Journal ArticleDOI
Mechanisms and consequences of Jak–STAT signaling in the immune system
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TLDR
Recent advances in Jak–STAT biology are reviewed, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.Abstract:
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.read more
Citations
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Journal ArticleDOI
Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function.
TL;DR: Ikaros zinc finger transcription factors are important regulators of the gene programs underlying the development of hematopoietic cell lineages as discussed by the authors, and the role of Ikaros factors in lymphoid cell development, differentiation, and function is discussed.
Journal ArticleDOI
TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization.
Alicia M. Wallis,Gail A. Bishop +1 more
TL;DR: This brief review presents current understanding of how the signaling adapter protein TRAF3 can both induce and block inhibitory signaling pathways in B and T lymphocytes, via association with kinases and phosphatases, and subsequent regulation of their localization within the cell.
Journal ArticleDOI
E2F is required for STAT3-mediated upregulation of cyclin B1 and Cdc2 expressions and contributes to G2-M phase transition.
Jingjie Sun,Yuping Du,Qiaoling Song,Jing Nan,Peizhu Guan,Jihui Guo,Xiao Wang,Jinbo Yang,Jinbo Yang,Chenyang Zhao +9 more
TL;DR: It is demonstrated that STAT3 participates in modulating G2-M phase checkpoint by regulating gene expressions of cyclin B1 and Cdc2 via E2F.
Journal ArticleDOI
Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses
TL;DR: In this paper , the authors define a central role for argininosuccinate synthetase (ASS1) in controlling inflammatory macrophage activation and antibacterial defense through depletion of cellular citrulline.
Journal ArticleDOI
STAT3 and STAT5 Signaling Thresholds Determine Distinct Regulation for Innate Receptor-Induced Inflammatory Cytokines, and STAT3/STAT5 Disease Variants Modulate These Outcomes.
TL;DR: It is identified that the threshold of STAT3, STAT5a, and STAT5b expression determines if PRR-induced proinflammatory cytokines are increased or decreased, define mechanisms for this reciprocal regulation, and elucidate consequences for disease variants in the STAT3/ STAT5A/STAT5B region.
References
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Journal ArticleDOI
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
TL;DR: The authors showed that CD4+CD25+ cells contribute to maintaining self-tolerance by downregulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage.
Journal ArticleDOI
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins
TL;DR: A previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that phosphorylate substrate proteins called STATs (signal transducers and activators of transcription).
Journal ArticleDOI
A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders
Robert Kralovics,Francesco Passamonti,Andreas Buser,Soon Siong Teo,Ralph Tiedt,Jakob Passweg,André Tichelli,Mario Cazzola,Radek C. Skoda +8 more
TL;DR: Genetic evidence and in vitro functional studies indicate that V617F gives hematopoietic precursors proliferative and survival advantages and a high proportion of patients with myeloproliferative disorders carry a dominant gain-of-function mutation of JAK2.
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Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
E. Joanna Baxter,Linda M. Scott,Peter J. Campbell,Clare L. East,Nasios Fourouclas,Soheila Swanton,George S. Vassiliou,Anthony J. Bench,Elaine M. Boyd,Natasha Curtin,Michael A. Scott,Wendy N. Erber,Anthony R. Green,Anthony R. Green +13 more
TL;DR: A single acquired mutation of JAK2 was noted in more than half of patients with a myeloproliferative disorder and its presence in all erythropoietin-independent erythroid colonies demonstrates a link with growth factor hypersensitivity, a key biological feature of these disorders.
Journal ArticleDOI
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
Chloé James,Valérie Ugo,Jean-Pierre Le Couedic,Judith Staerk,François Delhommeau,Catherine Lacout,Loïc Garçon,Hana Raslova,Roland Berger,Annelise Bennaceur-Griscelli,Jean-Luc Villeval,Stefan N. Constantinescu,Nicole Casadevall,William Vainchenker +13 more
TL;DR: A clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.