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Gene Review

STAT6  -  signal transducer and activator of...

Homo sapiens

Synonyms: D12S1644, IL-4 Stat, IL-4-STAT, STAT6B, STAT6C, ...
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Disease relevance of STAT6


Psychiatry related information on STAT6

  • Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type [8].

High impact information on STAT6


Chemical compound and disease context of STAT6

  • High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy [14].

Biological context of STAT6


Anatomical context of STAT6


Associations of STAT6 with chemical compounds

  • Also, simvastatin was unable to augment Ym1 expression in DCs developed from STAT6-/- or IL-4R alpha-/- mice [21].
  • Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression [2].
  • Both IL-4 and IL-13 increased specific STAT6-DNA binding in control cells, and this was inhibited by anti-STAT6 Ab (P < 0.05) or leflunomide (P < 0.05) [3].
  • Preincubation of human cultured smooth muscle cells with IL-4 (P < 0.001) or IL-13 (P < 0.05) significantly enhanced carbachol-induced contraction, and this was significantly inhibited by the STAT6 inhibitor leflunomide (P < 0.0001) [3].
  • The coculture of allergen-treated DC and CD4+ T cells also led to a dose-dependent expression of active signal transducer and activator of transcription-6 (STAT6), which was visible already after 1 hr [22].

Physical interactions of STAT6

  • However, cotransfection of all three chains did not further increase IL-4 binding or alter the extent of STAT6 activation suggesting that all three chains together do not seem to participate in IL-4 function [23].
  • Although only one consensus STAT6 binding site is contained in the TFF3 gene, located in the intron 1, it did not operate as an enhancer in the context of an SV40 promoter/luciferase construct [24].
  • To define the mechanism of coactivator recognition, we determined the crystal structure of the NCoA-1 PAS-B domain in complex with the STAT6 LXXLL motif [25].
  • Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits [26].
  • However, reconstitution of these X-SCID B cells with gammac enhanced IL-4-mediated responses including STAT6 phosphorylation and DNA binding activity and resulted in increased CD23 expression [27].

Enzymatic interactions of STAT6

  • By contrast, production of IL-4 and expression of phosphorylated STAT6 were not associated with the intensity of mononuclear cell infiltration [28].

Regulatory relationships of STAT6


Other interactions of STAT6

  • IL-13 efficiently caused activation of STAT6 protein in cells transfected with the IL-13Ralpha1 and IL-4Ralpha chains, and IL-13Ralpha2 inhibited this activation [16].
  • Only 4 of 24 NHL cases demonstrated constitutive STAT6 activation, whereas STAT3 activation was observed in 6 of 13 (46%) cases of B-cell NHL and 8 of 11 (73%) cases of T-cell NHL [17].
  • One sequence set was selected from random oligonucleotides by recombinant STAT1, STAT5A, or STAT6 [33].
  • Detailed analysis indicated that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as expected from the evolutionary relationships [33].
  • Thus, STAT6 activation mediates a transcriptional enhancement of TFF3 by induction of de novo synthesized protein in goblet cells [24].

