Protein and coding gene in humans
Signal transducer and activator of transcription 6 (STAT6 ) is a
transcription factor that belongs to the
Signal Transducer and Activator of Transcription (STAT) family of proteins.
[5] The
proteins of STAT family transmit signals from a
receptor complex to the nucleus and activate
gene expression . Similarly as other STAT family proteins, STAT6 is also activated by
growth factors and
cytokines . STAT6 is mainly activated by cytokines
interleukin-4 and
interleukin-13 .
[5]
Molecular biology
In the
human genome , STAT6 protein is encoded by the STAT6 gene, located on the
chromosome 12q13.3-q14.1.
[6] The gene encompasses over 19 kb and consists of 23
exons .
[7] STAT6 shares structural similarity with the other STAT proteins and is composed of the
N-terminal domain ,
DNA binding domain , SH3- like domain,
SH2 domain and transactivation domain (TAD).
[7]
STAT proteins are activated by the
Janus family (JAKs) tyrosine kinases in response to cytokine exposure.
[8] STAT6 is activated by cytokines interleukin-4 (IL-4), and interleukin-13 (IL-13) with their receptors that both contain the α subunit of the
IL-4 receptor (IL-4Rα).
[8] Tyrosine phosporylation of STAT6 after stimulation by IL-4 results in the formation of STAT6 homodimers that bind specific DNA elements via a DNA-binding domain.
[5]
[9]
Function
STAT6-mediated signaling pathway is required for the development of T-helper type 2 (Th2) cells and Th2 immune response.
[8] Expression of Th2 cytokines, including
IL-4 ,
IL-13 , and
IL-5 , was reduced in STAT6-deficient mice.
[5] STAT 6 protein is crucial in IL4 mediated biological responses. It was found that STAT6 induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. IL-4 stimulates the phosphorylation of IL-4 receptor, which recruits cytosolic STAT6 by its SH2 domain and STAT6 is phosphorylated on tyrosine 641 (Y641) by
JAK1 , which results in the dimerization and nuclear translocation of STAT6 to activate target genes.
[10]
Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of
immunoglobulins .
[11]
Activation of STAT6 signaling pathway is necessary in
macrophage function, and is required for the M2 subtype activation of macrophages.
[12]
[13]
[14] STAT6 protein also regulates other transcription factor as
Gata3 , which is important regulator of Th2 differentiation.
[5] STAT6 is also required for the development of
IL-9 -secreting
T cells .
[5]
STAT6 also plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma.
[8] Th2-cell derived cytokines as IL-4 and IL-13 induce the production of
IgE which is a major mediator in allergic response.
[9] Association studies searching for relation of polymorphisms in STAT6 with IgE level or asthma discovered a few
polymorphisms significantly associated with examined traits. Only two polymorphisms showed repeatedly significant clinical association and/or functional effect on STAT6 function (GT repeats in exon 1 and rs324011 polymorphism in intron 2).
[7]
Interactions
STAT6 has been shown to
interact with:
Pathology
Gene fusion
Amplification
STAT6 is amplified in a subset of dedifferentiated liposarcoma.
[22]
See also
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000166888 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000002147 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
a
b
c
d
e
f Goenka S, Kaplan MH (May 2011).
"Transcriptional regulation by STAT6" . Immunologic Research . 50 (1): 87–96.
doi :
10.1007/s12026-011-8205-2 .
PMC
3107597 .
PMID
21442426 .
^ Patel BK, Keck CL, O'Leary RS, Popescu NC, LaRochelle WJ (September 1998).
"Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a region implicated in multiple solid tumors" . Genomics . 52 (2): 192–200.
doi :
10.1006/geno.1998.5436 .
PMID
9782085 .
^
a
b
c Godava M, Vrtel R, Vodicka R (June 2013).
"STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma" . Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia . 157 (2): 172–80.
doi :
10.5507/bp.2013.043 .
PMID
23752766 .
^
a
b
c
d Walford HH, Doherty TA (October 2013).
"STAT6 and lung inflammation" . JAK-STAT . 2 (4): e25301.
doi :
10.4161/jkst.25301 .
PMC
3876430 .
PMID
24416647 .
^
a
b Leek JP, Hamlin PJ, Bell SM, Lench NJ (1997). "Assignment of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ hybridization". Cytogenetics and Cell Genetics . 79 (3–4): 208–9.
doi :
10.1159/000134723 .
PMID
9605853 .
^ Chen H, Sun H, You F, Sun W, Zhou X, Chen L, et al. (October 2011).
"Activation of STAT6 by STING is critical for antiviral innate immunity" . Cell . 147 (2): 436–46.
doi :
10.1016/j.cell.2011.09.022 .
PMID
22000020 .
^
"STAT6 signal transducer and activator of transcription 6 [Homo sapiens (human)] - Gene - NCBI" . www.ncbi.nlm.nih.gov . Retrieved 2021-05-01 .
