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Gene Review

STAT3  -  signal transducer and activator of...

Homo sapiens

Synonyms: ADMIO, APRF, Acute-phase response factor, HIES, Signal transducer and activator of transcription 3
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Disease relevance of STAT3


High impact information on STAT3

  • Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand [7].
  • Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals [8].
  • However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain [8].
  • We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching [9].
  • HGF stimulates recruitment of Stat-3 to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element SIE [10].

Chemical compound and disease context of STAT3


Biological context of STAT3


Anatomical context of STAT3

  • These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system [1].
  • To determine the effect of such hormones on the activation of interleukin 6 (IL-6)/STAT3 (signal transducer and activator of transcription-3) signaling, which may be involved in ovarian cancer, we investigated the status of STAT3, IL-6, and its receptor in immortalized human ovarian surface epithelial (HOSE) and ovarian cancer (OVCA) cell lines [2].
  • Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells [2].
  • STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes [18].
  • Granulocyte colony-stimulating factor, which utilizes a receptor highly related to gp130, also induces these two forms of STAT3 [17].

Associations of STAT3 with chemical compounds


Physical interactions of STAT3


Enzymatic interactions of STAT3

  • Dominant-negative STAT3 abolished the VEGF-induced nuclear translocation of phosphorylated STAT3 and inhibited HDMEC migration completely [34].
  • A STAT3 peptide was efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not by a kinase-inactive mTOR mutant or by p70 S6 kinase [35].
  • EXPERIMENTAL DESIGN: We examined IL-6 and phosphorylated STAT3 in COX-2-overexpressing [COX-2 sense-oriented (COX-2-S)] NSCLC cells and control cells [36].
  • Moreover, endogenous STAT3 was tyrosine phosphorylated and activated in human IL-5-stimulated BaF3 cells ectopically expressing the human IL-5R (BaF3/IL5R) [37].
  • The time course of enhanceosome occupation by GR and tyrosine-phosphorylated STAT3 shows that these transcription factors precede by approximately 5-10 min the arrival of RNA polymerase II (Pol II) [38].
  • Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position [39].

Regulatory relationships of STAT3

  • These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130 [40].
  • We found that two of the four tyrosine modules that are important for APRF activation also activate STAT1 [41].
  • Dominant-negative STAT3 also suppressed VEGF-induced HDMEC tube formation on Matrigel and on collagen gel [34].
  • Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation [42].
  • Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth [43].
  • To investigate the biological significance of Ras/ERK1/2-induced STAT3 Ser(727) phosphorylation for cell proliferation and transformation, N-Ras-transformed NIH-3T3 cells were employed [44].
  • Our results indicate that activated STAT3 transcriptionally induces Twist, which plays an important role in promoting migration, invasion, and anchorage-independent growth [45].

Other interactions of STAT3

  • Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130 [40].
  • Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS [46].
  • Moreover, the data show that JAK1 stimulation is also not sufficient for STAT3 activation [47].
  • Treatment with pharmacologic grade DNMT1 anti-sense oligonucleotides and STAT3 small-interfering RNA induces in the malignant T cells DNA demethylation and expression of SHP-1 gene [18].
  • 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 [48].

