Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regulation of JAK–STAT signalling in the immune system

Key Points

  • The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway has a crucial role in the control of immune responses.

  • Abnormal JAK–STAT signalling is associated with immune disorders.

  • The JAK–STAT pathway is regulated at many steps by various proteins, including suppressor of cytokine signalling (SOCS) proteins, protein inhibitor of activated STAT (PIAS) proteins and protein tyrosine phosphatases.

  • SOCS and PIAS proteins inhibit JAK–STAT signalling through distinct mechanisms.

  • The activity of JAKs and STATs is regulated by various post-translational modifications, including phosphorylation, methylation, ubiquitylation and ISGylation. The cross-talk between the JAK–STAT pathway and other signalling pathways has an important role in regulating immune cells.

Abstract

The cytokine-activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway has an important role in the control of immune responses. Dysregulation of JAK–STAT signalling is associated with various immune disorders. The signalling strength, kinetics and specificity of the JAK–STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the JAK–STAT pathway that will enhance our ability to design rational therapeutic strategies for immune diseases.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The JAK–STAT pathway.
Figure 2: Negative regulation of the JAK–STAT pathway.
Figure 3: The SOCS family of proteins.
Figure 4: Proposed mechanisms for inhibiting the JAK–STAT pathway by PIAS proteins.
Figure 5: The cross-talk between cytokine-signalling pathways.

References

  1. 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 264, 1415–1421 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Darnell, J. E., Jr. STATs and gene regulation. Science 277, 1630–1635 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Levy, D. E. & Darnell, J. E. Signalling: Stats: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  Google Scholar 

  4. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Fu, X. Y. & Zhang, J. J. Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter. Cell 74, 1135–1145 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Shuai, K. et al. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76, 821–828 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Horvath, C. M., Wen, Z. & Darnell, J. E., Jr. A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 9, 984–994 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Shuai, K., Stark, G. R., Kerr, I. M. & Darnell, J. E., Jr. A single phosphotyrosine residue of Stat91 required for gene activation by interferon-γ. Science 261, 1744–1746 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. Muller, M. et al. Complementation of a mutant cell line: central role of the 91 kDa polypeptide of ISGF3 in the interferon-α and -γ signal transduction pathways. EMBO J. 12, 4221–4228 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xu, X., Sun, Y. L. & Hoey, T. Cooperative DNA binding and sequence-selective recognition conferred by the STAT amino-terminal domain. Science 273, 794–797 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Shuai, K., Liao, J. & Song, M. M. Enhancement of antiproliferative activity of γ-interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Mol. Cell. Biol. 16, 4932–4941 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Igaz, P., Toth, S. & Falus, A. Biological and clinical significance of the JAK–STAT pathway; lessons from knockout mice. Inflamm. Res. 50, 435–441 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. O'Shea, J. J. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7, 1–11 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Ihle, J. N. et al. The roles of Jaks and Stats in cytokine signaling. Cancer. J. Sci. Am. 4 Suppl 1, S84–S91 (1998).

    PubMed  Google Scholar 

  15. Hilton, D. J. et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc. Natl Acad. Sci. USA 95, 114–119 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hilton, D. J. Negative regulators of cytokine signal transduction. Cell. Mol. Life. Sci. 55, 1568–1577 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Kile, B. T. et al. The SOCS box: a tale of destruction and degradation. Trends. Biochem. Sci. 27, 235–241 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Alexander, W. S. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Rev. Immunol. 2, 410–416 (2002).

    Article  CAS  Google Scholar 

  19. Greenhalgh, C. J. & Hilton, D. J. Negative regulation of cytokine signaling. J. Leukoc. Biol. 70, 348–356 (2001).

    CAS  PubMed  Google Scholar 

  20. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997). References 20–22 report the identification of the suppressors of cytokine signalling (SOCS) family of proteins.

