STAT3 (Signal Transducer and Activator of Transcription 3)

2004-05-01   Brent H Cochran 

Dept. of Physiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA

Identity

HGNC
LOCATION
17q21.2
LOCUSID
ALIAS
ADMIO,ADMIO1,APRF,HIES
FUSION GENES

DNA/RNA

Note

24 exons spanning 74444 bp.

Transcription

There are two major transcripts, STAT3a and STAT3b. STAT3a mRNA is 4973 bp. The STAT3b arises due to an alternate splice acceptor site in exon 23 which gives rise to a protein that is essentially truncated after amino acid 715. Another variant differs by 1 amino acid.

Proteins

Atlas Image

Description

There are two major isoforms of STAT3. The long form is known as STAT3 (or STAT3a) and is a 770 amino acid protein (93 kDa on gels). Notable features are STAT family DNA binding domain, an SH2 domain, a major tyrosine phosphorylation site at Y705 and a major serine phosphorylation site at S727. Phosphorylation leads to dimerization of STAT3 via intermolecular pTyr-SH2 interactions. STAT3 can also heterodimerize with STAT1. (Recent data suggests that STAT3 can possibly form a dimmer without tyrosine phosphorylation and that phosphorylation leads to changes dimmer conformation). Tyrosine of the protein activates its high affinity DNA binding activity (TTCNNNGAA) and can stimulate nuclear translocation of the protein. Stimulation of STAT3 tyrosine phosphorylation occurs in response to a variety of cytokines and growth factors including LIF, OSM, IL-6, leptin, EGF, PDGF, and HGF. The C terminal domain is a transcriptional activation domain whose activity is enhanced by phosphorylation of serine 727. The STAT3 beta isoform (84 kDa) is missing this domain (1-715 + 7 unique amino acids resulting from frameshift) and is sometimes used as a dominant negative though there is also evidence that it regulates distinct genes as well.

Expression

near ubiquitous

Localisation

Cytoplasmic, but translocates to the nucleus upon tyrosine phosphorylation.

Function

Transcription regulation.

Homology

Shares homology with the other 6 mammalian STAT genes: STAT1, STAT2, STAT4, STAT5A, STAT5B, STAT6.

Implicated in

Disease
Upregulated in many cancers including glioblastoma, head and neck cancer, prostate cancer, and breast cancer. A constitutively active form of STAT3 is oncogenic, though these mutations have not been identified in human cancer as yet. STAT 3 activation is associated with Crohns disease, and other inflammatory diseases such as pulmonary fibrosis and acute lung injury. STAT3 is critical for leptin signaling and its mutation leads to obesity in mice.

Bibliography

Pubmed IDLast YearTitleAuthors
108510592000Roles of STAT3 defined by tissue-specific gene targeting.Akira S et al
75124511994Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.Akira S et al
125945162003STAT3 signalling is required for leptin regulation of energy balance but not reproduction.Bates SH et al
96712981998Three-dimensional structure of the Stat3beta homodimer bound to DNA.Becker S et al
128324022003STATs dimerize in the absence of phosphorylation.Braunstein J et al
104586051999Stat3 as an oncogene.Bromberg JF et al
86754991996STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription.Caldenhoven E et al
94194151997Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.Garcia R et al
77748151995A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain.Horvath CM et al
136784252003Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells.Konnikova L et al
126159222003Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease.Lovato P et al
127464412003A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation.Ma J et al
150218792004The STAT3 isoforms alpha and beta have unique and specific functions.Maritano D et al
147295092004Activation of the STAT pathway in acute lung injury.Severgnini M et al
75430241995Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation.Wen Z et al
118536682002Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock.Yoo JY et al
81404221994Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.Zhong Z et al

Other Information

Locus ID:

NCBI: 6774
MIM: 102582
HGNC: 11364
Ensembl: ENSG00000168610

Variants:

dbSNP: 6774
ClinVar: 6774
TCGA: ENSG00000168610
COSMIC: STAT3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000168610ENST00000264657P40763
ENSG00000168610ENST00000389272G8JLH9
ENSG00000168610ENST00000404395P40763
ENSG00000168610ENST00000585517P40763
ENSG00000168610ENST00000588065K7EP08
ENSG00000168610ENST00000588969P40763

