Article

Janus kinases in immune cell signaling. Immunol Rev

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunological Reviews (Impact Factor: 10.12). 04/2009; 228(1):273-87. DOI: 10.1111/j.1600-065X.2008.00754.x
Source: PubMed

ABSTRACT

The Janus family kinases (Jaks), Jak1, Jak2, Jak3, and Tyk2, form one subgroup of the non-receptor protein tyrosine kinases. They are involved in cell growth, survival, development, and differentiation of a variety of cells but are critically important for immune cells and hematopoietic cells. Data from experimental mice and clinical observations have unraveled multiple signaling events mediated by Jaks in innate and adaptive immunity. Deficiency of Jak3 or Tyk2 results in defined clinical disorders, which are also evident in mouse models. A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome. By contrast, complete deletion of Jak1 or Jak2 in the mouse are not compatible with life and, unsurprisingly, do not have counterparts in human disease. However, activating mutations of each of the Jaks are found in association with malignant transformation, the most common being gain-of-function mutations of Jak2 in polycythemia vera and other myeloproliferative disorders. Our existing knowledge on Jak signaling pathways and fundamental work on their biochemical structure and intracellular interactions allow us to develop new strategies for controlling autoimmune diseases or malignancies by developing selective Jak inhibitors, which are now coming into clinical use. Despite the fact that Jaks were discovered only a little more than a decade ago, at the time of writing there are 20 clinical trials underway testing the safety and efficacy of Jak inhibitors.

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    • "As shown in Fig. 2 A, TYK2-deficient cells displayed low levels of IFN-R1 surface expression, whereas IFN-R2, IFN-R1, and IFN-R2, which are not known to bind TYK2, were normally expressed (not depicted). We also assessed the expression of IL-10R2 and IL-12R1, which are constitutively associated with TYK2 (Ghoreschi et al., 2009; Casanova et al., 2012; Stark and Darnell, 2012). As expected, IL-10R2– and IL-12R1– deficient cells did not express the corresponding receptors. "
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    • "In recent years, numerous studies have established that hyperactivation of the JAK/STAT signal pathway occurs in the synovium of RA patients and of animal models of arthritis, signifying an essential role of this signaling pathway in regulation of the inflammatory response (Mori et al., 2011). It is well known that JAKs associate with cytokine receptors and translate signals triggered by cytokine binding into intracellular responses (Ghoreschi et al., 2009). Recently it has been proposed that downregulation or inhibition of JAKs would effectually prevent cytokine signaling and thus treat RA; however, the precise role of JAK/STAT signaling in this disease remains unclear (Fridman et al., 2015). "
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