    Article  CAS  PubMed  Google Scholar 

  23. Nicholson, S. E. et al. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 18, 375–385 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sasaki, A. et al. CIS3/SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J. Biol. Chem. 275, 29338–29347 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Yoshimura, A. The CIS family: negative regulators of JAK–STAT signaling. Cytokine Growth Factor Rev. 9, 197–204 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Kamura, T. et al. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 12, 3872–3881 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, J. G. et al. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc. Natl Acad. Sci. USA 96, 2071–2076 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cohney, S. J. et al. SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Mol. Cell. Biol. 19, 4980–4988 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cacalano, N. A., Sanden, D. & Johnston, J. A. Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras. Nature Cell Biol. 3, 460–465 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Haan, S. et al. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J. Biol. Chem. 278, 31972–31979 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Starr, R. et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc. Natl Acad. Sci. USA 95, 14395–14399 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Naka, T. et al. Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. Proc. Natl Acad. Sci. USA 95, 15577–15582 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alexander, W. S. et al. SOCS1 is a critical inhibitor of interferon-γ signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597–608 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Marine, J. C. et al. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98, 609–616 (1999). References 33 and 34 show an essential role of SOCS1 in the negative regulation of interferon-γ (IFN-γ) signalling.

    Article  CAS  PubMed  Google Scholar 

  35. Marine, J. C. et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Roberts, A. W. et al. Placental defects and embryonic lethality in mice lacking suppressor of cytokine signaling 3. Proc. Natl Acad. Sci. USA 98, 9324–9329 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Takahashi, Y. et al. SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation. EMBO J. 22, 372–384 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Croker, B. A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nature Immunol. 4, 540–545 (2003).

    Article  CAS  Google Scholar 

  39. Lang, R. et al. SOCS3 regulates the plasticity of gp130 signaling. Nature Immunol. 4, 546–550 (2003).

    Article  CAS  Google Scholar 

  40. Yasukawa, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nature Immunol. 4, 551–556 (2003). References 38–40 show the in vivo specificity of SOCS3 in the negative regulation of interleukin-6 (IL-6) signalling.

    Article  CAS  Google Scholar 

  41. Costa-Pereira, A. P. et al. Mutational switch of an IL-6 response to an interferon-γ-like response. Proc. Natl Acad. Sci. USA 99, 8043–8047 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Neel, B. G. Structure and function of SH2-domain containing tyrosine phosphatases. Semin. Cell Biol. 4, 419–432 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Klingmuller, U., Lorenz, U., Cantley, L. C., Neel, B. G. & Lodish, H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729–738 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. David, M., Chen, H. E., Goelz, S., Larner, A. C. & Neel, B. G. Differential regulation of the α/β interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol. Cell. Biol. 15, 7050–7058 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. You, M., Yu, D. H. & Feng, G. S. Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol. Cell. Biol. 19, 2416–2424 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Penninger, J. M., Irie-Sasaki, J., Sasaki, T. & Oliveira-dos-Santos, A. J. CD45: new jobs for an old acquaintance. Nature Immunology 2, 389–396 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Neel, B. G. & Tonks, N. K. Protein tyrosine phosphatases in signal transduction. Curr. Opin. Cell Biol. 9, 193–204 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497–503 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Simoncic, P. D., Lee-Loy, A., Barber, D. L., Tremblay, M. L. & McGlade, C. J. The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3. Curr. Biol. 12, 446–453 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Ungureanu, D., Saharinen, P., Junttila, I., Hilton, D. J. & Silvennoinen, O. Regulation of Jak2 through the ubiquitin–proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1. Mol. Cell. Biol. 22, 3316–3326 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Blomstrom, D. C., Fahey, D., Kutny, R., Korant, B. D. & Knight, E., Jr. Molecular characterization of the interferon-induced 15-kDa protein. Molecular cloning and nucleotide and amino acid sequence. J. Biol. Chem. 261, 8811–8816 (1986).

    CAS  PubMed  Google Scholar 

  55. Daly, C. & Reich, N. C. Characterization of specific DNA-binding factors activated by double-stranded RNA as positive regulators of interferon α/β-stimulated genes. J. Biol. Chem. 270, 23739–23746 (1995).

    Article  CAS  PubMed  Google Scholar 

  56. Malakhov, M. P. et al. High-throughput Immunoblotting. Ubiquitin-like protein is g15 modifies key regulators of signal transduction. J. Biol. Chem. 278, 16608–16613 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Malakhov, M. P., Malakhova, O. A., Kim, K. I., Ritchie, K. J. & Zhang, D. E. UBP43 (USP18) specifically removes ISG15 from conjugated proteins. J. Biol. Chem. 277, 9976–9981 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Malakhova, O. A. et al. Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev. 17, 455–460 (2003). Together with reference 56, this study shows an important role of protein ISGylation in the positive regulation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT)-signalling pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. O'Brien, K. B., O'Shea, J. J. & Carter-Su, C. SH2-B family members differentially regulate JAK family tyrosine kinases. J. Biol. Chem. 277, 8673–8681 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Schindler, C., Shuai, K., Prezioso, V. R. & Darnell, J. E., Jr. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 257, 809–813 (1992).

