STAT3 (Signal Transducer and Activator of Transcription 3)

Identity

Other names	Acute Phase Response Factor, APRF
HGNC	STAT3
Location	17q21.2
Local_order	STAT3 is flanked by STAT5a and PTRF

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.

Protein

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 Crohn's 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.

External links

	Nomenclature
HGNC	STAT3   11364
Entrez_Gene	STAT3  6774  signal transducer and activator of transcription 3 (acute-phase response factor)
	Cards
Atlas	STAT3ID444
GeneCards	STAT3
Ensembl	STAT3 [Search_View]   ENSG00000168610 [Gene_View]
Genatlas	STAT3
GeneLynx	STAT3
eGenome	STAT3
euGene	6774
	Genomic and cartography
GoldenPath	STAT3  -  17q21.2   chr17:37718869-37794039 -  17q21   [Description]    (hg18-Mar_2006)
Ensembl	STAT3 - 17q21 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	STAT3
	Gene and transcription
Genbank	AF029311 [ ENTREZ ]
Genbank	AI631896 [ ENTREZ ]
Genbank	AJ012463 [ ENTREZ ]
Genbank	AK024535 [ ENTREZ ]
Genbank	AK092965 [ ENTREZ ]
RefSeq	NM_003150 [ SRS ]    NM_003150 [ ENTREZ ]
RefSeq	NM_139276 [ SRS ]    NM_139276 [ ENTREZ ]
RefSeq	NM_213662 [ SRS ]    NM_213662 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NG_007370 [ SRS ]    NG_007370 [ ENTREZ ]
RefSeq	NT_010755 [ SRS ]    NT_010755 [ ENTREZ ]
RefSeq	NW_001838436 [ SRS ]    NW_001838436 [ ENTREZ ]
RefSeq	NW_926828 [ SRS ]    NW_926828 [ ENTREZ ]
AceView	STAT3 AceView - NCBI
Unigene	Hs.463059 [ SRS ]    Hs.463059 [ NCBI ]     HS463059 [ spliceNest ]
Fast-db	10536 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P40763 [ SRS]    P40763 [ EXPASY ]     P40763 [ INTERPRO ]     P40763 [ UNIPROT ]
Prosite	PS50001 SH2 [ SRS ]    PS50001 SH2 [ Expasy ]
Interpro	IPR011992 EF-Hand_type [ SRS ]    IPR011992 EF-Hand_type [ EBI ]
Interpro	IPR000980 SH2 [ SRS ]    IPR000980 SH2 [ EBI ]
Interpro	IPR013800 STAT_TF_alpha [ SRS ]    IPR013800 STAT_TF_alpha [ EBI ]
Interpro	IPR001217 STAT_TF_core [ SRS ]    IPR001217 STAT_TF_core [ EBI ]
Interpro	IPR013801 STAT_TF_DNA-bd [ SRS ]    IPR013801 STAT_TF_DNA-bd [ EBI ]
Interpro	IPR012345 STAT_TF_DNA-bd_sub [ SRS ]    IPR012345 STAT_TF_DNA-bd_sub [ EBI ]
Interpro	IPR013799 STAT_TF_prot_interaction [ SRS ]    IPR013799 STAT_TF_prot_interaction [ EBI ]
CluSTr	P40763
Pfam	PF00017 SH2 [ SRS ]    PF00017 SH2 [ Sanger ]    pfam00017 [ NCBI-CDD ]
Pfam	PF01017 STAT_alpha [ SRS ]    PF01017 STAT_alpha [ Sanger ]    pfam01017 [ NCBI-CDD ]
Pfam	PF02864 STAT_bind [ SRS ]    PF02864 STAT_bind [ Sanger ]    pfam02864 [ NCBI-CDD ]
Pfam	PF02865 STAT_int [ SRS ]    PF02865 STAT_int [ Sanger ]    pfam02865 [ NCBI-CDD ]
Smart	SM00252 SH2 [EMBL]
Blocks	P40763
HPRD	00026
	Protein Interaction databases
DIP	P40763
IntAct	P40763
	Polymorphism : SNP, mutations, diseases
OMIM	102582;147060    [ map ]
GENECLINICS	102582;147060
SNP	STAT3 [dbSNP-NCBI]
SNP	NM_003150 [SNP-NCI]
SNP	NM_139276 [SNP-NCI]
SNP	NM_213662 [SNP-NCI]
SNP	STAT3 [GeneSNPs - Utah]  STAT3] [HGBASE - SRS]
HAPMAP	STAT3 [HAPMAP]
COSMIC	STAT3 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	STAT3
	General knowledge
Family Browser	STAT3 [UCSC Family Browser]
SOURCE	NM_003150
SOURCE	NM_139276
SOURCE	NM_213662
SMD	Hs.463059
SAGE	Hs.463059
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter
GO	transcription factor activity [Amigo]  transcription factor activity
GO	transcription factor activity [Amigo]  transcription factor activity
GO	signal transducer activity [Amigo]  signal transducer activity
GO	hematopoietin/interferon-class (D200-domain) cytokine receptor signal transducer activity [Amigo]  hematopoietin/interferon-class (D200-domain) cytokine receptor signal transducer activity
GO	calcium ion binding [Amigo]  calcium ion binding
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	nucleus [Amigo]  nucleus
GO	cytoplasm [Amigo]  cytoplasm
GO	regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent
GO	cell motility [Amigo]  cell motility
GO	signal transduction [Amigo]  signal transduction
GO	signal transduction [Amigo]  signal transduction
GO	JAK-STAT cascade [Amigo]  JAK-STAT cascade
GO	nervous system development [Amigo]  nervous system development
GO	transcription factor binding [Amigo]  transcription factor binding
GO	cytokine and chemokine mediated signaling pathway [Amigo]  cytokine and chemokine mediated signaling pathway
GO	interspecies interaction between organisms [Amigo]  interspecies interaction between organisms
BIOCARTA	TPO Signaling Pathway    [Genes]
BIOCARTA	EGF Signaling Pathway    [Genes]
BIOCARTA	Erk1/Erk2 Mapk Signaling pathway    [Genes]
BIOCARTA	Role of ERBB2 in Signal Transduction and Oncology    [Genes]
BIOCARTA	IL22 Soluble Receptor Signaling    [Genes]
BIOCARTA	IL 6 signaling pathway    [Genes]
BIOCARTA	Signaling of Hepatocyte Growth Factor Receptor    [Genes]
BIOCARTA	PDGF Signaling Pathway    [Genes]
BIOCARTA	Stat3 Signaling Pathway    [Genes]
KEGG	Jak-STAT signaling pathway
KEGG	Adipocytokine signaling pathway
PubGene	STAT3
TreeFam	STAT3
CTD	6774 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	STAT3 Related clones (RZPD - Berlin)
	PubMed
PubMed	451 Pubmed reference(s) in LocusLink

