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Gene Review

STAT4  -  signal transducer and activator of...

Homo sapiens

Synonyms: Signal transducer and activator of transcription 4
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Disease relevance of STAT4


High impact information on STAT4

  • Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells [8].
  • Here, we show that loss of GATA-3 expression by developing Th1 cells requires IL-12 signaling through Stat4 and does not simply result from an absence of IL-4 [9].
  • Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors [10].
  • In some cases known pathways may be used, as in the dendritic cell subset 1 exerting TH1 polarization by interleukin 12 (IL-12) production and STAT4 activation [11].
  • Expression of IL-12Rbeta2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-alpha/IFN-alphaR ligation resulted in Stat4 activation in both control and IL-12Rbeta1-deficient cells [12].

Chemical compound and disease context of STAT4


Biological context of STAT4


Anatomical context of STAT4


Associations of STAT4 with chemical compounds

  • Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation [19].
  • Our aim was to investigate the effects of dexamethasone on STAT4 activation by IFN-beta and IL-12 in human T cell blasts [20].
  • Moreover, IL-12 activation of STAT4 in human peripheral blood-derived T cells is not accompanied by stimulation of the Ras guanine nucleotide binding cycle or stimulation of MAPK Erk1,2 or initiation of the PI3K signaling pathways [21].
  • We show that STAT4 has a unique peptide specificity and binds to the peptide sequence pYLPSNID (where pY represents phosphotyrosine) [22].
  • A series of alanine replacements was performed in this phosphopeptide to elucidate which amino acids surrounding the pTyr800 residue are critical for STAT4 binding [23].

Physical interactions of STAT4

  • We then investigated the role of Ik binding elements in the human STAT4 promoter using Jurkat T cells [24].
  • To summarize, the site on the IL-12 receptor which binds STAT4 can be described as -T-X-X-G-pY(800)-L-, where the core G-pY(800)-L motif is critical for the binding; the threonine at the pY-4 position has only a minor contribution and X represents amino acids not critical for the binding [23].
  • This motif is found at tyrosine residue 800 in the beta2 subunit of the interleukin-12 receptor and is required for DNA binding and transcriptional activity of STAT4 [22].
  • Decreased levels of STAT4 protein lead to decreased STAT4 DNA-binding activity and reduced proliferation and secretion of IFN-gamma [25].

Enzymatic interactions of STAT4


Regulatory relationships of STAT4


Other interactions of STAT4

  • Specific covalent cross-linking of nonactivated signal transducer and activator of transcription (STAT)-3, and to a lesser extent of STAT1 and STAT4, correlated with PDT dose [29].
  • By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues [15].
  • Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines [15].
  • In ex vivo organ cultures of H. pylori-infected biopsies, neutralization of endogenous IL-12 down-regulated the expression of phosphorylated STAT4 and T-bet and reduced IFN-gamma production [30].
  • The levels of signal transducer and activator of transcription 4 (STAT4), STAT6, and T-box expressed in T cells (T-bet) in total proteins extracted from gastric biopsies were determined by Western blotting [30].