    Article  CAS  PubMed  Google Scholar 

  61. Shuai, K., Schindler, C., Prezioso, V. R. & Darnell, J. E., Jr. Activation of transcription by IFN-γ: tyrosine phosphorylation of a 91-kD DNA binding protein. Science 258, 1808–1812 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Meyer, T., Marg, A., Lemke, P., Wiesner, B. & Vinkemeier, U. DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1. Genes Dev. 17, 1992–2005 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. McBride, K. M., McDonald, C. & Reich, N. C. Nuclear export signal located within the DNA-binding domain of the STAT1transcription factor. EMBO J. 19, 6196–6206 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. McBride, K. M., Banninger, G., McDonald, C. & Reich, N. C. Regulated nuclear import of the STAT1 transcription factor by direct binding of importin-α. EMBO J. 21, 1754–1763 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wen, Z. & Darnell, J. E., Jr. Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3. Nucleic Acids Res. 25, 2062–2067 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wen, Z., Zhong, Z. & Darnell, J. E., Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Platanias, L. C. The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. Pharmacol. Ther. 98, 129–142 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Nair, J. S. et al. Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ. Proc. Natl Acad. Sci. USA 99, 5971–5976 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mowen, K. A. et al. Arginine methylation of STAT1 modulates IFNα/β induced transcription. Cell 104, 731–741 (2001). This study indicates that the activity of STAT1 is regulated by protein arginine methylation.

    Article  CAS  PubMed  Google Scholar 

  71. Altschuler, L., Wook, J. O., Gurari, D., Chebath, J. & Revel, M. Involvement of receptor-bound protein methyltransferase PRMT1 in antiviral and antiproliferative effects of type I interferons. J. Interferon Cytokine Res. 19, 189–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Abramovich, C., Yakobson, B., Chebath, J. & Revel, M. A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor. EMBO J. 16, 260–266 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. McDonald, C. & Reich, N. C. Cooperation of the transcriptional co-activators CBP and p300 with Stat6. J. Interferon Cytokine Res. 19, 711–722 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Shankaranarayanan, P., Chaitidis, P., Kuhn, H. & Nigam, S. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. J. Biol. Chem. 276, 42753–42760 (2001).

    Article  PubMed  Google Scholar 

  75. Kim, T. K. & Maniatis, T. Regulation of interferon-γ-activated STAT1 by the ubiquitin-proteasome pathway. Science 273, 1717–1719 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Parisien, J. P. et al. The V protein of human parainfluenza virus 2 antagonizes type I interferon responses by destabilizing signal transducer and activator of transcription 2. Virology 283, 230–239 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Parisien, J. P., Lau, J. F., Rodriguez, J. J., Ulane, C. M. & Horvath, C. M. Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of α/β interferon signal transduction. J. Virol. 76, 4190–4198 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ulane, C. M. & Horvath, C. M. Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components. Virology 304, 160–166 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Ulane, C. M., Rodriguez, J. J., Parisien, J. P. & Horvath, C. M. STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J. Virol. 77, 6385–6393 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rogers, R. S., Horvath, C. M. & Matunis, M. J. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J. Biol. Chem. 278, 30091–30097 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Ungureanu, D. et al. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood (in the press).

  82. Liu, B. et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Natl Acad. Sci. USA 95, 10626–10631 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Valdez, B. C., Henning, D., Perlaky, L., Busch, R. K. & Busch, H. Cloning and characterization of Gu/RH-II binding protein. Biochem. Biophys. Res. Commun. 234, 335–340 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Shuai, K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19, 2638–2644 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Wible, B. A. et al. Increased K+ efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3β in prostate cancer cells. J. Biol. Chem. 277, 17852–17862 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Moilanen, A. M. et al. A testis-specific androgen receptor coregulator that belongs to a novel family of nuclear proteins. J. Biol. Chem. 274, 3700–3704 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Wu, L. et al. Miz1, a novel zinc finger transcription factor that interacts with Msx2 and enhances its affinity for DNA. Mech. Dev. 65, 3–17 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Aravind, L. & Koonin, E. V. SAP — a putative DNA-binding motif involved in chromosomal organization. Trends Biochem. Sci. 25, 112–114 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Kipp, M. et al. SAF Mol. Cell Biol. 20, 7480–7489 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chung, C. D. et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 278, 1803–1805 (1997). This paper reports the first identification of protein inhibitor of activated STAT (PIAS) proteins in the negative regulation of STATs.

