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Gene Review

Stat1  -  signal transducer and activator of...

Mus musculus

Synonyms: 2010005J02Rik, AA408197, Signal transducer and activator of transcription 1
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Disease relevance of Stat1


High impact information on Stat1

  • Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease [6].
  • Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 and Shp2-Ras-Erk signaling pathways [7].
  • G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes [8].
  • Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is only tyrosine-phosphorylated after stimulation of T cells with interleukin (IL)-12 (refs 6,7) [9].
  • Actually, Stat1 interacts with Runx2 in its latent form in the cytoplasm, thereby inhibiting the nuclear localization of Runx2, an essential transcription factor for osteoblast differentiation [10].

Biological context of Stat1


Anatomical context of Stat1


Associations of Stat1 with chemical compounds

  • Jak PTK activation by these IFNs is commonly followed by tyrosine phosphorylation of the transcription factor Stat1 at Y701, which is essential for dimerization, translocation to the nucleus and DNA-binding activity [11].
  • Two weeks after bleomycin aspiration (3 U/kg), Stat1-/- mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice [1].
  • These studies show that several Stat, including phosphotyrosine Stat3, are present in TG neurons, the site of HSV latency, where they could act upon latent viral DNA to effect reactivation [2].
  • LPS+IFNgamma or hydrogen peroxide activated the Jak2/Stat1/IRF1 pathway and this effect was also inhibited by ascorbate [19].
  • A similar deficiency in LPS-induced gene expression was observed in livers and spleens from Stat1-/- mice [20].

Physical interactions of Stat1

  • The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins [21].
  • Whereas NF-kappaB was constitutively expressed in both cell types, Stat1 phosphorylation and nuclear binding activity were dependent upon IFN-gamma [22].
  • In macrophages, this was associated with complete inhibition of NF-kappaB nuclear binding activity and partial (approximately 20-25%) reduction of Stat1 activity [22].
  • EMSA analysis using a Stat 5 binding site showed both PRLs to cause equivalent binding of nuclear proteins and that most of what bound was complexed through Stat 5a [23].
  • Constitutive activation of Stat-related DNA-binding proteins in erythroid cells by the Friend spleen focus-forming virus [24].

Enzymatic interactions of Stat1

  • Stat1 was phosphorylated by IFN-alpha in Tyk2-deficient cells, although the level of phosphorylation was weaker than that observed in wild type mice [25].
  • The new function of Stat1 does not require the Tyr 701 that is phosphorylated when Stat1 becomes a transcriptional activator [10].
  • When expressed, SOCS-3 binds to phosphorylated Tyr(960) of the insulin receptor and prevents Stat 5B activation by insulin [26].
  • Studies are in progress to identify the mechanism by which Stat proteins are phosphorylated in SFFV-infected cells in the absence of Epo [24].
  • In fact, the two Stat proteins were tyrosine phosphorylated in IFN-gamma stimulated cells [27].

Regulatory relationships of Stat1

  • While IFN-alpha (1000 U/ml) suppressed the number of granulocyte-macrophage colony-forming units (CFU-GM) or erythroid burst-forming units (BFU-E) from wild-type mouse bone marrow cells, this suppression was partially inhibited by a deficiency in Tyk2 and completely inhibited by a deficiency in Stat1 [25].
  • Stat 1 and 3 were also activated presumably downstream to JAK2 activation [28].
  • In fact, IL-6-induced activation of the Stat1 and Stat3 transcription factors is markedly diminished in the absence of the IFN-alpha/beta signalling complex [29].
  • In the case of growth factors whose receptors have intrinsic tyrosine protein kinase activity, it is thought that Stat proteins can be activated either directly by the receptor or indirectly through JAK proteins [30].
  • The effect of flagellin on iNOS gene expression was inhibited by a Stat1 mutant protein [31].

Other interactions of Stat1

  • Phosphorylation of Stat1 by limitin is partially dependent on Tyk2 [32].
  • Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LPS [33].
  • Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by induction and nuclear translocation of Daxx [32].
  • However, at low suboptimal doses of IFN-gamma, Stat1 activation was decreased in TLR2-stimulated cells [34].
  • The peptide data also indicate that p77 and p80 are phosphorylated on tyrosine 699, a position analogous to the tyrosine that is phosphorylated in Stat1 and Stat2 in response to interferon [35].

