Biology:STAT3

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene.[1] It is a member of the STAT protein family.

Function

STAT3 is a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK), forms homo- or heterodimers, and translocates to the cell nucleus where it acts as a transcription activator. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as interferons, epidermal growth factor (EGF), Interleukin (IL-)5 and IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by Mitogen-activated protein kinases (MAPK)[2] and through c-src non-receptor tyrosine kinase.[3][4] STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis.[5]

STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[6] It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.[7]

STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases.[8] During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.[9]

STAT3 caused upregulation in E-selectin, a factor in metastasis of cancers.[10]

Hyperactivation of STAT3 occurs in COVID-19 infection and other viral infections.[11][12]

Clinical significance

Loss-of-function mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.[13]

Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts,[14] while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[15][16][17][18] It has anti-apoptotic as well as proliferative effects.[15]

STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.[19][20][21] In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown.

Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.[22]

Interactions

STAT3 has been shown to interact with:


Niclosamide seems to inhibit the STAT3 signalling pathway.[52]

Nicotinamide (a type of Vitamin B3) naturally inhibits STAT3.[53] However NAC (Acetylcysteine) inhibits STAT3 inhibitors.[54]

References

  1. ↑ "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway". Cell 77 (1): 63–71. April 1994. doi:10.1016/0092-8674(94)90235-6. PMID 7512451. 
  2. ↑ "p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth". Endocrine-Related Cancer 20 (2): 197–212. April 2013. doi:10.1530/ERC-12-0194. PMID 23329648. 
  3. ↑ "Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis". Oncogene 23 (48): 8017–23. October 2004. doi:10.1038/sj.onc.1208159. PMID 15489919. 
  4. ↑ "Structure, function, and regulation of STAT proteins". Molecular BioSystems 2 (11): 536–50. November 2006. doi:10.1039/B606246F. PMID 17216035. .
  5. ↑ "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Molecular and Cellular Biology 24 (21): 9390–400. November 2004. doi:10.1128/MCB.24.21.9390-9400.2004. 15485908. PMID 15485908. 
  6. ↑ "Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality". Proceedings of the National Academy of Sciences of the United States of America 94 (8): 3801–4. April 1997. doi:10.1073/pnas.94.8.3801. PMID 9108058. Bibcode: 1997PNAS...94.3801T. 
  7. ↑ "STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells". The EMBO Journal 18 (15): 4261–9. August 1999. doi:10.1093/emboj/18.15.4261. PMID 10428964. 
  8. ↑ "STAT3 regulates cytokine-mediated generation of inflammatory helper T cells". The Journal of Biological Chemistry 282 (13): 9358–63. March 2007. doi:10.1074/jbc.C600321200. PMID 17277312. 
  9. ↑ "T-cell STAT3 is required for the maintenance of humoral immunity to LCMV". European Journal of Immunology 45 (2): 418–27. February 2015. doi:10.1002/eji.201445060. PMID 25393615. 
  10. ↑ Coppo, R.; Orso, F.; Virga, F.; Dalmasso, A.; Baruffaldi, D.; Nie, L.; Clapero, F.; Dettori, D. et al. (2021). "ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3". Cancer Letters 510: 13–23. doi:10.1016/j.canlet.2021.04.005. ISSN 0304-3835. PMID 33862151. 
  11. ↑ Matsuyama T, Kubli SP, Yoshinaga SK, Pfeffer K, Mak TW (2020). "An aberrant STAT pathway is central to COVID-19.". Cell Death Differ 27 (12): 3209–3225. doi:10.1038/s41418-020-00633-7. PMID 33037393. 
  12. ↑ Chang Z, Wang Y, Zhou X, Long JE (2018). "STAT3 roles in viral infection: antiviral or proviral?". Future Virol 13 (8): 557–574. doi:10.2217/fvl-2018-0033. PMID 32201498. 
