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STAT6
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. 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.

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Molecular biology

In the human genome, STAT6 protein is encoded by the STAT6 gene, located on the chromosome 12q13.3-q14.1.3 The gene encompasses over 19 kb and consists of 23 exons.4 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).5

STAT proteins are activated by the Janus family (JAKs) tyrosine kinases in response to cytokine exposure.6 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).7 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.89

Function

STAT6-mediated signaling pathway is required for the development of T-helper type 2 (Th2) cells and Th2 immune response.10 Expression of Th2 cytokines, including IL-4, IL-13, and IL-5, was reduced in STAT6-deficient mice.11 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.12 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.13

Activation of STAT6 signaling pathway is necessary in macrophage function, and is required for the M2 subtype activation of macrophages.141516 STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation.17 STAT6 is also required for the development of IL-9-secreting T cells.18

STAT6 also plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma.19 Th2-cell derived cytokines as IL-4 and IL-13 induce the production of IgE which is  a major mediator in allergic response.20 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).21

Interactions

STAT6 has been shown to interact with:

Pathology

See also

Further reading

References

  1. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  2. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  3. 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. https://zenodo.org/record/1229761 ↩

  4. 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. https://doi.org/10.5507%2Fbp.2013.043 ↩

  5. 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. https://doi.org/10.5507%2Fbp.2013.043 ↩

  6. Walford HH, Doherty TA (October 2013). "STAT6 and lung inflammation". JAK-STAT. 2 (4): e25301. doi:10.4161/jkst.25301. PMC 3876430. PMID 24416647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876430 ↩

  7. Walford HH, Doherty TA (October 2013). "STAT6 and lung inflammation". JAK-STAT. 2 (4): e25301. doi:10.4161/jkst.25301. PMC 3876430. PMID 24416647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876430 ↩

  8. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  9. 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. /wiki/Doi_(identifier) ↩

  10. Walford HH, Doherty TA (October 2013). "STAT6 and lung inflammation". JAK-STAT. 2 (4): e25301. doi:10.4161/jkst.25301. PMC 3876430. PMID 24416647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876430 ↩

  11. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  12. 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. https://doi.org/10.1016%2Fj.cell.2011.09.022 ↩

  13. "STAT6 signal transducer and activator of transcription 6 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-05-01. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=6778 ↩

  14. Binnemars-Postma K, Bansal R, Storm G, Prakash J (February 2018). "Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer". FASEB Journal. 32 (2): 969–978. doi:10.1096/fj.201700629R. PMID 29066614. S2CID 3342014. https://doi.org/10.1096%2Ffj.201700629R ↩

  15. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484610 ↩

  16. 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. 978-1-4939-9194-5 ↩

  17. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  18. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107597 ↩

  19. Walford HH, Doherty TA (October 2013). "STAT6 and lung inflammation". JAK-STAT. 2 (4): e25301. doi:10.4161/jkst.25301. PMC 3876430. PMID 24416647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876430 ↩

  20. 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. /wiki/Doi_(identifier) ↩

  21. 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. https://doi.org/10.5507%2Fbp.2013.043 ↩

  22. 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. /wiki/Doi_(identifier) ↩

  23. 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. https://doi.org/10.1074%2Fjbc.M108132200 ↩

  24. 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. /wiki/Doi_(identifier) ↩

  25. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195723 ↩

  26. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC108921 ↩

  27. 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. https://doi.org/10.1074%2Fjbc.M108132200 ↩

  28. 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. https://doi.org/10.1074%2Fjbc.M203556200 ↩

  29. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC126276 ↩

  30. Zhou Z, Yao J, Wu D, Huang X, Wang Y, Li X, et al. (12 March 2024). "Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging". Immunity. 57 (3): 513–527.e6. doi:10.1016/j.immuni.2024.01.001. /wiki/Doi_(identifier) ↩

  31. 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. https://doi.org/10.1200%2FJCO.2005.00.232 ↩

  32. 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. https://doi.org/10.1038%2Fmodpathol.2013.247 ↩