    Article  CAS  PubMed  Google Scholar 

  91. Arora, T. et al. PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J. Biol. Chem. 278, 21327–21330 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Liu, B., Gross, M., ten Hoeve, J. & Shuai, K. A transcriptional co-repressor of Stat1 with an essential LXXLL signature motif. Proc. Natl Acad. Sci. USA 98, 3203–3207 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Liao, J., Fu, Y. & Shuai, K. Distinct roles of the NH2- and COOH-terminal domains of the protein inhibitor of activated signal transducer and activator of transcription (STAT)1 (PIAS1) in cytokine-induced PIAS1–Stat1 interaction. Proc. Natl Acad. Sci. USA 97, 5267–5272 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rycyzyn, M. A. & Clevenger, C. V. The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer. Proc. Natl Acad. Sci. USA 99, 6790–6795 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tussie-Luna, M. I., Bayarsaihan, D., Seto, E., Ruddle, F. H. & Roy, A. L. Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxβ. Proc. Natl Acad. Sci. USA 99, 12807–12812 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Long, J., Matsuura, I., He, D., Wang, G., Shuai, K., and Liu, F. Repression of Smad transcriptional activity by PIASy. Proc. Natl Acad. Sci. USA 100, 9791–9796 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735–744 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713–718 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Sachdev, S. et al. PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev. 15, 3088–3103 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gross, M. et al. Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20, 3880–3887 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Betz, A., Lampen, N., Martinek, S., Young, M. W. & Darnell, J. E., Jr. A Drosophila PIAS homologue negatively regulates stat92E. Proc. Natl Acad. Sci. USA 98, 9563–9568 (2001). This paper provides genetic evidence that Drosophila PIAS might negatively regulate the Drosophila JAK–STAT pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen, Y. et al. Identification of Shp-2 as a Stat5A phosphatase. J. Biol. Chem. 278, 16520–16527 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Chughtai, N., Schimchowitsch, S., Lebrun, J. J. & Ali, S. Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the β-casein gene promoter in mammary cells. J. Biol. Chem. 277, 31107–31114 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Aoki, N. & Matsuda, T. A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. J. Biol. Chem. 275, 39718–39726 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. David, M., Grimley, P. M., Finbloom, D. S. & Larner, A. C. A nuclear tyrosine phosphatase downregulates interferon-induced gene expression. Mol. Cell. Biol. 13, 7515–7521 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Haspel, R. L. & Darnell, J. E., Jr. A nuclear protein tyrosine phosphatase is required for the inactivation of Stat1. Proc. Natl Acad. Sci. USA 96, 10188–10193 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662–5668 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wu, T. R. et al. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei. J. Biol. Chem. 277, 47572–47580 (2002). References 107 and 108 report the identification of a STAT1 protein tyrosine phosphatase. In addition, the data indicate the existence of substrate specificity in the dephosphorylation of STATs in the nucleus.

    Article  CAS  PubMed  Google Scholar 

  109. Yoo, J. Y., Huso, D. L., Nathans, D. & Desiderio, S. Specific ablation of Stat3β distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell 108, 331–344 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Henriksen, M. A., Betz, A., Fuccillo, M. V. & Darnell, J. E., Jr. Negative regulation of STAT92E by an N-terminally truncated STAT protein derived from an alternative promoter site. Genes Dev. 16, 2379–2389 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Hu, X. et al. Sensitization of IFN-γ Jak-STAT signaling during macrophage activation. Nature Immunol. 3, 859–866 (2002).

    Article  CAS  Google Scholar 

  112. Dickensheets, H. L., Venkataraman, C., Schindler, U. & Donnelly, R. P. Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Proc. Natl Acad. Sci. USA 96, 10800–10805 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ito, S. et al. Interleukin-10 inhibits expression of both interferon α- and interferon γ-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93, 1456–1463 (1999).

    CAS  PubMed  Google Scholar 

  114. Magrangeas, F., Boisteau, O., Denis, S., Jacques, Y. & Minvielle, S. Negative cross-talk between interleukin-3 and interleukin-11 is mediated by suppressor of cytokine signalling-3 (SOCS-3). Biochem. J. 353, 223–230 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).

