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. 2000 Nov;59(Suppl 1):i115–i118. doi: 10.1136/ard.59.suppl_1.i115

Jaks and Stats as therapeutic targets

J O'Shea, R Visconti, T Cheng, M Gadina
PMCID: PMC1766632  PMID: 11053101

Abstract

Cytokines have critical functions in regulating immune responses. A large number of these factors bind related receptors termed the Type I and Type II families of cytokine receptors. These receptors activate Janus kinases (Jaks) and Stat family of transcription factors. The essential and specific function of Jaks and Stats is particularly well illustrated by human and mouse mutations. The possibility that these molecules could be targeted to produce novel immunosuppressive compounds is considered in this review.



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Selected References

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  1. Baird A. M., Thomis D. C., Berg L. J. T cell development and activation in Jak3-deficient mice. J Leukoc Biol. 1998 Jun;63(6):669–677. doi: 10.1002/jlb.63.6.669. [DOI] [PubMed] [Google Scholar]
  2. Becker S., Groner B., Müller C. W. Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature. 1998 Jul 9;394(6689):145–151. doi: 10.1038/28101. [DOI] [PubMed] [Google Scholar]
  3. Bode J. G., Gatsios P., Ludwig S., Rapp U. R., Häussinger D., Heinrich P. C., Graeve L. The mitogen-activated protein (MAP) kinase p38 and its upstream activator MAP kinase kinase 6 are involved in the activation of signal transducer and activator of transcription by hyperosmolarity. J Biol Chem. 1999 Oct 15;274(42):30222–30227. doi: 10.1074/jbc.274.42.30222. [DOI] [PubMed] [Google Scholar]
  4. Bright J. J., Du C., Sriram S. Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol. 1999 May 15;162(10):6255–6262. [PubMed] [Google Scholar]
  5. Cacalano N. A., Migone T. S., Bazan F., Hanson E. P., Chen M., Candotti F., O'Shea J. J., Johnston J. A. Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. EMBO J. 1999 Mar 15;18(6):1549–1558. doi: 10.1093/emboj/18.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Candotti F., Oakes S. A., Johnston J. A., Giliani S., Schumacher R. F., Mella P., Fiorini M., Ugazio A. G., Badolato R., Notarangelo L. D. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997 Nov 15;90(10):3996–4003. [PubMed] [Google Scholar]
  7. Chen M., Cheng A., Candotti F., Zhou Y. J., Hymel A., Fasth A., Notarangelo L. D., O'Shea J. J. Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: evidence for interactions between the kinase and pseudokinase domains. Mol Cell Biol. 2000 Feb;20(3):947–956. doi: 10.1128/mcb.20.3.947-956.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen M., Cheng A., Chen Y. Q., Hymel A., Hanson E. P., Kimmel L., Minami Y., Taniguchi T., Changelian P. S., O'Shea J. J. The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6910–6915. doi: 10.1073/pnas.94.13.6910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen X., Vinkemeier U., Zhao Y., Jeruzalmi D., Darnell J. E., Jr, Kuriyan J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell. 1998 May 29;93(5):827–839. doi: 10.1016/s0092-8674(00)81443-9. [DOI] [PubMed] [Google Scholar]
  10. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  11. Druker B. J., Lydon N. B. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000 Jan;105(1):3–7. doi: 10.1172/JCI9083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Durbin J. E., Hackenmiller R., Simon M. C., Levy D. E. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996 Feb 9;84(3):443–450. doi: 10.1016/s0092-8674(00)81289-1. [DOI] [PubMed] [Google Scholar]