Analytical, diagnostic and therapeutic context of STAT3


  1. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Sumimoto, H., Imabayashi, F., Iwata, T., Kawakami, Y. J. Exp. Med. (2006) [Pubmed]
  2. Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. Syed, V., Ulinski, G., Mok, S.C., Ho, S.M. J. Natl. Cancer Inst. (2002) [Pubmed]
  3. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. Shouda, T., Yoshida, T., Hanada, T., Wakioka, T., Oishi, M., Miyoshi, K., Komiya, S., Kosai, K., Hanakawa, Y., Hashimoto, K., Nagata, K., Yoshimura, A. J. Clin. Invest. (2001) [Pubmed]
  4. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. He, B., You, L., Uematsu, K., Zang, K., Xu, Z., Lee, A.Y., Costello, J.F., McCormick, F., Jablons, D.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  5. STAT3 is constitutively activated in Hodgkin cell lines. Kube, D., Holtick, U., Vockerodt, M., Ahmadi, T., Haier, B., Behrmann, I., Heinrich, P.C., Diehl, V., Tesch, H. Blood (2001) [Pubmed]
  6. Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Lo, H.W., Cao, X., Zhu, H., Ali-Osman, F. Clin. Cancer Res. (2008) [Pubmed]
  7. Interleukin 20: discovery, receptor identification, and role in epidermal function. Blumberg, H., Conklin, D., Xu, W.F., Grossmann, A., Brender, T., Carollo, S., Eagan, M., Foster, D., Haldeman, B.A., Hammond, A., Haugen, H., Jelinek, L., Kelly, J.D., Madden, K., Maurer, M.F., Parrish-Novak, J., Prunkard, D., Sexson, S., Sprecher, C., Waggie, K., West, J., Whitmore, T.E., Yao, L., Kuechle, M.K., Dale, B.A., Chandrasekher, Y.A. Cell (2001) [Pubmed]
  8. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C.S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C.A., Roberts, J.L., Gao, X.B., Mobbs, C., Shulman, G.I., Diano, S., Horvath, T.L. Nat. Med. (2007) [Pubmed]
  9. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Kitamura, T., Feng, Y., Ido Kitamura, Y., Chua, S.C., Xu, A.W., Barsh, G.S., Rossetti, L., Accili, D. Nat. Med. (2006) [Pubmed]
  10. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Boccaccio, C., Andò, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C., Comoglio, P.M. Nature (1998) [Pubmed]
  11. Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. Bharti, A.C., Donato, N., Aggarwal, B.B. J. Immunol. (2003) [Pubmed]
  12. A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box. Hanada, T., Yoshida, T., Kinjyo, I., Minoguchi, S., Yasukawa, H., Kato, S., Mimata, H., Nomura, Y., Seki, Y., Kubo, M., Yoshimura, A. J. Biol. Chem. (2001) [Pubmed]
  13. HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Gray, M.J., Zhang, J., Ellis, L.M., Semenza, G.L., Evans, D.B., Watowich, S.S., Gallick, G.E. Oncogene (2005) [Pubmed]
  14. Prostacyclin receptor induces STAT1 and STAT3 phosphorylations in human erythroleukemia cells: a mechanism requiring PTX-insensitive G proteins, ERK and JNK. Lo, R.K., Wise, H., Wong, Y.H. Cell. Signal. (2006) [Pubmed]
  15. Different patterns of regulation of Tyr-phosphorylated STAT1 and STAT3 in human hepatoma Hep3B cells by the phosphatase inhibitor orthovanadate. Sehgal, P.B., Kumar, V., Guo, G., Murray, W.C. Arch. Biochem. Biophys. (2003) [Pubmed]
  16. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Ogata, H., Kobayashi, T., Chinen, T., Takaki, H., Sanada, T., Minoda, Y., Koga, K., Takaesu, G., Maehara, Y., Iida, M., Yoshimura, A. Gastroenterology (2006) [Pubmed]