Analytical, diagnostic and therapeutic context of Stat1


  1. Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis. Walters, D.M., Antao-Menezes, A., Ingram, J.L., Rice, A.B., Nyska, A., Tani, Y., Kleeberger, S.R., Bonner, J.C. Am. J. Pathol. (2005) [Pubmed]
  2. Signal transducers and activators of transcription (Stat) are detectable in mouse trigeminal ganglion neurons. Kriesel, J.D., Jones, B.B., Hwang, I.P., Dahms, K.M., Spruance, S.L. J. Interferon Cytokine Res. (2001) [Pubmed]
  3. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Varinou, L., Ramsauer, K., Karaghiosoff, M., Kolbe, T., Pfeffer, K., Müller, M., Decker, T. Immunity (2003) [Pubmed]
  4. Resolution of primary severe acute respiratory syndrome-associated coronavirus infection requires Stat1. Hogan, R.J., Gao, G., Rowe, T., Bell, P., Flieder, D., Paragas, J., Kobinger, G.P., Wivel, N.A., Crystal, R.G., Boyer, J., Feldmann, H., Voss, T.G., Wilson, J.M. J. Virol. (2004) [Pubmed]
  5. All four Sendai Virus C proteins bind Stat1, but only the larger forms also induce its mono-ubiquitination and degradation. Garcin, D., Marq, J.B., Strahle, L., le Mercier, P., Kolakofsky, D. Virology (2002) [Pubmed]
  6. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Durbin, J.E., Hackenmiller, R., Simon, M.C., Levy, D.E. Cell (1996) [Pubmed]
  7. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Jenkins, B.J., Grail, D., Nheu, T., Najdovska, M., Wang, B., Waring, P., Inglese, M., McLoughlin, R.M., Jones, S.A., Topley, N., Baumann, H., Judd, L.M., Giraud, A.S., Boussioutas, A., Zhu, H.J., Ernst, M. Nat. Med. (2005) [Pubmed]
  8. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Harada, M., Qin, Y., Takano, H., Minamino, T., Zou, Y., Toko, H., Ohtsuka, M., Matsuura, K., Sano, M., Nishi, J., Iwanaga, K., Akazawa, H., Kunieda, T., Zhu, W., Hasegawa, H., Kunisada, K., Nagai, T., Nakaya, H., Yamauchi-Takihara, K., Komuro, I. Nat. Med. (2005) [Pubmed]
  9. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Thierfelder, W.E., van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Sangster, M.Y., Vignali, D.A., Doherty, P.C., Grosveld, G.C., Ihle, J.N. Nature (1996) [Pubmed]
  10. Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Kim, S., Koga, T., Isobe, M., Kern, B.E., Yokochi, T., Chin, Y.E., Karsenty, G., Taniguchi, T., Takayanagi, H. Genes Dev. (2003) [Pubmed]
  11. Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-gamma, but not IFN-alpha, signaling. Takaoka, A., Tanaka, N., Mitani, Y., Miyazaki, T., Fujii, H., Sato, M., Kovarik, P., Decker, T., Schlessinger, J., Taniguchi, T. EMBO J. (1999) [Pubmed]
  12. Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Yamamoto, K., Quelle, F.W., Thierfelder, W.E., Kreider, B.L., Gilbert, D.J., Jenkins, N.A., Copeland, N.G., Silvennoinen, O., Ihle, J.N. Mol. Cell. Biol. (1994) [Pubmed]
  13. Activation of Tyk2 and Stat3 is required for the apoptotic actions of interferon-beta in primary pro-B cells. Gamero, A.M., Potla, R., Wegrzyn, J., Szelag, M., Edling, A.E., Shimoda, K., Link, D.C., Dulak, J., Baker, D.P., Tanabe, Y., Grayson, J.M., Larner, A.C. J. Biol. Chem. (2006) [Pubmed]
  14. IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-gamma. Saito, H., Morita, Y., Fujimoto, M., Narazaki, M., Naka, T., Kishimoto, T. J. Immunol. (2000) [Pubmed]
  15. A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Wang, C.Z., Su, H.W., Hsu, Y.C., Shen, M.R., Tang, M.J. Mol. Biol. Cell (2006) [Pubmed]
  16. Stat1 controls postnatal bone formation by regulating fibroblast growth factor signaling in osteoblasts. Xiao, L., Naganawa, T., Obugunde, E., Gronowicz, G., Ornitz, D.M., Coffin, J.D., Hurley, M.M. J. Biol. Chem. (2004) [Pubmed]
  17. IFN-gamma induces apoptosis in developing mast cells. Mann-Chandler, M.N., Kashyap, M., Wright, H.V., Norozian, F., Barnstein, B.O., Gingras, S., Parganas, E., Ryan, J.J. J. Immunol. (2005) [Pubmed]
  18. A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion. Navarro, A., Anand-Apte, B., Tanabe, Y., Feldman, G., Larner, A.C. J. Leukoc. Biol. (2003) [Pubmed]
  19. Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells. Wu, F., Schuster, D.P., Tyml, K., Wilson, J.X. Free Radic. Biol. Med. (2007) [Pubmed]
  20. Requirement for STAT1 in LPS-induced gene expression in macrophages. Ohmori, Y., Hamilton, T.A. J. Leukoc. Biol. (2001) [Pubmed]
  21. Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. Campbell, G.S., Meyer, D.J., Raz, R., Levy, D.E., Schwartz, J., Carter-Su, C. J. Biol. Chem. (1995) [Pubmed]
  22. UVB light suppresses nitric oxide production by murine keratinocytes and macrophages. Sur, R., Heck, D.E., Mariano, T.M., Jin, Y., Murphy, W.J., Laskin, J.D. Biochem. Pharmacol. (2002) [Pubmed]
  23. Different biological effects of unmodified prolactin and a molecular mimic of phosphorylated prolactin involve different signaling pathways. Wu, W., Coss, D., Lorenson, M.Y., Kuo, C.B., Xu, X., Walker, A.M. Biochemistry (2003) [Pubmed]
  24. Constitutive activation of Stat-related DNA-binding proteins in erythroid cells by the Friend spleen focus-forming virus. Ohashi, T., Masuda, M., Ruscetti, S.K. Leukemia (1997) [Pubmed]
  25. Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth. Kato, K., Kamezaki, K., Shimoda, K., Numata, A., Haro, T., Aoki, K., Ishikawa, F., Takase, K., Ariyama, H., Matsuda, T., Miyamoto, T., Nagafuji, K., Gondo, H., Nakayama, K., Harada, M. Br. J. Haematol. (2003) [Pubmed]
  26. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. Emanuelli, B., Peraldi, P., Filloux, C., Chavey, C., Freidinger, K., Hilton, D.J., Hotamisligil, G.S., Van Obberghen, E. J. Biol. Chem. (2001) [Pubmed]
  27. Activation of the transcription factor ISGF3 by interferon-gamma. Matsumoto, M., Tanaka, N., Harada, H., Kimura, T., Yokochi, T., Kitagawa, M., Schindler, C., Taniguchi, T. Biol. Chem. (1999) [Pubmed]
  28. Prolactin concurrently activates src-PLD and JAK/Stat signaling pathways to induce proliferation while promoting differentiation in embryonic astrocytes. Mangoura, D., Pelletiere, C., Leung, S., Sakellaridis, N., Wang, D.X. Int. J. Dev. Neurosci. (2000) [Pubmed]
  29. Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling. Mitani, Y., Takaoka, A., Kim, S.H., Kato, Y., Yokochi, T., Tanaka, N., Taniguchi, T. Genes Cells (2001) [Pubmed]
  30. In vitro activation of Stat3 by epidermal growth factor receptor kinase. Park, O.K., Schaefer, T.S., Nathans, D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  31. Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes. Mizel, S.B., Honko, A.N., Moors, M.A., Smith, P.S., West, A.P. J. Immunol. (2003) [Pubmed]
  32. Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by induction and nuclear translocation of Daxx. Aoki, K., Shimoda, K., Oritani, K., Matsuda, T., Kamezaki, K., Muromoto, R., Numata, A., Tamiya, S., Haro, T., Ishikawa, F., Takase, K., Yamamoto, T., Yumioka, T., Miyamoto, T., Nagafuji, K., Gondo, H., Nagafuchi, S., Nakayama, K., Harada, M. Exp. Hematol. (2003) [Pubmed]
  33. The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals. Kamezaki, K., Shimoda, K., Numata, A., Matsuda, T., Nakayama, K., Harada, M. Int. Immunol. (2004) [Pubmed]
  34. Toll-like receptor 2 stimulation decreases IFN-gamma receptor expression in mouse RAW264.7 macrophages. Curry, H., Alvarez, G.R., Zwilling, B.S., Lafuse, W.P. J. Interferon Cytokine Res. (2004) [Pubmed]
  35. Interleukin-3 signals through multiple isoforms of Stat5. Azam, M., Erdjument-Bromage, H., Kreider, B.L., Xia, M., Quelle, F., Basu, R., Saris, C., Tempst, P., Ihle, J.N., Schindler, C. EMBO J. (1995) [Pubmed]
  36. Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Ho, J.M., Beattie, B.K., Squire, J.A., Frank, D.A., Barber, D.L. Blood (1999) [Pubmed]
  37. Interferon-gamma-induced MHC class I expression and defects in Jak/Stat signalling in methylcholanthrene-induced sarcomas. Svane, I.M., Engel, A.M., Nielsen, M., Werdelin, O. Scand. J. Immunol. (1997) [Pubmed]
  38. The Role of Interleukin-11 in Pregnancy Involves Up-Regulation of {alpha}2-Macroglobulin Gene through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 Pathway in the Decidua. Bao, L., Devi, S., Bowen-Shauver, J., Ferguson-Gottschall, S., Robb, L., Gibori, G. Mol. Endocrinol. (2006) [Pubmed]
  39. Specific activation of AP-1 but not Stat3 in regenerating liver in mice. Heim, M.H., Gamboni, G., Beglinger, C., Gyr, K. Eur. J. Clin. Invest. (1997) [Pubmed]
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