  13. Elder R. T., Xu X., Williams J. W., Gong H., Finnegan A., Chong A. S. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J Immunol. 1997 Jul 1;159(1):22–27. [PubMed] [Google Scholar]
  14. Ho J. M., Beattie B. K., Squire J. A., Frank D. A., Barber D. L. Fusion of the ets transcription factor TEL to Jak2 results in constitutive Jak-Stat signaling. Blood. 1999 Jun 15;93(12):4354–4364. [PubMed] [Google Scholar]
  15. Hoey T., Grusby M. J. STATs as mediators of cytokine-induced responses. Adv Immunol. 1999;71:145–162. doi: 10.1016/s0065-2776(08)60401-0. [DOI] [PubMed] [Google Scholar]
  16. Ihle J. N., Witthuhn B. A., Quelle F. W., Yamamoto K., Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol. 1995;13:369–398. doi: 10.1146/annurev.iy.13.040195.002101. [DOI] [PubMed] [Google Scholar]
  17. Kaplan D. H., Shankaran V., Dighe A. S., Stockert E., Aguet M., Old L. J., Schreiber R. D. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7556–7561. doi: 10.1073/pnas.95.13.7556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kaplan M. H., Schindler U., Smiley S. T., Grusby M. J. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996 Mar;4(3):313–319. doi: 10.1016/s1074-7613(00)80439-2. [DOI] [PubMed] [Google Scholar]
  19. Kaplan M. H., Sun Y. L., Hoey T., Grusby M. J. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996 Jul 11;382(6587):174–177. doi: 10.1038/382174a0. [DOI] [PubMed] [Google Scholar]
  20. Kennedy M. K., Glaccum M., Brown S. N., Butz E. A., Viney J. L., Embers M., Matsuki N., Charrier K., Sedger L., Willis C. R. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med. 2000 Mar 6;191(5):771–780. doi: 10.1084/jem.191.5.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kirken R. A., Erwin R. A., Taub D., Murphy W. J., Behbod F., Wang L., Pericle F., Farrar W. L. Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. J Leukoc Biol. 1999 Jun;65(6):891–899. doi: 10.1002/jlb.65.6.891. [DOI] [PubMed] [Google Scholar]
  22. Kovarik P., Stoiber D., Eyers P. A., Menghini R., Neininger A., Gaestel M., Cohen P., Decker T. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13956–13961. doi: 10.1073/pnas.96.24.13956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lacronique V., Boureux A., Monni R., Dumon S., Mauchauffé M., Mayeux P., Gouilleux F., Berger R., Gisselbrecht S., Ghysdael J. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood. 2000 Mar 15;95(6):2076–2083. [PubMed] [Google Scholar]
  24. Lacronique V., Boureux A., Valle V. D., Poirel H., Quang C. T., Mauchauffé M., Berthou C., Lessard M., Berger R., Ghysdael J. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science. 1997 Nov 14;278(5341):1309–1312. doi: 10.1126/science.278.5341.1309. [DOI] [PubMed] [Google Scholar]
  25. Leonard W. J., O'Shea J. J. Jaks and STATs: biological implications. Annu Rev Immunol. 1998;16:293–322. doi: 10.1146/annurev.immunol.16.1.293. [DOI] [PubMed] [Google Scholar]
  26. Liu X., Robinson G. W., Wagner K. U., Garrett L., Wynshaw-Boris A., Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997 Jan 15;11(2):179–186. doi: 10.1101/gad.11.2.179. [DOI] [PubMed] [Google Scholar]
  27. Lodolce J. P., Boone D. L., Chai S., Swain R. E., Dassopoulos T., Trettin S., Ma A. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity. 1998 Nov;9(5):669–676. doi: 10.1016/s1074-7613(00)80664-0. [DOI] [PubMed] [Google Scholar]
  28. Macchi P., Villa A., Giliani S., Sacco M. G., Frattini A., Porta F., Ugazio A. G., Johnston J. A., Candotti F., O'Shea J. J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65–68. doi: 10.1038/377065a0. [DOI] [PubMed] [Google Scholar]
  29. Malaviya R., Zhu D., Dibirdik I., Uckun F. M. Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis. J Biol Chem. 1999 Sep 17;274(38):27028–27038. doi: 10.1074/jbc.274.38.27028. [DOI] [PubMed] [Google Scholar]
