functions as a C/EBPbeta cofactor in the regulation of the MAD1 gene
  • is required for optimal function of the electron transport chain
  • playing a dual role with STAT1 and JAK1 in myogenic differentiation, participating in myoblast proliferation and actively repressing differentiation
  • essential signaling component potentially contributing to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia caused by PTPN11 gain-of-function mutations
  • activates the receptor tyrosine kinase like orphan receptor-1 gene in chronic lymphocytic leukemia cells
  • functions in various cellular processes including neuronal differentiation
  • acts as a phase-specific regulator of axonal regeneration that selectively controls the timing of growth induction after CNS and PNS lesions
  • controls the timely initiation of axonal growth but does not affect axonal elongation
  • important regulator of stem cell self-renewal, cancer cell survival, and inflammation
  • plays a critical role in KRAS-induced pancreatic tumorigenesis
  • is absolutely required for small-intestine crypt stem cell survival
  • inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state
  • might protect T-cells from apoptosis by limiting their production of IL2 through up-regulation of FOXO1/FOXO3A expression
  • may contribute to mechanisms that inhibited proliferation in lymphocytes
  • similar to their role in regulating lifespan of worms, convergence of FOXO1 and STAT3 pathways may serve to extend lifespan of T-lymphocytes
  • constitutively activated STAT3 regulates expression of MUC1, which mediates lung cancer cell survival and metastasis)
  • STAT3 is a transcription factor for the S1PR1 gene
  • inhibits IL2 production by T lymphocytes
  • required for proper induction of IL6 by NFKB1
  • NFKB1 and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors
  • activated STAT1 and STAT3 regulate VEGFA expression indirectly, by modulating HIF1A activity
  • crosstalk between cellular metabolism (fatty acids), pro-inflammatory signaling (STAT3), innate immunity (EIF2AK2), and translational control (EIF2S1) that regulates autophagy
  • novel chaperone function for NDUFA13 in the recruitment of STAT3 into mitochondria
  • is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer
  • CELLULAR PROCESS cell cycle, checkpoint
    cell life, antiapoptosis
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    text required in cell culture for transformation and blocking of apoptosis
    PATHWAY
    metabolism
    signaling signal transduction
  • IL6 and related cytokines induced signal transduction by JAK kinases
  • GCG, GCGR signaling correlates with STAT3 activation and macrophage polarization
  • a component
  • component of the interferon stimulated gene factor 3 complexes
  • forming a complex with STAT1, bridged by EP300, involved in the cooperative signaling of CIF and BMP2 and subsequent induction of astrocytes from neural progenitors
  • MAP3K7/NLK/STAT3 cascade participating in the TGFB-mediated mesoderm induction
  • interacting with DNMT1 and HDAC1 for epigenetic silencing of PTPN6 in various tumors
  • complex JAK2, STAT2, and STAT3 required for early myogenic differentiation
  • SIN3A complex acts as a context-dependent ISGF3/STAT3 transcriptional switch
  • HIC1 forms complexes with the signal transducers and activators of transcription 3 (STAT3) and attenuates STAT3-mediated transcription
  • INTERACTION
    DNA
  • FOXO1 or FOXO3a promoter
  • VEGF promoter
  • SHP-1 promoter
  • RNA
    small molecule other,
    protein
  • IFNAR-1 chain of the human type I interferon receptor
  • glucocorticoid receptor
  • c-Fes
  • p300
  • c-Jun
  • IL-2Rbeta chain
  • p21WAF1/CIP1/SDI1
  • p94(fer)
  • RPA p32
  • TSH receptor, TSHR
  • Rac1 GTPase
  • JAK1 and JAK2
  • NcoA/SRC1a
  • HNF-3
  • Protein kinase PKR
  • PIAS3
  • ErbB-2
  • nuclear factor kappaB (NF-kappaB) p65 and p50
  • chaperone glucose-regulated protein 58, GRP58
  • EZI
  • Hsp90
  • Tip60
  • GRIM-19
  • protein inhibitor of activated STAT3, PIAS3
  • nucleophosmin-anaplastic lymphoma kinase, NPM-ALK
  • STRA13
  • BRG1 and CDK9
  • prothymosin-alpha
  • IRAK1
  • (HIF)-1alpha, CBP/p300 and Ref-1/APE
  • DNMT1 and histone deacetylase 1
  • Epidermal growth factor receptor, EGFR
  • Daxx
  • RBM8A
  • ARL2BP
  • TRIM28
  • KAP1
  • S1P-S1PR1 axis
  • SOX6
  • STAP2 upregulated PTK6-mediated activation of STAT3 in breast cancer cells
  • may directly mediate EMT(epithelial-mesenchymal transition) progression and regulate ZEB1 expression in colorectal cancer
  • STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells
  • SIN3A directly interacts with STAT3 and promotes its deacetylation
  • OSM-mediated inhibition of TGFB1-induced CTGF mRNA expression depends on STAT3
  • GCG induces STAT3 activation in human macrophages
  • Il6/STAT3 modulates estrogen-induced GREB1 transcriptional activity in breast cancer cells
  • STAT1 inhibited VEGFA expression, while STAT3 promoted the expression of VEGFA
  • STAT1 and STAT3 have opposing roles in modulating HIF1A activity and subsequently, VEGFA expression
  • control of HIF1A by STAT1 and STAT3 is an important mechanism by which VEGFA expression is regulated in smooth muscle cells (SMC)
  • unsuspected mechanism of autophagy control that involves STAT3 and EIF2AK2 as interacting partners
  • EGFR, SFKs, and STAT3 can serve as substrates for the protein tyrosine phosphatase TCPTP (PTPN2)
  • TRAF6 is a new STAT3 interactor
  • STAT3 may act as a competitive inhibitor of EIF2AK2
  • binds directly to the WASF3 promoter and increases transcription levels, which correlates with increased migration potential
  • STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation, but STAT5B represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene
  • BTG2 negatively regulated cancer cell growth by inhibiting IL6 expression through downregulation of STAT3 activation
