Regulation of JAK-STAT signalling in the immune system

Nature Reviews Immunology

Volumn 3, Issue 11, 2003, Pages 900-911

  Shuai, Ke ^a,b   Liu, Bin ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; JANUS KINASE; REGULATOR PROTEIN; STAT PROTEIN;

IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOPATHOLOGY; IMMUNOREGULATION; KINETICS; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

EID: 0242468041     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1226     Document Type: Review

References (143)

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).
2. Darnell, J. E., Jr. STATs and gene regulation. Science 277, 1630-1635 (1997).
3. Levy, D. E. & Darnell, J. E. Signalling: Stats: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651-662 (2002).
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).
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).
6. Shuai, K. et al. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76, 821-828 (1994).
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).
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).
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).
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).
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).
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).
13. O'Shea, J. J. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7, 1-11 (1997).
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).
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).
16. Hilton, D. J. Negative regulators of cytokine signal transduction. Cell. Mol. Life. Sci. 55, 1568-1577 (1999).
17. Kile, B. T. et al. The SOCS box: a tale of destruction and degradation. Trends. Biochem. Sci. 27, 235-241 (2002).
18. Alexander, W. S. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Rev. Immunol. 2, 410-416 (2002).
19. Greenhalgh, C. J. & Hilton, D. J. Negative regulation of cytokine signaling. J. Leukoc. Biol. 70, 348-356 (2001).
20. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917-921 (1997).
21. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921-924 (1997).
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.
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).
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).
25. Yoshimura, A. The CIS family: negative regulators of JAK-STAT signaling. Cytokine Growth Factor Rev. 9, 197-204 (1998).
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).
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).
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).
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).
30. Haan, S. et al. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J. Biol. Chem. 278, 31972-31979 (2003).
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).
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).
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).
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.
35. Marine, J. C. et al. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617-627 (1999).
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).
37. Takahashi, Y. et al. SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation. EMBO J. 22, 372-384 (2003).
38. Croker, B. A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nature Immunol. 4, 540-545 (2003).
39. Lang, R. et al. SOCS3 regulates the plasticity of gp130 signaling. Nature Immunol. 4, 546-550 (2003).
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.
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).
42. Neel, B. G. Structure and function of SH2-domain containing tyrosine phosphatases. Semin. Cell Biol. 4, 419-432 (1993).
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).
44. David, M., Chen, H. E., Goelz, S., Larner, A. C. & Neel, B. G. Differential regulation of the α/γ interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Mol. Cell. Biol. 15, 7050-7058 (1995).
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).
46. Penninger, J. M., Irie-Sasaki, J., Sasaki, T. & Oliveira-dos-Santos, A. J. CD45: new jobs for an old acquaintance. Naure. Immunol. 2, 389-396 (2001).
47. Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349-354 (2001).
48. Neel, B. G. & Tonks, N. K. Protein tyrosine phosphatases in signal transduction. Curr. Opin. Cell Biol. 9, 193-204 (1997).
49. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771-47774 (2001).
50. Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497-503 (2002).
51. Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489-495 (2002).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
63. McBride, K. M., McDonald, C. & Reich, N. C. Nuclear export signal located within the DNA-binding domain of the STAT1 transcription factor. EMBO J. 19, 6196-6206 (2000).
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).
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).
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).
67. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628-2637 (2000).
68. Platanias, L. C. The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. Pharmacol. Ther. 98, 129-142 (2003).
69. 2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ. Proc. Natl Acad. USA 99, 5971-5976 (2002).
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.
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. Interterfon Cytokine Res. 19, 189-195 (1999).
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).
73. McDonald, C. & Reich, N. C. Cooperation of the transcriptional co-activators CBP and p300 with Stat6. J. Interterfon Cytokine Res. 19, 711-722 (1999).
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).
75. Kim, T. K. & Maniatis, T. Regulation of interferon-γ-activated STAT1 by the ubiquitin-proteasome pathway. Science 273, 1717-1719 (1996).
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).
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).
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).
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).
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).
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).
83. Valdez, B. C. Henning, D., Perlaky. L., Busch, R. K. & Busch, H. Cloning and characterization of Gu/RH-II binding protein. Biochem. Biophy. Res. Com. 234, 335-340 (1997).
84. Shuai, K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19, 2638-2644 (2000).
85. + efflux and apoptosis induced by the potassium channel modulatory protein KChAP/PIAS3β in prostate cancer cells. J. Biol. Chem. 277, 17852-17862 (2002).
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).
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).
88. Aravind, L. & Koonin, E. V. SAP - a putative DNA-binding motif involved in chromosomal organization. Trends Biochem. Sci. 25, 112-114 (2000).
89. Kipp, M. et al. SAF Cell. Biol. 20, 7480-7489 (2000).
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.
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).
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).
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).
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).
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).
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).
97. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735-744 (2001).
98. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713-718 (2001).
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).
100. Gross, M. et al. Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20, 3880-3887 (2001).
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, 9863-9868 (2001). This paper provides genetic evidence that Drosophila PIAS might negatively regulate the Drosophila JAK-STAT pathway.
102. Chen, Y. et al. Identification of Shp-2 as a Stat5A phosphatase. J. Biol. Chem. 278, 16520-16527 (2003).
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).
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).
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).
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).
107. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662-5668 (2002).
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.
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).
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).
111. Hu, X. et al. Sensitization of IFN-γ Jak-STAT signaling during macrophage activation. Nature Immunol. 3, 859-866 (2002).
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).
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).
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).
115. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725-734 (2002).
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).
117. Kinjyo, I. et al. SCCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583-591 (2002).
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.
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).
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).
121. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284, 479-482 (1999).
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.
123. Leonard, W. J. & O'Shea, J. J. Jaks and STATs: biological implications. Annu Rev. Immu. 16, 293-322 (1998).
124. Notarangelo, L. D. et al. Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum. Mutat. 18, 255-263 (2001).
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).
126. H2-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.
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).
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).
129. Abendroth, A. et al. Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J. Virol. 74, 1900-1907 (2000).
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).
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).
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).
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).
134. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503-533 (2001).
135. Melchior, F. SUMO - nonclassical ubiquitin. Annu. Rev. Cell. Dev. Biol. 16, 591-626 (2000).
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).
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).
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).
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).
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).
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).
142. + thymocytes, and B cell maturation. J. Exp. Med. 183, 1707-1718 (1996).
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).