^ Binnemars-Postma, Karin; Bansal, Ruchi; Storm, Gert; Prakash, Jai (February 2018).
"Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer" . The FASEB Journal . 32 (2): 969–978.
doi :
10.1096/fj.201700629R .
ISSN
0892-6638 .
PMID
29066614 .
S2CID
3342014 .
^ Gong M, Zhuo X, Ma A (June 2017).
"STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis" . Medical Science Monitor Basic Research . 23 : 240–249.
doi :
10.12659/msmbr.904014 .
PMC
5484610 .
PMID
28615615 .
^ Waqas SF, Ampem G, Röszer T (2019). "Analysis of IL-4/STAT6 Signaling in Macrophages". Nuclear Receptors . Methods in Molecular Biology. Vol. 1966. pp. 211–224.
doi :
10.1007/978-1-4939-9195-2_17 .
ISBN
978-1-4939-9194-5 .
PMID
31041750 .
S2CID
141465649 .
^
a
b McDonald C, Reich NC (July 1999). "Cooperation of the transcriptional coactivators CBP and p300 with Stat6". Journal of Interferon & Cytokine Research . 19 (7): 711–22.
doi :
10.1089/107999099313550 .
PMID
10454341 .
^
a
b Litterst CM, Pfitzner E (December 2001).
"Transcriptional activation by STAT6 requires the direct interaction with NCoA-1" . The Journal of Biological Chemistry . 276 (49): 45713–21.
doi :
10.1074/jbc.M108132200 .
PMID
11574547 .
^ Gupta S, Jiang M, Anthony A, Pernis AB (December 1999).
"Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4" . The Journal of Experimental Medicine . 190 (12): 1837–48.
doi :
10.1084/jem.190.12.1837 .
PMC
2195723 .
PMID
10601358 .
^ Shen CH, Stavnezer J (June 1998).
"Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription" . Molecular and Cellular Biology . 18 (6): 3395–404.
doi :
10.1128/mcb.18.6.3395 .
PMC
108921 .
PMID
9584180 .
^ Litterst CM, Pfitzner E (September 2002).
"An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1" . The Journal of Biological Chemistry . 277 (39): 36052–60.
doi :
10.1074/jbc.M203556200 .
PMID
12138096 .
^ Yang J, Aittomäki S, Pesu M, Carter K, Saarinen J, Kalkkinen N, et al. (September 2002).
"Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II" . The EMBO Journal . 21 (18): 4950–8.
doi :
10.1093/emboj/cdf463 .
PMC
126276 .
PMID
12234934 .
^ Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S (June 2005).
"Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer" . Journal of Clinical Oncology . 23 (16): 3706–12.
doi :
10.1200/JCO.2005.00.232 .
PMID
15867200 .
^ Doyle LA, Tao D, Mariño-Enríquez A (September 2014).
"STAT6 is amplified in a subset of dedifferentiated liposarcoma" . Modern Pathology . 27 (9): 1231–7.
doi :
10.1038/modpathol.2013.247 .
PMID
24457460 .
Further reading
Jiang H, Harris MB, Rothman P (June 2000).
"IL-4/IL-13 signaling beyond JAK/STAT" . The Journal of Allergy and Clinical Immunology . 105 (6 Pt 1): 1063–70.
doi :
10.1067/mai.2000.107604 .
PMID
10856136 .
Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (February 2002). "Signaling through the JAK/STAT pathway, recent advances and future challenges". Gene . 285 (1–2): 1–24.
doi :
10.1016/S0378-1119(02)00398-0 .
PMID
12039028 .
Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (September 1994). "An interleukin-4-induced transcription factor: IL-4 Stat". Science . 265 (5179): 1701–6.
Bibcode :
1994Sci...265.1701H .
doi :
10.1126/science.8085155 .
PMID
8085155 .
Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. (April 1996). "Essential role of Stat6 in IL-4 signalling". Nature . 380 (6575): 627–30.
Bibcode :
1996Natur.380..627T .
doi :
10.1038/380627a0 .
PMID
8602263 .
S2CID
4340375 .
Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al. (April 1996). "Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene". Nature . 380 (6575): 630–3.
Bibcode :
1996Natur.380..630S .
doi :
10.1038/380630a0 .
PMID
8602264 .
S2CID
4334441 .
Kotanides H, Reich NC (October 1996).
"Interleukin-4-induced STAT6 recognizes and activates a target site in the promoter of the interleukin-4 receptor gene" . The Journal of Biological Chemistry . 271 (41): 25555–61.
doi :
10.1074/jbc.271.41.25555 .
PMID
8810328 .
Mikita T, Campbell D, Wu P, Williamson K, Schindler U (October 1996).
"Requirements for interleukin-4-induced gene expression and functional characterization of Stat6" . Molecular and Cellular Biology . 16 (10): 5811–20.
doi :
10.1128/mcb.16.10.5811 .
PMC
231582 .
PMID
8816495 .
Shen CH, Stavnezer J (June 1998).
"Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription" . Molecular and Cellular Biology . 18 (6): 3395–404.
doi :
10.1128/mcb.18.6.3395 .
PMC
108921 .
PMID
9584180 .
Leek JP, Hamlin PJ, Bell SM, Lench NJ (1998). "Assignment of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ hybridization". Cytogenetics and Cell Genetics . 79 (3–4): 208–9.
doi :
10.1159/000134723 .
PMID
9605853 .
Mikita T, Kurama M, Schindler U (August 1998).
"Synergistic activation of the germline epsilon promoter mediated by Stat6 and C/EBP beta" . Journal of Immunology . 161 (4): 1822–8.
doi :
10.4049/jimmunol.161.4.1822 .
PMID
9712049 .
S2CID
82211469 .
Patel BK, Keck CL, O'Leary RS, Popescu NC, LaRochelle WJ (September 1998).
"Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a region implicated in multiple solid tumors" . Genomics . 52 (2): 192–200.
doi :
10.1006/geno.1998.5436 .
PMID
9782085 .
Zhu M, John S, Berg M, Leonard WJ (January 1999).
"Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling" . Cell . 96 (1): 121–30.
doi :
10.1016/S0092-8674(00)80965-4 .
PMID
9989503 .
S2CID
14758136 .
McDonald C, Reich NC (July 1999). "Cooperation of the transcriptional coactivators CBP and p300 with Stat6". Journal of Interferon & Cytokine Research . 19 (7): 711–22.
doi :
10.1089/107999099313550 .
PMID
10454341 .
Harris MB, Chang CC, Berton MT, Danial NN, Zhang J, Kuehner D, et al. (October 1999).
"Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching" . Molecular and Cellular Biology . 19 (10): 7264–75.
doi :
10.1128/mcb.19.10.7264 .
PMC
84719 .
PMID
10490661 .
Gupta S, Jiang M, Pernis AB (October 1999).
"IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells" . Journal of Immunology . 163 (7): 3834–41.
doi :
10.4049/jimmunol.163.7.3834 .
PMID
10490982 .
S2CID
255676952 .
Gupta S, Jiang M, Anthony A, Pernis AB (December 1999).
"Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4" . The Journal of Experimental Medicine . 190 (12): 1837–48.
doi :
10.1084/jem.190.12.1837 .
PMC
2195723 .
PMID
10601358 .
Daniel C, Salvekar A, Schindler U (May 2000).
"A gain-of-function mutation in STAT6" . The Journal of Biological Chemistry . 275 (19): 14255–9.
doi :
10.1074/jbc.C000129200 .
PMID
10747856 .
Arinobu Y, Sugimoto R, Akaiwa M, Arima K, Otsuka T, Hamasaki N, Izuhara K (October 2000). "Augmentation of signal transducer and activation of transcription (STAT)6 and STAT3 expression in stimulated B and T cells". Biochemical and Biophysical Research Communications . 277 (2): 317–24.
doi :
10.1006/bbrc.2000.3674 .
PMID
11032724 .
Masuda A, Matsuguchi T, Yamaki K, Hayakawa T, Yoshikai Y (July 2001).
"Interleukin-15 prevents mouse mast cell apoptosis through STAT6-mediated Bcl-xL expression" . The Journal of Biological Chemistry . 276 (28): 26107–13.
doi :
10.1074/jbc.M011475200 .
PMID
11369758 .
External links
(1) Basic domains
(1.1) Basic
leucine zipper (
bZIP )(1.2) Basic helix-loop-helix (
bHLH )
Group A Group B Group C bHLH-
PAS Group D Group E Group F bHLH-COE
(1.3)
bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2)
Zinc finger DNA-binding domains
(2.1)
Nuclear receptor (Cys4 )
subfamily 1 subfamily 2 subfamily 3 subfamily 4 subfamily 5 subfamily 6 subfamily 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4) β-Scaffold factors with minor groove contacts
(0) Other transcription factors
Chemokine
CSF
Interferon
IFNAR (α/β, I)
Agonists:
Albinterferon
Interferon alpha (interferon alfa, IFN-α)
Interferon alfa (
IFNA1 ,
IFNA2 ,
IFNA4 ,
IFNA5 ,
IFNA6 ,
IFNA7 ,
IFNA8 ,
IFNA10 ,
IFNA13 ,
IFNA14 ,
IFNA16 ,
IFNA17 ,
IFNA21 )
Interferon alfa 2a
Interferon alfa 2b
Interferon alfa n1
Interferon alfacon-1
Interferon alpha-n3
Interferon beta (IFN-β) (
IFNB1 ,
IFNB3 )
Interferon beta 1a
Interferon beta 1b
Interferon kappa (IFN-ε/κ/τ/ζ, IFNK)
Interferon omega (IFN-ω, IFNW1)
Peginterferon alfa-2a
Peginterferon alfa-2b
IFNGR (γ, II)
IFNLR (λ, III)
See IL-28R (IFNLR)
here instead.
Interleukin
TGFβ
TNF Others