  • in cancer, constitutive activation of STAT3 makes a major contribution to the ability of cancer cells to survive and grow, but the simultaneous upregulation of EGFR and secretion of IL6 can cooperate to desensitize the cancer cells to the actions of negative regulators, especially SOCS3
  • KLF4 expression resulted from the codependent and synergistic action of NANOG and STAT3 in embryonic stem cells and during initiation of reprogramming
  • UBL4A promotes STAT3 dephosphorylation via mediating the interaction between TC45 (the nuclear isoform of PTPN2) and STAT3 specifically
  • STAT3 binding stabilizes NFKB1 on the UBD promoter and leads to maximum induction of UBD gene expression
  • PTPRT-modulated STAT3 signaling implicated in the regulation of high-fat diet-induced obesity
  • SOX5 and MAF cooperatively induce Th17 cell differentiation via the induction of RORC as downstream targets of STAT3
  • STAT3 protein regulates vascular smooth muscle cell phenotypic switch by interaction with MYOCD
  • TNFSF18 could promote Th17 cell differentiation by MAPK14 and STAT3 signaling in autoimmune arthritis
  • BTG2 is regulated by STAT3 signaling and inhibits adipocyte differentiation
  • ARL3 is a novel STAT3-binding partner (ARL3 recognizes the DNA-binding domain as well as the C-terminal region of STAT3, and their binding was the strongest when both proteins were activated
  • SENP3 could thus enhance STAT3 phosphorylation by de-conjugating the SUMO2/3 modification of STAT3
  • DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation
  • genetically linked tumor suppressors SH2D4A and SORBS3 functionally cooperate to inhibit STAT3 signaling in in hepatocellular carcinoma
  • STAT3 and the Ikaros zinc finger transcription factors IKZF3, IKZF1 cooperate to regulate BCL66 expression
  • cell & other
    REGULATION
    activated by cytokines and growth factors via specific tyrosine phosphorylation, dimerization, and nuclear translocation
    c-Fes
    type I interferons
    induced by IL6ST( GP130)
    inhibited by protein phosphatase 2D
    PIAS3
    NDRG2 via SOCS1 induction in a MAPK14 dependent manner
    pyrimethamine
    repressed by GRIM-19
    Phosphorylated by IL6, resulting in activation of STAT3-responsive genes
    Protein kinase C
    Other regulated by tyrosine phosphorylation
    coregulated by EP30 and NCOA1
    regulated by SOCS3 (prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance)
    STAT3 signaling is regulated by PKD1 and is a driving factor for renal epithelial proliferation during normal renal development and during cyst growth
    ASSOCIATED DISORDERS
    corresponding disease(s) HIES
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in cisplastin-resistant cells
    tumoral       gain of function
    in many cancers and transformed cell lines and required in cell culture for transformation and blocking of apoptosis
    tumoral   deletion    
    in abnormal myeloid cells
    constitutional       gain of function
    in maternal heart in pregnancy and postpartum
    constitutional     --low  
    with activated CTSD in myocardium of postpartum cardiomyopathy
    tumoral     --over  
    with NFkappaB in head and neck squamous cell carcinomas
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target STAT3 beta expression can rescue the embryonic lethality of a STAT3-null mutation
    SystemTypeDisorderPubmed
    neurologyacquired 
    activating STAT3 might provide an opportunity to jumpstart regeneration, and thus prime axons in the injured spinal cord for application of complementary therapies that improve axonal elongation
    cancerhemopathy 
    possible therapeutic target in lymphoma
    cancerhead and neck 
    inhibition of signal activation of both NF-kappaB and STAT3 together with reexpression of TP53 could be the most effective strategy for cytotoxic therapy of head and neck squamous cell carcinomas
    miscelleaneousurinary 
    STAT3 promotes renal cyst growth and could be a promising drug target in polycystic kidney disease
    cancerdigestivepancreas
    therapeutic target in pancreatic ductal adenocarcinomas
    cancer  
    development of means to manipulate endogenous STAT3 alternative splicing in a physiological context allowed us to validate STAT3beta as a potent antitumorigenic molecule
    diabete  
    new therapeutic targets for diabetes mellitus
    ANIMAL & CELL MODELS
  • Stat3 activity was impaired in Stat3beta(-/-) cells
  • Stat3beta-deficient mice exhibit diminished recovery from endotoxic shock and hyperresponsiveness of a subset of endotoxin-inducible genes in liver
  • mice with STAT3 tissue-specific disruption in bone marrow cells during hematopoiesis die within 4-6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation
  • mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment and develop heart dysfunction with advancing age
  • mice with liver-specific deficiency in STAT-3 show insulin resistance associated with increased hepatic expression of gluconeogenic genes
  • deletion of Stat-3 in mouse respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function but exposure of adult Stat-3-deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress
  • epithelial cell injury and inflammatory responses were increased in the Stat-3-deleted mice
  • the epidermis of Stat3-deficient mice showed a significantly reduced proliferative response following treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) because of a defect in G1-to-S-phase cell cycle progression and mice were completely resistant to skin tumor development when 12-dimethylbenz[a]anthracene (DMBA) was used as the initiator and TPA as the promoter (
  • reactive astrocytes in Nes-Stat3(-/-) mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury
  • selective deletion of Stat3 in DRG neurons of Stat3-floxed mice impairs regeneration of peripheral DRG branches after a nerve cut
  • a sustained activation of the transcription factor signal transducer and activator of STAT3 in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys