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
Tyrosine Kinase 2 Signalling Drives Pathogenic T cells in Colitis.
Leonie C. De Vries,Mohammed Ghiboub,Patricia van Hamersveld,Olaf Welting,Caroline Verseijden,Matthew J Bell,Inmaculada Rioja,Rab K. Prinjha,Pim J. Koelink,Birgit Strobl,Mathias Müller,Geert R. D'Haens,Manon E. Wildenberg,Wouter J. de Jonge,Wouter J. de Jonge +14 more
TL;DR: It is concluded that TYK2 is a promising drug target for the treatment of IBD because it prevented weight loss and limited endoscopic activity during T cell transfer colitis and reduced human Th1 differentiation and ameliorated the course of murine T cellTransfer colitis.
Journal ArticleDOI
Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage.
TL;DR: In this paper, the authors investigated the immunomodulatory potential of four JAKis (tofacitinib, baricitinib and upadacitininib) currently approved for rheumatoid arthritis treatment by the European Medicines Agency.
Journal ArticleDOI
The impact of TNFSF14 on prognosis and immune microenvironment in clear cell renal cell carcinoma
TL;DR: TNFSF14 has crucial impact on progression, prognosis and immune microenvironment in RCC and may be a potential biomarker for predicting the efficacy and response rate of RCC immunotherapy.
Journal ArticleDOI
Combination of tumor mutation burden and immune infiltrates for the prognosis of lung adenocarcinoma.
TL;DR: In this paper, the authors explored the potential role of a signature of genes associated with TMB and immune infiltrates in the prognosis of lung adenocarcinoma (LUAD) patients.
Journal ArticleDOI
JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells
Yuya Fujita,Naoki Matsuoka,Jumpei Temmoku,Makiko Furuya-Yashiro,Tomoyuki Asano,Shuzo Sato,Haruki Matsumoto,Hiroshi Watanabe,Hideko Kozuru,Hiroshi Yatsuhashi,Atsushi Kawakami,Kiyoshi Migita +11 more
TL;DR: It is concluded that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells, and although baricitinib and upadacitinib almost completely blocked GM- CSF- mediated Jak2/ STAT5 signaling, the inhibitory effects of tofacitinIB were weaker at lower concentrations suggesting that variation exists among these JAKs in the inhibition of JAK 2 signaling pathways.
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.
Journal ArticleDOI
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.