Analytical, diagnostic and therapeutic context of STAT6


  1. Constitutive STAT6 activation in primary mediastinal large B-cell lymphoma. Guiter, C., Dusanter-Fourt, I., Copie-Bergman, C., Boulland, M.L., Le Gouvello, S., Gaulard, P., Leroy, K., Castellano, F. Blood (2004) [Pubmed]
  2. STAT-6-mediated control of P-selectin by substance P and interleukin-4 in human dermal endothelial cells. Miyazaki, Y., Satoh, T., Nishioka, K., Yokozeki, H. Am. J. Pathol. (2006) [Pubmed]
  3. Interleukin-4- and -13-induced hypercontractility of human intestinal muscle cells-implication for motility changes in Crohn's disease. Akiho, H., Lovato, P., Deng, Y., Ceponis, P.J., Blennerhassett, P., Collins, S.M. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  4. Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Liu, H., Jacobs, B.S., Liu, J., Prayson, R.A., Estes, M.L., Barnett, G.H., Barna, B.P. Cancer Immunol. Immunother. (2000) [Pubmed]
  5. STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells. Gooch, J.L., Christy, B., Yee, D. Neoplasia (2002) [Pubmed]
  6. Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer. Cui, X., Zhang, L., Luo, J., Rajasekaran, A., Hazra, S., Cacalano, N., Dubinett, S.M. Oncogene (2007) [Pubmed]
  7. Constitutively active STAT6 predisposes toward a lymphoproliferative disorder. Kaplan, M.H., Sehra, S., Chang, H.C., O'Malley, J.T., Mathur, A.N., Bruns, H.A. Blood (2007) [Pubmed]
  8. Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: A speculative hypothesis. Tsai, S.J. Med. Hypotheses (2006) [Pubmed]
  9. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Cai, S., Lee, C.C., Kohwi-Shigematsu, T. Nat. Genet. (2006) [Pubmed]
  10. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Kuperman, D.A., Huang, X., Koth, L.L., Chang, G.H., Dolganov, G.M., Zhu, Z., Elias, J.A., Sheppard, D., Erle, D.J. Nat. Med. (2002) [Pubmed]
  11. Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family. Simard, J., Ricketts, M.L., Gingras, S., Soucy, P., Feltus, F.A., Melner, M.H. Endocr. Rev. (2005) [Pubmed]
  12. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Russell, S.M., Tayebi, N., Nakajima, H., Riedy, M.C., Roberts, J.L., Aman, M.J., Migone, T.S., Noguchi, M., Markert, M.L., Buckley, R.H., O'Shea, J.J., Leonard, W.J. Science (1995) [Pubmed]
  13. An interleukin-4-induced transcription factor: IL-4 Stat. Hou, J., Schindler, U., Henzel, W.J., Ho, T.C., Brasseur, M., McKnight, S.L. Science (1994) [Pubmed]
  14. Gene expression and angiotropism in primary CNS lymphoma. Rubenstein, J.L., Fridlyand, J., Shen, A., Aldape, K., Ginzinger, D., Batchelor, T., Treseler, P., Berger, M., McDermott, M., Prados, M., Karch, J., Okada, C., Hyun, W., Parikh, S., Haqq, C., Shuman, M. Blood (2006) [Pubmed]
  15. Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Dickensheets, H.L., Venkataraman, C., Schindler, U., Donnelly, R.P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. The interleukin-13 receptor alpha2 chain: an essential component for binding and internalization but not for interleukin-13-induced signal transduction through the STAT6 pathway. Kawakami, K., Taguchi, J., Murata, T., Puri, R.K. Blood (2001) [Pubmed]
  17. Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Skinnider, B.F., Elia, A.J., Gascoyne, R.D., Patterson, B., Trumper, L., Kapp, U., Mak, T.W. Blood (2002) [Pubmed]
  18. An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1. Litterst, C.M., Pfitzner, E. J. Biol. Chem. (2002) [Pubmed]
  19. IL-4 suppresses osteoclast development and mature osteoclast function by a STAT6-dependent mechanism: irreversible inhibition of the differentiation program activated by RANKL. Moreno, J.L., Kaczmarek, M., Keegan, A.D., Tondravi, M. Blood (2003) [Pubmed]
  20. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. Shankaranarayanan, P., Chaitidis, P., Kühn, H., Nigam, S. J. Biol. Chem. (2001) [Pubmed]
  21. Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. Arora, M., Chen, L., Paglia, M., Gallagher, I., Allen, J.E., Vyas, Y.M., Ray, A., Ray, P. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  22. Production of interleukin-13 by human dendritic cells after stimulation with protein allergens is a key factor for induction of T helper 2 cytokines and is associated with activation of signal transducer and activator of transcription-6. Bellinghausen, I., Brand, P., Böttcher, I., Klostermann, B., Knop, J., Saloga, J. Immunology (2003) [Pubmed]
  23. Interleukin-13 receptor alpha' but not alpha chain: a functional component of interleukin-4 receptors. Murata, T., Taguchi, J., Puri, R.K. Blood (1998) [Pubmed]
  24. IL-4 and IL-13 up-regulate intestinal trefoil factor expression: requirement for STAT6 and de novo protein synthesis. Blanchard, C., Durual, S., Estienne, M., Bouzakri, K., Heim, M.H., Blin, N., Cuber, J.C. J. Immunol. (2004) [Pubmed]
  25. Structure of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. Razeto, A., Ramakrishnan, V., Litterst, C.M., Giller, K., Griesinger, C., Carlomagno, T., Lakomek, N., Heimburg, T., Lodrini, M., Pfitzner, E., Becker, S. J. Mol. Biol. (2004) [Pubmed]
  26. Activation of STAT6 is not dependent on phosphotyrosine-mediated docking to the interleukin-4 receptor and can be blocked by dominant-negative mutants of both receptor subunits. Moriggl, R., Erhardt, I., Kammer, W., Berchtold, S., Schnarr, B., Lischke, A., Groner, B., Friedrich, K. Eur. J. Biochem. (1998) [Pubmed]
  27. Interleukin-4 signaling in B lymphocytes from patients with X-linked severe combined immunodeficiency. Taylor, N., Candotti, F., Smith, S., Oakes, S.A., Jahn, T., Isakov, J., Puck, J.M., O'Shea, J.J., Weinberg, K., Johnston, J.A. J. Biol. Chem. (1997) [Pubmed]
  28. 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]
  29. Interleukin 4 regulates phosphorylation of serine 756 in the transactivation domain of Stat6. Roles for multiple phosphorylation sites and Stat6 function. Wang, Y., Malabarba, M.G., Nagy, Z.S., Kirken, R.A. J. Biol. Chem. (2004) [Pubmed]
  30. STAT6 and Ets-1 form a stable complex that modulates Socs-1 expression by interleukin-4 in keratinocytes. Travagli, J., Letourneur, M., Bertoglio, J., Pierre, J. J. Biol. Chem. (2004) [Pubmed]
  31. Activation of STAT proteins and cytokine genes in human Th1 and Th2 cells generated in the absence of IL-12 and IL-4. Moriggl, R., Kristofic, C., Kinzel, B., Volarevic, S., Groner, B., Brinkmann, V. J. Immunol. (1998) [Pubmed]
  32. Interleukin-13 upregulates eotaxin expression in airway epithelial cells by a STAT6-dependent mechanism. Matsukura, S., Stellato, C., Georas, S.N., Casolaro, V., Plitt, J.R., Miura, K., Kurosawa, S., Schindler, U., Schleimer, R.P. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  33. DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. Ehret, G.B., Reichenbach, P., Schindler, U., Horvath, C.M., Fritz, S., Nabholz, M., Bucher, P. J. Biol. Chem. (2001) [Pubmed]
  34. Interleukin-4 and interleukin-13 act on glomerular visceral epithelial cells. Van Den Berg, J.G., Aten, J., Chand, M.A., Claessen, N., Dijkink, L., Wijdenes, J., Lakkis, F.G., Weening, J.J. J. Am. Soc. Nephrol. (2000) [Pubmed]
  35. MIP-T3 associates with IL-13Ralpha1 and suppresses STAT6 activation in response to IL-13 stimulation. Niu, Y., Murata, T., Watanabe, K., Kawakami, K., Yoshimura, A., Inoue, J., Puri, R.K., Kobayashi, N. FEBS Lett. (2003) [Pubmed]
  36. Regulatory mechanisms of Th2 cytokine-induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor-kappaB. Kobayashi, I., Yamamoto, S., Nishi, N., Tsuji, K., Imayoshi, M., Inada, S., Ichiamaru, T., Hamasaki, Y. Ann. Allergy Asthma Immunol. (2004) [Pubmed]
  37. Crystallization and preliminary crystallographic studies of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation domain. Razeto, A., Pfitzner, E., Becker, S. Acta Crystallogr. D Biol. Crystallogr. (2004) [Pubmed]
  38. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. Dawson, H.D., Collins, G., Pyle, R., Key, M., Weeraratna, A., Deep-Dixit, V., Nadal, C.N., Taub, D.D. BMC Immunol. (2006) [Pubmed]
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