Home LiteratureArticle Details
PMID: 25527793 Published · ppublish English Journal Article Review

Mechanisms of Jak/STAT signaling in immunity and disease.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 194 ·No. 1 ·2015-01-01 ·Pages 21-7

Villarino AV, Kanno Y, Ferdinand JR, O'Shea JJ

Abstract

More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell-extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead.

MeSH Terms
Cytokines/metabolism DNA-Binding Proteins/immunology Gene Expression Regulation/immunology Humans Immunity Janus Kinases/immunology Phosphorylation STAT Transcription Factors/immunology Signal Transduction Transcription, Genetic/genetics
Chemicals
Cytokines DNA-Binding Proteins STAT Transcription Factors Janus Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Villarino Alejandro V
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
Kanno Yuka
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
Ferdinand John R
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
O'Shea John J
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892 osheaj@arb.niams.nih.gov.
References (76)
76 references, click to expand
  1. Arginine methylation of STAT1: a reassessment.
    Cell. 2004 Nov 24;119(5):587-9; discussion 589-590 PMID: 15550240
  2. SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ.
    Blood. 2011 Jul 28;118(4):1002-7 PMID: 21636857
  3. Cytokine signaling modules in inflammatory responses.
    Immunity. 2008 Apr;28(4):477-87 PMID: 18400190
  4. Genome-wide analyses reveal the extent of opportunistic STAT5 binding that does not yield transcriptional activation of neighboring genes.
    Nucleic Acids Res. 2012 May;40(10):4461-72 PMID: 22319210
  5. Super-enhancers in the control of cell identity and disease.
    Cell. 2013 Nov 7;155(4):934-47 PMID: 24119843
  6. Discovering susceptibility genes for asthma and allergy.
    Nat Rev Immunol. 2008 Mar;8(3):169-82 PMID: 18301422
  7. Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation.
    Blood. 2010 Sep 2;116(9):1548-58 PMID: 20508164
  8. Cell signaling. Stat acetylation--a key facet of cytokine signaling?
    Science. 2005 Jan 14;307(5707):217-8 PMID: 15653493
  9. Genomic views of STAT function in CD4+ T helper cell differentiation.
    Nat Rev Immunol. 2011 Apr;11(4):239-50 PMID: 21436836
  10. Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody.
    Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6269-74 PMID: 24733900
  11. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5.
    Nat Immunol. 2011 Mar;12(3):247-54 PMID: 21278738
  12. Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation.
    Mol Cell Biol. 2004 Jan;24(1):407-19 PMID: 14673173
  13. Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.
    Immunity. 2012 Apr 20;36(4):586-99 PMID: 22520852
  14. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor.
    Science. 2014 May 16;344(6185):1249783 PMID: 24833397
  15. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.
    Nat Genet. 2014 Aug;46(8):812-4 PMID: 25038750
  16. STATs in cancer inflammation and immunity: a leading role for STAT3.
    Nat Rev Cancer. 2009 Nov;9(11):798-809 PMID: 19851315
  17. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.
    Mol Cell. 2012 Mar 9;45(5):598-609 PMID: 22306293
  18. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation.
    Nat Immunol. 2013 Nov;14(11):1190-8 PMID: 24056746
  19. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells.
    Cell. 2008 Jun 13;133(6):1106-17 PMID: 18555785
  20. Charting histone modifications and the functional organization of mammalian genomes.
    Nat Rev Genet. 2011 Jan;12(1):7-18 PMID: 21116306
  21. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).
    Nature. 1995 Sep 7;377(6544):65-8 PMID: 7659163
  22. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity.
    Immunity. 2003 Dec;19(6):793-802 PMID: 14670297
  23. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development.
    Science. 1995 Nov 3;270(5237):797-800 PMID: 7481768
  24. Activation of STAT6 by STING is critical for antiviral innate immunity.
    Cell. 2011 Oct 14;147(2):436-46 PMID: 22000020
  25. The JAK-STAT pathway at twenty.
    Immunity. 2012 Apr 20;36(4):503-14 PMID: 22520844
  26. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression.
    J Interferon Cytokine Res. 1997 Mar;17(3):121-34 PMID: 9085936
  27. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin.
    Nature. 2009 Oct 8;461(7265):819-22 PMID: 19783980
  28. Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling.
    Immunity. 2013 Sep 19;39(3):454-69 PMID: 24012417
  29. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling.
    J Exp Med. 2000 Sep 4;192(5):719-28 PMID: 10974037
  30. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation.
    Science. 2014 Apr 18;344(6181):310-3 PMID: 24744378
  31. Selectivity and therapeutic inhibition of kinases: to be or not to be?
    Nat Immunol. 2009 Apr;10(4):356-60 PMID: 19295632
  32. The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6.
    Nat Immunol. 2014 May;15(5):449-56 PMID: 24681564
  33. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors.
    Immunity. 2009 Dec 18;31(6):941-52 PMID: 20064451
  34. SUMO-specific protease 1 is critical for early lymphoid development through regulation of STAT5 activation.
    Mol Cell. 2012 Jan 27;45(2):210-21 PMID: 22284677
  35. MicroRNAs and STAT interplay.
    Semin Cancer Biol. 2012 Feb;22(1):70-5 PMID: 22210182
  36. The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome.