Analytical, diagnostic and therapeutic context of STAT4


  1. Depressed IL-12-mediated signal transduction in T cells from patients with Sézary syndrome is associated with the absence of IL-12 receptor beta 2 mRNA and highly reduced levels of STAT4. Showe, L.C., Fox, F.E., Williams, D., Au, K., Niu, Z., Rook, A.H. J. Immunol. (1999) [Pubmed]
  2. Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I. Higashi, T., Tsukada, J., Yoshida, Y., Mizobe, T., Mouri, F., Minami, Y., Morimoto, H., Tanaka, Y. Genes Cells (2005) [Pubmed]
  3. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Durali, D., de Goër de Herve, M.G., Giron-Michel, J., Azzarone, B., Delfraissy, J.F., Taoufik, Y. Blood (2003) [Pubmed]
  4. Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma. Robertson, M.J., Chang, H.C., Pelloso, D., Kaplan, M.H. Blood (2005) [Pubmed]
  5. Evaluation of microsatellite markers in association studies: a search for an immune-related susceptibility gene in sarcoidosis. Tanaka, G., Matsushita, I., Ohashi, J., Tsuchiya, N., Ikushima, S., Oritsu, M., Hijikata, M., Nagata, T., Yamamoto, K., Tokunaga, K., Keicho, N. Immunogenetics (2005) [Pubmed]
  6. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Kobayashi, S., Ikari, K., Kaneko, H., Kochi, Y., Yamamoto, K., Shimane, K., Nakamura, Y., Toyama, Y., Mochizuki, T., Tsukahara, S., Kawaguchi, Y., Terai, C., Hara, M., Tomatsu, T., Yamanaka, H., Horiuchi, T., Tao, K., Yasutomo, K., Hamada, D., Yasui, N., Inoue, H., Itakura, M., Okamoto, H., Kamatani, N., Momohara, S. Arthritis Rheum. (2008) [Pubmed]
  7. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Dieudé, P., Guedj, M., Wipff, J., Ruiz, B., Hachulla, E., Diot, E., Granel, B., Sibilia, J., Tiev, K., Mouthon, L., Cracowski, J.L., Carpentier, P.H., Amoura, Z., Fajardy, I., Avouac, J., Meyer, O., Kahan, A., Boileau, C., Allanore, Y. Arthritis Rheum. (2009) [Pubmed]
  8. 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]
  9. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Ouyang, W., Ranganath, S.H., Weindel, K., Bhattacharya, D., Murphy, T.L., Sha, W.C., Murphy, K.M. Immunity (1998) [Pubmed]
  10. N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation. Ota, N., Brett, T.J., Murphy, T.L., Fremont, D.H., Murphy, K.M. Nat. Immunol. (2004) [Pubmed]
  11. Dendritic cell regulation of TH1-TH2 development. Moser, M., Murphy, K.M. Nat. Immunol. (2000) [Pubmed]
  12. Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor beta1 (IL-12Rbeta1): evidence for an IL-12Rbeta1-independent pathway of IL-12 responsiveness in human T cells. Verhagen, C.E., de Boer T, n.u.l.l., Smits, H.H., Verreck, F.A., Wierenga, E.A., Kurimoto, M., Lammas, D.A., Kumararatne, D.S., Sanal, O., Kroon, F.P., van Dissel JT, n.u.l.l., Sinigaglia, F., Ottenhoff, T.H. J. Exp. Med. (2000) [Pubmed]
  13. Inhibition of STAT4 activation by lisofylline is associated with the protection of autoimmune diabetes. Yang, Z., Chen, M., Fialkow, L.B., Ellett, J.D., Wu, R., Nadler, J.L. Ann. N. Y. Acad. Sci. (2003) [Pubmed]
  14. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Bacon, C.M., Petricoin, E.F., Ortaldo, J.R., Rees, R.C., Larner, A.C., Johnston, J.A., O'Shea, J.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  15. Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling. Dumoutier, L., Tounsi, A., Michiels, T., Sommereyns, C., Kotenko, S.V., Renauld, J.C. J. Biol. Chem. (2004) [Pubmed]
  16. Positive modulation of IL-12 signaling by sphingosine kinase 2 associating with the IL-12 receptor beta 1 cytoplasmic region. Yoshimoto, T., Furuhata, M., Kamiya, S., Hisada, M., Miyaji, H., Magami, Y., Yamamoto, K., Fujiwara, H., Mizuguchi, J. J. Immunol. (2003) [Pubmed]
  17. IL-2 induces STAT4 activation in primary NK cells and NK cell lines, but not in T cells. Wang, K.S., Ritz, J., Frank, D.A. J. Immunol. (1999) [Pubmed]
  18. cDNA cloning, expression and chromosome mapping of the human STAT4 gene: both STAT4 and STAT1 genes are mapped to 2q32.2-->q32.3. Yamamoto, K., Kobayashi, H., Arai, A., Miura, O., Hirosawa, S., Miyasaka, N. Cytogenet. Cell Genet. (1997) [Pubmed]
  19. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation. Cho, S.S., Bacon, C.M., Sudarshan, C., Rees, R.C., Finbloom, D., Pine, R., O'Shea, J.J. J. Immunol. (1996) [Pubmed]
  20. Effects of glucocorticoids on STAT4 activation in human T cells are stimulus-dependent. Fahey, A.J., Robins, R.A., Kindle, K.B., Heery, D.M., Constantinescu, C.S. J. Leukoc. Biol. (2006) [Pubmed]
  21. IL-12 selectively regulates STAT4 via phosphatidylinositol 3-kinase and Ras-independent signal transduction pathways. Athié-M, V., Flotow, H., Hilyard, K.L., Cantrell, D.A. Eur. J. Immunol. (2000) [Pubmed]
  22. Identification of a STAT4 binding site in the interleukin-12 receptor required for signaling. Naeger, L.K., McKinney, J., Salvekar, A., Hoey, T. J. Biol. Chem. (1999) [Pubmed]
  23. Direct interaction of STAT4 with the IL-12 receptor. Yao, B.B., Niu, P., Surowy, C.S., Faltynek, C.R. Arch. Biochem. Biophys. (1999) [Pubmed]
  24. STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells. Yap, W.H., Yeoh, E., Tay, A., Brenner, S., Venkatesh, B. FEBS Lett. (2005) [Pubmed]
  25. Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation. Wang, K.S., Zorn, E., Ritz, J. Blood (2001) [Pubmed]
  26. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. Frucht, D.M., Aringer, M., Galon, J., Danning, C., Brown, M., Fan, S., Centola, M., Wu, C.Y., Yamada, N., El Gabalawy, H., O'Shea, J.J. J. Immunol. (2000) [Pubmed]
  27. TGF-beta does not inhibit IL-12- and IL-2-induced activation of Janus kinases and STATs. Sudarshan, C., Galon, J., Zhou, Y., O'Shea, J.J. J. Immunol. (1999) [Pubmed]
  28. Impairment of STAT activation by IL-12 in a patient with atypical mycobacterial and staphylococcal infections. Gollob, J.A., Veenstra, K.G., Jyonouchi, H., Kelly, A.M., Ferrieri, P., Panka, D.J., Altare, F., Fieschi, C., Casanova, J.L., Frank, D.A., Mier, J.W. J. Immunol. (2000) [Pubmed]
  29. Photodynamic therapy causes cross-linking of signal transducer and activator of transcription proteins and attenuation of interleukin-6 cytokine responsiveness in epithelial cells. Liu, W., Oseroff, A.R., Baumann, H. Cancer Res. (2004) [Pubmed]
  30. Interleukin-12 Drives the Th1 Signaling Pathway in Helicobacter pylori-Infected Human Gastric Mucosa. Pellicanò, A., Sebkova, L., Monteleone, G., Guarnieri, G., Imeneo, M., Pallone, F., Luzza, F. Infect. Immun. (2007) [Pubmed]
  31. Members of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway are present and active in human sperm. D'Cruz, O.J., Vassilev, A.O., Uckun, F.M. Fertil. Steril. (2001) [Pubmed]
  32. The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo. Kishimoto, K., Dong, V.M., Issazadeh, S., Fedoseyeva, E.V., Waaga, A.M., Yamada, A., Sho, M., Benichou, G., Auchincloss, H., Grusby, M.J., Khoury, S.J., Sayegh, M.H. J. Clin. Invest. (2000) [Pubmed]
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