    Article  CAS  Google Scholar 

  116. Kumar, A., Commane, M., Flickinger, T. W., Horvath, C. M. & Stark, G. R. Defective TNF-α-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science 278, 1630–1632 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583–591 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677–687 (2002). References 117 and 118 uncover a role of SOCS1 in lipopolysaccharide signalling.

    Article  CAS  PubMed  Google Scholar 

  119. Morita, Y. et al. Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor α-induced cell death in fibroblasts. Proc. Natl Acad. Sci. USA 97, 5405–5410 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ulloa, L., Doody, J. & Massaguae, J. Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284, 479–482 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Ivaska, J., Bosca, L. & Parker, P. J. PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1. Nature Cell Biol. 5, 363–369 (2003). This paper reports cross-talk between IFN- and integrin-signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  123. Leonard, W. J. & O'Shea, J. J. Jaks and STATs: biological implications. Annu. Rev. Immu. 16, 293–322 (1998).

    Article  CAS  Google Scholar 

  124. Notarangelo, L. D. et al. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum. Mutat. 18, 255–263 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Mullings, R. E. et al. Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium. J. Allergy Clin. Immunol. 108, 832–838 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. Seki, Y. I. et al. SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nature Med. 9, 1047–1054 (2003). This paper provides evidence that increased SOCS3 expression might contribute to the pathophysiology of T-helper-2-cell-mediated immune diseases.

    Article  PubMed  Google Scholar 

  127. Morrison, T. E., Mauser, A., Wong, A., Ting, J. P. & Kenney, S. C. Inhibition of IFN-γ signaling by an Epstein–Barr virus immediate-early protein. Immunity 15, 787–799 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Miller, D. M. et al. Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J. Exp. Med. 187, 675–683 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Abendroth, A. et al. Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J. Virol. 74, 1900–1907 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dupuis, S. et al. Human interferon-γ-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol. Rev. 178, 129–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Dupuis, S. et al. Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency. Nature Genet. 33, 388–391 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Welte, T. et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc. Natl Acad. Sci. USA 100, 1879–1884 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lovato, P. et al. Constitutive STAT3 activation in intestinal T cells from patients with Crohn's disease. J. Biol. Chem. 278, 16777–16781 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Melchior, F. SUMO — nonclassical ubiquitin. Annu. Rev. Cell. Dev. Biol. 16, 591–626 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Jackson, P. K. A new RING for SUMO: wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev. 15, 3053–3058 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 186, 683–693 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Shultz, L. D., Coman, D. R., Bailey, C. L., Beamer, W. G. & Sidman, C. L. 'Viable motheaten,' a new allele at the motheaten locus. I. Pathology. Am. J. Pathol. 116, 179–192 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Shultz, L. D., Rajan, T. V. & Greiner, D. L. Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency. Trends Biotechnol. 15, 302–307 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Qu, C. K., Nguyen, S., Chen, J. & Feng, G. S. Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 97, 911–914 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Byth, K. F. et al. CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation. J. Exp. Med. 183, 1707–1718 (1996).

    Article  CAS  PubMed  Google Scholar 

  143. Kishihara, K. et al. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143–156 (1993).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by the National Institutes of Health, American Cancer Society and United States Army Medical Research and Materiel Command (K.S.). B.L. is a Leukaemia and Lymphoma Special Fellow.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ke Shuai.

Related links

Related links

DATABASES

LocusLink

BMP2

CAMK2

CD45

CIS

EPOR

JAK1

JAK2

JAK3

LEF1

LIF

PIAS1

PIAS3

PIASX

PIASY

PRMT1

PTP1B

SHP1

SHP2

SOCS1

SOCS2

SOCS3

STAT1

STAT2

STAT3

STAT4

STAT5A

STAT5B

STAT6

TC-PTP

TYK2

UBP43

Further information

Ke Shuai's homepage

Glossary

LEPTIN

A hormone that regulates energy homeostasis and body weight. Leptin is mainly produced in white adipose tissue. Leptin binds to its receptor to signal through the JAK–STAT pathway.

NUCLEAR FACTOR-κB

(NF-κB). A family of transcription factors important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of their respective inhibitors, known as inhibitor of κB (IκB). Phosphorylation of IκB occurs through tissue-specific kinases, IκB kinase 1 (IKK1) and IKK2.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Shuai, K., Liu, B. Regulation of JAK–STAT signalling in the immune system. Nat Rev Immunol 3, 900–911 (2003). https://doi.org/10.1038/nri1226

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1226

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing