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
JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression
TL;DR: Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape.
Journal ArticleDOI
JAK-STAT pathway targeting for the treatment of inflammatory bowel disease.
Azucena Salas,Cristian Hernández-Rocha,Marjolijn Duijvestein,William A. Faubion,Dermot P.B. McGovern,Severine Vermeire,Stefania Vetrano,Niels Vande Casteele +7 more
TL;DR: New approaches such as selective or gut-specific JAK inhibitors, and a greater understanding of disease-specific mechanisms of action to facilitate personalized approaches to treatment, could improve the risk–benefit profiles of this class of therapy.
Journal ArticleDOI
The JAK/STAT signaling pathway: from bench to clinic.
TL;DR: In this article, the authors discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway and highlight the role of the pathway and its inhibitors in various diseases.
Journal ArticleDOI
Interferon target-gene expression and epigenomic signatures in health and disease
TL;DR: The mechanisms by which IFN signatures and IFN epigenomic signatures are generated, as well as the functional consequences of these signatures in homeostasis and autoimmune diseases are reviewed.
Journal ArticleDOI
The Immunobiology of the Interleukin-12 Family: Room for Discovery.
TL;DR: Significant knowledge gaps are presented, including how similar signals from these cytokines can mediate distinct outcomes, and how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
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.