  17. STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. Boulton, T.G., Zhong, Z., Wen, Z., Darnell, J.E., Stahl, N., Yancopoulos, G.D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  18. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Zhang, Q., Wang, H.Y., Marzec, M., Raghunath, P.N., Nagasawa, T., Wasik, M.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Kojima, H., Sasaki, T., Ishitani, T., Iemura, S., Zhao, H., Kaneko, S., Kunimoto, H., Natsume, T., Matsumoto, K., Nakajima, K. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  20. Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Dong, S., Tweardy, D.J. Blood (2002) [Pubmed]
  21. Mechanism by which H-2g, a glucose analog of blood group H antigen, mediates angiogenesis. Zhu, K., Amin, M.A., Zha, Y., Harlow, L.A., Koch, A.E. Blood (2005) [Pubmed]
  22. Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Chen, T., Wang, L.H., Farrar, W.L. Cancer Res. (2000) [Pubmed]
  23. Activation of STAT3 by G alpha(s) distinctively requires protein kinase A, JNK, and phosphatidylinositol 3-kinase. Liu, A.M., Lo, R.K., Wong, C.S., Morris, C., Wise, H., Wong, Y.H. J. Biol. Chem. (2006) [Pubmed]
  24. Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. Agarwal, C., Tyagi, A., Kaur, M., Agarwal, R. Carcinogenesis (2007) [Pubmed]
  25. Nucleocytoplasmic shuttling of persistently activated STAT3. Herrmann, A., Vogt, M., Mönnigmann, M., Clahsen, T., Sommer, U., Haan, S., Poli, V., Heinrich, P.C., Müller-Newen, G. J. Cell. Sci. (2007) [Pubmed]
  26. Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages. Williams, L.M., Sarma, U., Willets, K., Smallie, T., Brennan, F., Foxwell, B.M. J. Biol. Chem. (2007) [Pubmed]
  27. Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Brantley, E.C., Nabors, L.B., Gillespie, G.Y., Choi, Y.H., Palmer, C.A., Harrison, K., Roarty, K., Benveniste, E.N. Clin. Cancer Res. (2008) [Pubmed]
  28. Reciprocal regulation of c-Src and STAT3 in non-small cell lung cancer. Byers, L.A., Sen, B., Saigal, B., Diao, L., Wang, J., Nanjundan, M., Cascone, T., Mills, G.B., Heymach, J.V., Johnson, F.M. Clin. Cancer Res. (2009) [Pubmed]
  29. Constitutive activation of Jak/STAT proteins in Epstein-Barr virus-infected B-cell lines from patients with posttransplant lymphoproliferative disorder. Nepomuceno, R.R., Snow, A.L., Robert Beatty, P., Krams, S.M., Martinez, O.M. Transplantation (2002) [Pubmed]
  30. Molecular interactions between STAT3 and protein inhibitor of activated STAT3, and androgen receptor. Yamamoto, T., Sato, N., Sekine, Y., Yumioka, T., Imoto, S., Junicho, A., Fuse, H., Matsuda, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  31. Opposing effects of PML and PML/RAR alpha on STAT3 activity. Kawasaki, A., Matsumura, I., Kataoka, Y., Takigawa, E., Nakajima, K., Kanakura, Y. Blood (2003) [Pubmed]
  32. Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. Yang, C.H., Shi, W., Basu, L., Murti, A., Constantinescu, S.N., Blatt, L., Croze, E., Mullersman, J.E., Pfeffer, L.M. J. Biol. Chem. (1996) [Pubmed]
  33. The effect of suppressor of cytokine signaling 3 on GH signaling in beta-cells. Rønn, S.G., Hansen, J.A., Lindberg, K., Karlsen, A.E., Billestrup, N. Mol. Endocrinol. (2002) [Pubmed]
  34. Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. Yahata, Y., Shirakata, Y., Tokumaru, S., Yamasaki, K., Sayama, K., Hanakawa, Y., Detmar, M., Hashimoto, K. J. Biol. Chem. (2003) [Pubmed]
  35. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Yokogami, K., Wakisaka, S., Avruch, J., Reeves, S.A. Curr. Biol. (2000) [Pubmed]
  36. Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Dalwadi, H., Krysan, K., Heuze-Vourc'h, N., Dohadwala, M., Elashoff, D., Sharma, S., Cacalano, N., Lichtenstein, A., Dubinett, S. Clin. Cancer Res. (2005) [Pubmed]