Bibliography

Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.

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Cell. 1994 ; 77 (1) : 63-71.

PMID 7512451

Stat3 and Stat4: members of the family of signal transducers and activators of transcription.

Zhong Z, Wen Z, Darnell JE Jr

Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (11) : 4806-4810.

PMID 7545930

Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6.

Zhong Z, Wen Z, Darnell JE Jr

Science (New York, N.Y.). 1994 ; 264 (5155) : 95-98.

PMID 8140422

A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain.

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PMID 7774815

Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation.

Wen Z, Zhong Z, Darnell JE Jr

Cell. 1995 ; 82 (2) : 241-250.

PMID 7543024

STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription.

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The Journal of biological chemistry. 1996 ; 271 (22) : 13221-13227.

PMID 8675499

Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.

Garcia R, Yu CL, Hudnall A, Catlett R, Nelson KL, Smithgall T, Fujita DJ, Ethier SP, Jove R

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 1997 ; 8 (12) : 1267-1276.

PMID 9419415

Three-dimensional structure of the Stat3beta homodimer bound to DNA.

Becker S, Groner B, Mˆºller CW

Nature. 1998 ; 394 (6689) : 145-151.

PMID 9671298

Stat3 activation is required for cellular transformation by v-src.

Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr

Molecular and cellular biology. 1998 ; 18 (5) : 2553-2558.

PMID 9566875

Stat3 as an oncogene.

Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr

Cell. 1999 ; 98 (3) : 295-303.

PMID 10458605

Roles of STAT3 defined by tissue-specific gene targeting.

Akira S

Oncogene. 2000 ; 19 (21) : 2607-2611.

PMID 10851059

Specific ablation of Stat3beta distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock.

Yoo JY, Huso DL, Nathans D, Desiderio S

Cell. 2002 ; 108 (3) : 331-344.

PMID 11853668

STAT3 signalling is required for leptin regulation of energy balance but not reproduction.

Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, Banks AS, Lavery HJ, Haq AK, Maratos-Flier E, Neel BG, Schwartz MW, Myers MG Jr

Nature. 2003 ; 421 (6925) : 856-859.

PMID 12594516

STATs dimerize in the absence of phosphorylation.

Braunstein J, Brutsaert S, Olson R, Schindler C

The Journal of biological chemistry. 2003 ; 278 (36) : 34133-34140.

PMID 12832402

Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells.

Konnikova L, Kotecki M, Kruger MM, Cochran BH

BMC cancer. 2003 ; 3 : page 23.

PMID 13678425

Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease.

Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, Eriksen KW, Woetmann A, ˆ̣dum N

The Journal of biological chemistry. 2003 ; 278 (19) : 16777-16781.

PMID 12615922

A novel sequence in the coiled-coil domain of Stat3 essential for its nuclear translocation.

Ma J, Zhang T, Novotny-Diermayr V, Tan AL, Cao X

The Journal of biological chemistry. 2003 ; 278 (31) : 29252-29260.

PMID 12746441

The STAT3 isoforms alpha and beta have unique and specific functions.

Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, Murray-Tait V, Chiarle R, Poli V

Nature immunology. 2004 ; 5 (4) : 401-409.

PMID 15021879

Activation of the STAT pathway in acute lung injury.

Severgnini M, Takahashi S, Rozo LM, Homer RJ, Kuhn C, Jhung JW, Perides G, Steer M, Hassoun PM, Fanburg BL, Cochran BH, Simon AR

American journal of physiology. Lung cellular and molecular physiology. 2004 ; 286 (6) : L1282-L1292.

PMID 14729509

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Contributor(s)

Written	05-2004	Brent H Cochran
		Dept. of Physiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA

Citation

This paper should be referenced as such :

Cochran BH . STAT3 (Signal Transducer and Activator of Transcription 3). Atlas Genet Cytogenet Oncol Haematol. May 2004 . URL : http://AtlasGeneticsOncology.org/Genes/STAT3ID444.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:17:44 2008