    Mol Cell. 2012 Jul 13;47(1):38-49 PMID: 22633955
  37. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12281-6 PMID: 12213961
  38. Cutting edge: influence of Tmevpg1, a long intergenic noncoding RNA, on the expression of Ifng by Th1 cells.
    J Immunol. 2012 Sep 1;189(5):2084-8 PMID: 22851706
  39. Stat proteins and oncogenesis.
    J Clin Invest. 2002 May;109(9):1139-42 PMID: 11994401
  40. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γ locus.
    Cell. 2013 Feb 14;152(4):743-54 PMID: 23415224
  41. Epigenetic control of T-helper-cell differentiation.
    Nat Rev Immunol. 2009 Feb;9(2):91-105 PMID: 19151746
  42. A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis.
    Vet Dermatol. 2013 Dec;24(6):587-97, e141-2 PMID: 24581322
  43. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells.
    Cancer Cell. 2013 Jun 10;23(6):839-52 PMID: 23684459
  44. A validated regulatory network for Th17 cell specification.
    Cell. 2012 Oct 12;151(2):289-303 PMID: 23021777
  45. Comparative evolutionary genomics of the STAT family of transcription factors.
    JAKSTAT. 2012 Jan 1;1(1):23-33 PMID: 24058748
  46. A role for the ITAM signaling module in specifying cytokine-receptor functions.
    Nat Immunol. 2014 Apr;15(4):333-42 PMID: 24608040
  47. Serine phosphorylation of STATs.
    Oncogene. 2000 May 15;19(21):2628-37 PMID: 10851062
  48. Bringing genome-wide association findings into clinical use.
    Nat Rev Genet. 2013 Aug;14(8):549-58 PMID: 23835440
  49. Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2.
    Nat Immunol. 2011 Dec;12(12):1212-20 PMID: 22037603
  50. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells.
    Immunity. 2013 Mar 21;38(3):514-27 PMID: 23453633
  51. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation.
    Immunity. 2010 Jun 25;32(6):840-51 PMID: 20620946
  52. Regulation of microRNA expression and abundance during lymphopoiesis.
    Immunity. 2010 Jun 25;32(6):828-39 PMID: 20605486
  53. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders.
    Nat Rev Cancer. 2007 Sep;7(9):673-83 PMID: 17721432
  54. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells.
    J Exp Med. 2007 Oct 1;204(10):2383-96 PMID: 17846149
  55. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.
    Cell. 1993 Apr 9;73(1):147-57 PMID: 8462096
  56. STATs shape the active enhancer landscape of T cell populations.
    Cell. 2012 Nov 21;151(5):981-93 PMID: 23178119
  57. Toward a new STATe: the role of STATs in mitochondrial function.
    Semin Immunol. 2014 Feb;26(1):20-8 PMID: 24434063
  58. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes.
    Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21499-504 PMID: 21098664
  59. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity.
    Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3041-5 PMID: 7708771
  60. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants.
    Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17921-6 PMID: 24127591
  61. Comprehensive meta-analysis of Signal Transducers and Activators of Transcription (STAT) genomic binding patterns discerns cell-specific cis-regulatory modules.
    BMC Genomics. 2013;14:4 PMID: 23324445
  62. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection.
    Immunity. 2003 Nov;19(5):645-55 PMID: 14614852
  63. Nonconventional initiation complex assembly by STAT and NF-kappaB transcription factors regulates nitric oxide synthase expression.
    Immunity. 2010 Jul 23;33(1):25-34 PMID: 20637660
  64. Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation.
    J Immunol. 1996 Dec 1;157(11):4781-9 PMID: 8943379
  65. The composition and signaling of the IL-35 receptor are unconventional.
    Nat Immunol. 2012 Mar;13(3):290-9 PMID: 22306691
  66. JAKs and STATs in immunity, immunodeficiency, and cancer.
    N Engl J Med. 2013 Jan 10;368(2):161-70 PMID: 23301733
  67. Maintaining cell identity through global control of genomic organization.
    Immunity. 2010 Jul 23;33(1):12-24 PMID: 20643336
  68. Nucleic acid-based approaches to STAT inhibition.
    JAKSTAT. 2012 Oct 1;1(4):285-91 PMID: 24058785
  69. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling.
    Nat Struct Mol Biol. 2011 Sep;18(9):971-6 PMID: 21841788
  70. A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3.
    Blood. 2014 May 8;123(19):2978-87 PMID: 24632714
  71. STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling.
    Nat Immunol. 2014 Feb;15(2):168-76 PMID: 24413774
  72. Inborn errors of human JAKs and STATs.
    Immunity. 2012 Apr 20;36(4):515-28 PMID: 22520845
  73. Transcription factor-specific requirements for coactivators and their acetyltransferase functions.
    Science. 1998 Jan 30;279(5351):703-7 PMID: 9445475
  74. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity.
    Annu Rev Immunol. 2012;30:707-31 PMID: 22224760
  75. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response.
    Immunity. 2013 Feb 21;38(2):250-62 PMID: 23352233
  76. STAT5 outcompetes STAT3 to regulate the expression of the oncogenic transcriptional modulator BCL6.
    Mol Cell Biol. 2013 Aug;33(15):2879-90 PMID: 23716595
Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.1401867
Email
osheaj@arb.niams.nih.gov
Published
2015-01-01
Pages
21-7
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC4524500
Subset
IM
Grants
Intramural NIH HHS · Z01 AR041106-13 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.1401867 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2