  37. Activation of the STAT3/acute phase response factor transcription factor by interleukin-5. Caldenhoven, E., van Dijk, T., Raaijmakers, J.A., Lammers, J.W., Koenderman, L., De Groot, R.P. J. Biol. Chem. (1995) [Pubmed]
  38. STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene. Lerner, L., Henriksen, M.A., Zhang, X., Darnell, J.E. Genes Dev. (2003) [Pubmed]
  39. Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Zhang, X., Guo, A., Yu, J., Possemato, A., Chen, Y., Zheng, W., Polakiewicz, R.D., Kinzler, K.W., Vogelstein, B., Velculescu, V.E., Wang, Z.J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  40. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Lütticken, C., Wegenka, U.M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A.G., Wilks, A.F., Yasukawa, K., Taga, T. Science (1994) [Pubmed]
  41. Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130. I. Definition of a novel phosphotyrosine motif mediating STAT1 activation. Gerhartz, C., Heesel, B., Sasse, J., Hemmann, U., Landgraf, C., Schneider-Mergener, J., Horn, F., Heinrich, P.C., Graeve, L. J. Biol. Chem. (1996) [Pubmed]
  42. Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation. Shi, C.S., Kehrl, J.H. J. Biol. Chem. (2004) [Pubmed]
  43. Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Niwa, Y., Kanda, H., Shikauchi, Y., Saiura, A., Matsubara, K., Kitagawa, T., Yamamoto, J., Kubo, T., Yoshikawa, H. Oncogene (2005) [Pubmed]
  44. Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation. Plaza-Menacho, I., van der Sluis, T., Hollema, H., Gimm, O., Buys, C.H., Magee, A.I., Isacke, C.M., Hofstra, R.M., Eggen, B.J. J. Biol. Chem. (2007) [Pubmed]
  45. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. Cheng, G.Z., Zhang, W.Z., Sun, M., Wang, Q., Coppola, D., Mansour, M., Xu, L.M., Costanzo, C., Cheng, J.Q., Wang, L.H. J. Biol. Chem. (2008) [Pubmed]
  46. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. Hong, F., Jaruga, B., Kim, W.H., Radaeva, S., El-Assal, O.N., Tian, Z., Nguyen, V.A., Gao, B. J. Clin. Invest. (2002) [Pubmed]
  47. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. Beadling, C., Guschin, D., Witthuhn, B.A., Ziemiecki, A., Ihle, J.N., Kerr, I.M., Cantrell, D.A. EMBO J. (1994) [Pubmed]
  48. 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]
  49. Enhancement of gp130-mediated tyrosine phosphorylation of STAT3 and its DNA-binding activity in dexamethasone-treated AIDS-associated Kaposi's sarcoma cells: selective synergy between dexamethasone and gp130-related growth factors in Kaposi's sarcoma cell proliferation. Murakami-Mori, K., Mori, S., Taga, T., Kishimoto, T., Nakamura, S. J. Immunol. (1997) [Pubmed]
  50. Regulation of neutrophil adhesion by pituitary growth hormone accompanies tyrosine phosphorylation of Jak2, p125FAK, and paxillin. Ryu, H., Lee, J.H., Kim, K.S., Jeong, S.M., Kim, P.H., Chung, H.T. J. Immunol. (2000) [Pubmed]
  51. Functional interaction of STAT3 transcription factor with the coactivator NcoA/SRC1a. Giraud, S., Bienvenu, F., Avril, S., Gascan, H., Heery, D.M., Coqueret, O. J. Biol. Chem. (2002) [Pubmed]
  52. Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6.receptor complex. Ward, L.D., Hammacher, A., Howlett, G.J., Matthews, J.M., Fabri, L., Moritz, R.L., Nice, E.C., Weinstock, J., Simpson, R.J. J. Biol. Chem. (1996) [Pubmed]
  53. Cellular physiology of STAT3: Where's the cytoplasmic monomer? Ndubuisi, M.I., Guo, G.G., Fried, V.A., Etlinger, J.D., Sehgal, P.B. J. Biol. Chem. (1999) [Pubmed]
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