December 2014

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels

Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

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June 2014

Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation b...

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Structural basis for the recognition of interferon-α receptor by tyrosine kinase 2

Nat Struct Mol Biol. 2014 May;21(5):443-8. doi: 10.1038/nsmb.2807. Epub 2014 Apr 6

Janus kinases, JAKs, are essential in the mediation of cytokine and interferon signalling whilst also being crucial to body processes such as immune function, hematopoeises, metabolism and cellular growth. However, it is not known is how the four members of the JAK family interact with and are activated by over 30 cytokine receptors with near perfect affinity and specificity. Currently, there are no crystal structures available for any JAK bound to a cytokine receptor. This study sought address ...

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April 2014

Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors

Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279

Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...

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October 2013

The JAK inhibitor, tofacitinib, reduces the t cell stimulatory capacity of human monocyte-derived dendritic cells

Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203756

The role of JAKs is highly important in lymphocyte differentiation, but their function in dendritic cells in unknown. In this study, the authors used tofacitinib, a JAK inhibitor, to assess the function of these kinases in dendritic cell activity. The results show that tofacitinib reduced the expression of CD80/CD86 by suppressing the activation of interferon regulatory factor (IRF)-7 and production of type 1 interferon (IFN), and also decreased T cell stimulatory capability. This suggests a nov...

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June 2013

Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

Molecular Immunology 2007; 44:2497-506

This review from 2007 provides an overview of the largest cytokine receptor family, the haematopoietin receptors, as well as other key components involved in one of the major cytokine signalling pathways implicated in autoimmune and inflammatory diseases. This includes the Janus kinases (Jaks), signal transducers and activators of transcription (Stats) and suppressors of cytokine signalling genes (Socs). Essentially, when a cytokine binds to a receptor from this group a functional cytokine recep...

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Small molecules targeting JAKs—a new approach in the treatment of rheumatoid arthritis

Rheumatology 2013: doi: 10.1093/rheumatology/kes417

This article focuses on the development of new small molecular inhibitors of Janus kinases (Jaks) in clinical trials for rheumatoid arthritis (RA). Of these, tofacitinib is at the most advanced stage of its clinical development and this article includes an overview of the results from the main tofacitinib clinical trials to date. These include the ORAL-Start study in methotrexate (MTX)-naïve patients; ORAL-Scan in inadequate responders to MTX; ORAL-Solo and ORAL-Sync in inadequate responders to ...

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Janus kinases inhibitors in autoimmune diseases

Annals of the Rheumatic Diseases 2013; 72:ii111-ii115

This review describes the role of various cytokines in rheumatoid arthritis (RA) and related diseases. This includes an overview of the different types of cytokine receptors including type I, which bind some of the interleukins (ILs), colony stimulating factors (CSFs) and hormones such as erythropoietin, prolactin and growth hormone (GH); and type II, which bind to interferons and IL-10-related proteins. In addition, the cytoplasmic domain of type I and II cytokine receptors bind to members of a...

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