Janus kinases in immune cell signaling - PubMed (original) (raw)

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Janus kinases in immune cell signaling

Kamran Ghoreschi et al. Immunol Rev. 2009 Mar.

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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Figures

Fig. 1

Fig. 1. Schematic structure of Jaks

The Jak family comprises four structurally related kinases: Jak1, Jak2, Jak3, and Tyk2. Seven Jak homology regions (JH) containing the catalytically active kinase domain (JH1), the enzymatically inactive pseudokinase domain (JH2), the SH2 domain (JH3, JH4), and a FERM domain (JH6, JH7) form the Jak protein. The FERM domain mediates Jak binding to the transmembrane cytokine receptor and regulates kinase activity.

Fig. 2

Fig. 2. Development of hematopoietic malignancies by Jaks and possible control mechanisms

Lymphoproliferative and myeloproliferative diseases may be caused by different Jak activating mutations (A) or fusion proteins based on chromosomal translocation (B). Both genetic changes result in constitutive activation of Jak2 and downstream STAT activation responsible for cell transformation and uncontrolled proliferation. The regulatory functions of SOCS can either not cope with the constitutive activation or are silenced by Jak2V617F hyperphosphorylation (A). The generation and use of selective Jak2 or Jak2V617F inhibitors may interrupt the signaling cascade and prevent tumor progression. When tumor-protective IFN-γ-dominated immune responses are impaired due to the absence of Tyk2, the development of TEL-Jak2-mediated T-lymphoid leukemia is accelerated in mice (B).

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