  30. Meraz M. A., White J. M., Sheehan K. C., Bach E. A., Rodig S. J., Dighe A. S., Kaplan D. H., Riley J. K., Greenlund A. C., Campbell D. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996 Feb 9;84(3):431–442. doi: 10.1016/s0092-8674(00)81288-x. [DOI] [PubMed] [Google Scholar]
  31. Meydan N., Grunberger T., Dadi H., Shahar M., Arpaia E., Lapidot Z., Leeder J. S., Freedman M., Cohen A., Gazit A. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 1996 Feb 15;379(6566):645–648. doi: 10.1038/379645a0. [DOI] [PubMed] [Google Scholar]
  32. Mohammadi M., Froum S., Hamby J. M., Schroeder M. C., Panek R. L., Lu G. H., Eliseenkova A. V., Green D., Schlessinger J., Hubbard S. R. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998 Oct 15;17(20):5896–5904. doi: 10.1093/emboj/17.20.5896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mohammadi M., McMahon G., Sun L., Tang C., Hirth P., Yeh B. K., Hubbard S. R., Schlessinger J. Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science. 1997 May 9;276(5314):955–960. doi: 10.1126/science.276.5314.955. [DOI] [PubMed] [Google Scholar]
  34. Neubauer H., Cumano A., Müller M., Wu H., Huffstadt U., Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998 May 1;93(3):397–409. doi: 10.1016/s0092-8674(00)81168-x. [DOI] [PubMed] [Google Scholar]
  35. Nosaka T., van Deursen J. M., Tripp R. A., Thierfelder W. E., Witthuhn B. A., McMickle A. P., Doherty P. C., Grosveld G. C., Ihle J. N. Defective lymphoid development in mice lacking Jak3. Science. 1995 Nov 3;270(5237):800–802. doi: 10.1126/science.270.5237.800. [DOI] [PubMed] [Google Scholar]
  36. O'Shea J. J. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity. 1997 Jul;7(1):1–11. doi: 10.1016/s1074-7613(00)80505-1. [DOI] [PubMed] [Google Scholar]
  37. Parganas E., Wang D., Stravopodis D., Topham D. J., Marine J. C., Teglund S., Vanin E. F., Bodner S., Colamonici O. R., van Deursen J. M. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998 May 1;93(3):385–395. doi: 10.1016/s0092-8674(00)81167-8. [DOI] [PubMed] [Google Scholar]
  38. Park S. Y., Saijo K., Takahashi T., Osawa M., Arase H., Hirayama N., Miyake K., Nakauchi H., Shirasawa T., Saito T. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity. 1995 Dec;3(6):771–782. doi: 10.1016/1074-7613(95)90066-7. [DOI] [PubMed] [Google Scholar]
  39. Peeters P., Raynaud S. D., Cools J., Wlodarska I., Grosgeorge J., Philip P., Monpoux F., Van Rompaey L., Baens M., Van den Berghe H. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood. 1997 Oct 1;90(7):2535–2540. [PubMed] [Google Scholar]
  40. Puel A., Ziegler S. F., Buckley R. H., Leonard W. J. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998 Dec;20(4):394–397. doi: 10.1038/3877. [DOI] [PubMed] [Google Scholar]
  41. Richter M. F., Duménil G., Uzé G., Fellous M., Pellegrini S. Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. J Biol Chem. 1998 Sep 18;273(38):24723–24729. doi: 10.1074/jbc.273.38.24723. [DOI] [PubMed] [Google Scholar]
  42. Rodig S. J., Meraz M. A., White J. M., Lampe P. A., Riley J. K., Arthur C. D., King K. L., Sheehan K. C., Yin L., Pennica D. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998 May 1;93(3):373–383. doi: 10.1016/s0092-8674(00)81166-6. [DOI] [PubMed] [Google Scholar]
  43. 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. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995 Nov 3;270(5237):797–800. doi: 10.1126/science.270.5237.797. [DOI] [PubMed] [Google Scholar]
  44. Saharinen P., Takaluoma K., Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol. 2000 May;20(10):3387–3395. doi: 10.1128/mcb.20.10.3387-3395.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Shimoda K., van Deursen J., Sangster M. Y., Sarawar S. R., Carson R. T., Tripp R. A., Chu C., Quelle F. W., Nosaka T., Vignali D. A. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996 Apr 18;380(6575):630–633. doi: 10.1038/380630a0. [DOI] [PubMed] [Google Scholar]
  46. Siemasko K., Chong A. S., Jäck H. M., Gong H., Williams J. W., Finnegan A. Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol. 1998 Feb 15;160(4):1581–1588. [PubMed] [Google Scholar]
  47. Sudbeck E. A., Liu X. P., Narla R. K., Mahajan S., Ghosh S., Mao C., Uckun F. M. Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin Cancer Res. 1999 Jun;5(6):1569–1582. [PubMed] [Google Scholar]
  48. Takeda K., Noguchi K., Shi W., Tanaka T., Matsumoto M., Yoshida N., Kishimoto T., Akira S. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3801–3804. doi: 10.1073/pnas.94.8.3801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Takeda K., Tanaka T., Shi W., Matsumoto M., Minami M., Kashiwamura S., Nakanishi K., Yoshida N., Kishimoto T., Akira S. Essential role of Stat6 in IL-4 signalling. Nature. 1996 Apr 18;380(6575):627–630. doi: 10.1038/380627a0. [DOI] [PubMed] [Google Scholar]
  50. 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. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996 Jul 11;382(6587):171–174. doi: 10.1038/382171a0. [DOI] [PubMed] [Google Scholar]
  51. Thomis D. C., Gurniak C. B., Tivol E., Sharpe A. H., Berg L. J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science. 1995 Nov 3;270(5237):794–797. doi: 10.1126/science.270.5237.794. [DOI] [PubMed] [Google Scholar]
  52. Trieu V. N., Liu R., Liu X. P., Uckun F. M. A specific inhibitor of janus kinase-3 increases survival in a transgenic mouse model of amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2000 Jan 7;267(1):22–25. doi: 10.1006/bbrc.1999.1905. [DOI] [PubMed] [Google Scholar]
  53. Uckun F. M., Ek O., Liu X. P., Chen C. L. In vivo toxicity and pharmacokinetic features of the janus kinase 3 inhibitor WHI-P131 [4-(4'hydroxyphenyl)-amino-6,7- dimethoxyquinazoline. Clin Cancer Res. 1999 Oct;5(10):2954–2962. [PubMed] [Google Scholar]
  54. Udy G. B., Towers R. P., Snell R. G., Wilkins R. J., Park S. H., Ram P. A., Waxman D. J., Davey H. W. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7239–7244. doi: 10.1073/pnas.94.14.7239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Vinkemeier U., Moarefi I., Darnell J. E., Jr, Kuriyan J. Structure of the amino-terminal protein interaction domain of STAT-4. Science. 1998 Feb 13;279(5353):1048–1052. doi: 10.1126/science.279.5353.1048. [DOI] [PubMed] [Google Scholar]
  56. Waldmann T. A., O'Shea J. The use of antibodies against the IL-2 receptor in transplantation. Curr Opin Immunol. 1998 Oct;10(5):507–512. doi: 10.1016/s0952-7915(98)80215-x. [DOI] [PubMed] [Google Scholar]
  57. Wang L. H., Kirken R. A., Erwin R. A., Yu C. R., Farrar W. L. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response. J Immunol. 1999 Apr 1;162(7):3897–3904. [PubMed] [Google Scholar]
  58. Yan H., Piazza F., Krishnan K., Pine R., Krolewski J. J. Definition of the interferon-alpha receptor-binding domain on the TYK2 kinase. J Biol Chem. 1998 Feb 13;273(7):4046–4051. doi: 10.1074/jbc.273.7.4046. [DOI] [PubMed] [Google Scholar]
  59. Zauberman A., Zipori D., Krupsky M., Ben-Levy R. Stress activated protein kinase p38 is involved in IL-6 induced transcriptional activation of STAT3. Oncogene. 1999 Jul 1;18(26):3886–3893. doi: 10.1038/sj.onc.1202738. [DOI] [PubMed] [Google Scholar]

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