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Jak-STAT signaling pathwayKEGGko04630
Adipocytokine signaling pathwayKEGGko04920
Pancreatic cancerKEGGko05212
Acute myeloid leukemiaKEGGko05221
Non-small cell lung cancerKEGGko05223
Jak-STAT signaling pathwayKEGGhsa04630
Adipocytokine signaling pathwayKEGGhsa04920
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
Acute myeloid leukemiaKEGGhsa05221
Non-small cell lung cancerKEGGhsa05223
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
MeaslesKEGGko05162
MeaslesKEGGhsa05162
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
FoxO signaling pathwayKEGGhsa04068
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
JAK-STAT signalingKEGGhsa_M00684
JAK-STAT signalingKEGGM00684
Metabolism of proteinsREACTOMER-HSA-392499
Protein foldingREACTOMER-HSA-391251
Chaperonin-mediated protein foldingREACTOMER-HSA-390466
Association of TriC/CCT with target proteins during biosynthesisREACTOMER-HSA-390471
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
FGFR1 mutant receptor activationREACTOMER-HSA-1839124
Signaling by cytosolic FGFR1 fusion mutantsREACTOMER-HSA-1839117
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-6 signalingREACTOMER-HSA-1059683
Growth hormone receptor signalingREACTOMER-HSA-982772
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to STAT3REACTOMER-HSA-198745
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of pluripotent stem cellsREACTOMER-HSA-452723
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferationREACTOMER-HSA-2892247
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
Insulin resistanceKEGGhsa04931
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Interleukin-6 family signalingREACTOMER-HSA-6783589
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Activates STAT3REACTOMER-HSA-8849474
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Signaling by METREACTOMER-HSA-6806834
MET activates STAT3REACTOMER-HSA-8875791
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Interleukin-10 signalingREACTOMER-HSA-6783783

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134992438CAMK1DGenePathwayassociated
PA24684AKT1GenePathwayassociated
PA24685AKT2GenePathwayassociated
PA24686AKT3GenePathwayassociated
PA248NFKB1GenePathwayassociated
PA26048CAMK1GenePathwayassociated
PA26049CAMK1GGenePathwayassociated
PA27749ELK1GenePathwayassociated
PA28212FOSGenePathwayassociated
PA283MAPK8GenePathwayassociated
PA296RELAGenePathwayassociated
PA29988JAK1GenePathwayassociated
PA30006JUNGenePathwayassociated
PA30616MAPK1GenePathwayassociated
PA30622MAPK3GenePathwayassociated
PA31353MYCGenePathwayassociated
PA31600NFKB2GenePathwayassociated
PA33759PRKCAGenePathwayassociated
PA33761PRKCBGenePathwayassociated
PA33766PRKCGGenePathwayassociated
PA338STAT5AGenePathwayassociated
PA36042SP1GenePathwayassociated
PA36183STAT1GenePathwayassociated
PA36184STAT2GenePathwayassociated
PA36185STAT4GenePathwayassociated
PA36186STAT5BGenePathwayassociated
PA443624Carcinoma, Renal CellDiseaseClinicalAnnotationassociatedPD17602083
PA451999interferonsChemicalClinicalAnnotationassociatedPD17602083
PA90CAMK2AGenePathwayassociated
PA91CAMK2BGenePathwayassociated
PA92CAMK2DGenePathwayassociated
PA93CAMK2GGenePathwayassociated

References

Pubmed IDYearTitleCitations
198513152009STATs in cancer inflammation and immunity: a leading role for STAT3.1324
185873942008Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.951
253426312014Revisiting STAT3 signalling in cancer: new and unexpected biological functions.562
200329752010The transcriptional network for mesenchymal transformation of brain tumours.511
119603722002Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis.374
178817452007STAT3 mutations in the hyper-IgE syndrome.367
247443782014The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation.343
216331652011The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors.334
207976232010STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer.333
176760332007Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.320

Citation

Brent H Cochran

STAT3 (Signal Transducer and Activator of Transcription 3)

Atlas Genet Cytogenet Oncol Haematol. 2004-05-01

Online version: http://atlasgeneticsoncology.org/gene/444/stat3