  13. ↑ "STAT3 signaling and the hyper-IgE syndrome". The New England Journal of Medicine 357 (16): 1655–8. October 2007. doi:10.1056/NEJMe078197. PMID 17881746. 
  14. ↑ "Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations". Blood 125 (4): 591–9. January 2015. doi:10.1182/blood-2014-09-602763. PMID 25359994. 
  15. ↑ 15.0 15.1 "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs". Current Cancer Drug Targets 6 (2): 107–21. March 2006. doi:10.2174/156800906776056491. PMID 16529541. 
  16. ↑ "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor". Cancer Research 66 (6): 3162–8. March 2006. doi:10.1158/0008-5472.CAN-05-3757. PMID 16540667. 
  17. ↑ "Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions". Molecular Cancer 5 (1): 15. April 2006. doi:10.1186/1476-4598-5-15. PMID 16603078. 
  18. ↑ "Activation of STAT3 is a marker of poor prognosis in human colorectal cancer". Oncology Reports 15 (6): 1445–51. June 2006. doi:10.3892/or.15.6.1445. PMID 16685378. 
  19. ↑ "Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway". Genes & Development 22 (4): 449–62. February 2008. doi:10.1101/gad.1606508. PMID 18258752. 
  20. ↑ "Signal transducer and activator of transcription 3 (STAT3) protein suppresses adenoma-to-carcinoma transition in Apcmin/+ mice via regulation of Snail-1 (SNAI) protein stability". The Journal of Biological Chemistry. 22 287 (22): 18182–9. May 2012. doi:10.1074/jbc.M111.328831. PMID 22496368. 
  21. ↑ "Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice". Gastroenterology 138 (3): 1003–11.e1–5. March 2010. doi:10.1053/j.gastro.2009.11.049. PMID 19962983. 
  22. ↑ Vlahopoulos, SA (August 2017). "Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode.". Cancer Biology & Medicine 14 (3): 254–270. doi:10.20892/j.issn.2095-3941.2017.0029. PMID 28884042. 
  23. ↑ 23.0 23.1 "Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways". The Journal of Biological Chemistry 277 (9): 7076–85. March 2002. doi:10.1074/jbc.M108255200. PMID 11751884. 
  24. ↑ "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications 283 (1): 179–87. April 2001. doi:10.1006/bbrc.2001.4758. PMID 11322786. 
  25. ↑ "A Stat3-interacting protein (StIP1) regulates cytokine signal transduction". Proceedings of the National Academy of Sciences of the United States of America 97 (18): 10120–5. August 2000. doi:10.1073/pnas.170192197. PMID 10954736. Bibcode: 2000PNAS...9710120C. 
  26. ↑ "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science 284 (5413): 479–82. April 1999. doi:10.1126/science.284.5413.479. PMID 10205054. Bibcode: 1999Sci...284..479N. 
  27. ↑ 27.0 27.1 "Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells". Molecular and Cellular Biology 24 (21): 9390–400. November 2004. doi:10.1128/MCB.24.21.9390-9400.2004. PMID 15485908. 
  28. ↑ "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". The Journal of Biological Chemistry 274 (24): 17209–18. June 1999. doi:10.1074/jbc.274.24.17209. PMID 10358079. 
  29. ↑ "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Experimental & Molecular Medicine 40 (5): 479–85. October 2008. doi:10.3858/emm.2008.40.5.479. PMID 18985005. 
  30. ↑ 30.0 30.1 "Constitutive activation of STAT transcription factors in acute myelogenous leukemia". European Journal of Haematology 67 (2): 63–71. August 2001. doi:10.1034/j.1600-0609.2001.t01-1-00385.x. PMID 11722592. 
  31. ↑ "Interacting regions in Stat3 and c-Jun that participate in cooperative transcriptional activation". Molecular and Cellular Biology 19 (10): 7138–46. October 1999. doi:10.1128/MCB.19.10.7138. PMID 10490649. 
  32. ↑ "Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway". Cellular Immunology 211 (1): 30–6. July 2001. doi:10.1006/cimm.2001.1815. PMID 11585385. 
  33. ↑ "Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR". Current Biology 10 (1): 47–50. January 2000. doi:10.1016/S0960-9822(99)00268-7. PMID 10660304. 
  34. ↑ "Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR)". The Journal of Biological Chemistry 280 (2): 1037–43. January 2005. doi:10.1074/jbc.M405204200. PMID 15522880. 
  35. ↑ "Reciprocal inhibition between MyoD and STAT3 in the regulation of growth and differentiation of myoblasts". The Journal of Biological Chemistry 278 (45): 44178–87. November 2003. doi:10.1074/jbc.M304884200. PMID 12947115. 
