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
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Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression
Christopher Groth,Christopher Groth,Xiaoying Hu,Xiaoying Hu,Rebekka Weber,Rebekka Weber,Viktor Fleming,Viktor Fleming,Peter Altevogt,Peter Altevogt,Jochen Utikal,Jochen Utikal,Viktor Umansky,Viktor Umansky +13 more
TL;DR: The current state of knowledge on the origin and function of MDSCs in cancer is analyzed, with a special emphasis on the immunosuppressive pathways pursued by M DSCs to inhibit T cell functions, resulting in tumour progression.
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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.
Lei Zhong,Y. Li,Liang Xiong,Wen-Jing Wang,Ming Wu,Ting Yuan,Wei Yang,Chenyu Tian,Zhuang Miao,Tianqi Wang,Shengyong Yang +10 more
TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
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Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Commentary
Ross L. Levine,Ralph Tiedt,Hui Hao-Shen,Marta Anna Sobas,Renate Looser,Stephan Dirnhofer,Jürg Schwaller,Radek C. Skoda +7 more
TL;DR: In this article, the authors generated JAK2-V617F transgenic mice with the sequences encoding the kinase domain placed in the inverse orientation and flanked by antiparallel loxP sites.
Journal ArticleDOI
Targeting STAT3 in Cancer Immunotherapy
TL;DR: The importance of STAT3 signaling pathway in tumorigenesis and its immune regulation is outlined, the current status for the development ofSTAT3-targeting therapeutic approaches is highlighted, and recent advances in STAT3-based combination immunotherapy are discussed.
Journal ArticleDOI
Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines
TL;DR: The IL-6 family of cytokines in autoimmune diseases is reviewed from the viewpoints of their structure, signaling, and biological features and possible mechanisms of their functional pleiotropy are discussed.
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.