  36. ↑ "The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3". Proceedings of the National Academy of Sciences of the United States of America 100 (16): 9342–7. August 2003. doi:10.1073/pnas.1633516100. PMID 12867595. Bibcode: 2003PNAS..100.9342Z. 
  37. ↑ 37.0 37.1 "Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB". The Biochemical Journal 367 (Pt 1): 97–105. October 2002. doi:10.1042/BJ20020588. PMID 12057007. 
  38. ↑ "STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene". Genes & Development 17 (20): 2564–77. October 2003. doi:10.1101/gad.1135003. PMID 14522952. 
  39. ↑ "STAT3 acts as a co-activator of glucocorticoid receptor signaling". The Journal of Biological Chemistry 272 (49): 30607–10. December 1997. doi:10.1074/jbc.272.49.30607. PMID 9388192. 
  40. ↑ "Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a". The Journal of Biological Chemistry 277 (10): 8004–11. March 2002. doi:10.1074/jbc.M111486200. PMID 11773079. 
  41. ↑ "Opposing effects of PML and PML/RAR alpha on STAT3 activity". Blood 101 (9): 3668–73. May 2003. doi:10.1182/blood-2002-08-2474. PMID 12506013. 
  42. ↑ "Regulation of STAT3 by direct binding to the Rac1 GTPase". Science 290 (5489): 144–7. October 2000. doi:10.1126/science.290.5489.144. PMID 11021801. Bibcode: 2000Sci...290..144S. 
  43. ↑ "Activation of signal transducer and activator of transcription 3 by oncogenic RET/PTC (rearranged in transformation/papillary thyroid carcinoma) tyrosine kinase: roles in specific gene regulation and cellular transformation". Molecular Endocrinology 17 (6): 1155–66. June 2003. doi:10.1210/me.2002-0401. PMID 12637586. 
  44. ↑ "MEN2A-RET-induced cellular transformation by activation of STAT3". Oncogene 20 (38): 5350–8. August 2001. doi:10.1038/sj.onc.1204715. PMID 11536047. 
  45. ↑ "Replication protein a 32 kDa subunit (RPA p32) binds the SH2 domain of STAT3 and regulates its transcriptional activity". Cell Biology International 24 (7): 467–73. 2000. doi:10.1006/cbir.2000.0525. PMID 10875894. 
  46. ↑ "Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin". Biochemical and Biophysical Research Communications 288 (1): 252–7. October 2001. doi:10.1006/bbrc.2001.5759. PMID 11594781. 
  47. ↑ "Identification of both positive and negative domains within the epidermal growth factor receptor COOH-terminal region for signal transducer and activator of transcription (STAT) activation". The Journal of Biological Chemistry 277 (34): 30716–23. August 2002. doi:10.1074/jbc.M202823200. PMID 12070153. 
  48. ↑ "Stat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1". Nature Communications 8: 15289. May 2017. doi:10.1038/ncomms15289. PMID 28474672. Bibcode: 2017NatCo...815289M. 
  49. ↑ "Activation and association of Stat3 with Src in v-Src-transformed cell lines". Molecular and Cellular Biology 16 (4): 1595–603. April 1996. doi:10.1128/MCB.16.4.1595. PMID 8657134. 
  50. ↑ "Activation of Stat3 transcription factor by Herpesvirus saimiri STP-A oncoprotein". Journal of Virology 78 (12): 6489–97. June 2004. doi:10.1128/JVI.78.12.6489-6497.2004. PMID 15163742. 
  51. ↑ "STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3". Proceedings of the National Academy of Sciences of the United States of America 102 (23): 8150–5. June 2005. doi:10.1073/pnas.0501643102. PMID 15919823. Bibcode: 2005PNAS..102.8150L. 
  52. ↑ "Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway". ACS Medicinal Chemistry Letters 1 (9): 454–9. 2010. doi:10.1021/ml100146z. PMID 24900231. 
  53. ↑ Wang W, Hu Y, Yang C, Zhu S, Wang X, Zhang Z (2018). "Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial-Mesenchymal Transition.". Mol Cell Proteomics 17 (10): 2005–2017. doi:10.1074/mcp.RA118.000882. PMID 29980616. 
  54. ↑ Uchihara Y, Ohe T, Mashino T, Kidokoro T, Tago K, Tamura H (2019). "N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties.". Pharmacol Rep 71 (6): 1067–1078. doi:10.1016/j.pharep.2019.05.021. PMID 31627175. https://pubmed.ncbi.nlm.nih.gov/31627175. 

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