Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Kunihiro Yamaoka¹ , Pipsa Saharinen², Marko Pesu¹ , Vance ET Holt III¹ , Olli Silvennoinen³ ^,4 and John J O'Shea¹

¹Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA
²Molecular and Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland
³Institute for Medical Technology, University of Tampere, FIN-33014 Tampere, Finland
⁴Department of Clinical Microbiology, Tampere University Hospital, FIN-33014 Tampere, Finland

Correspondence:

John J O'Shea.

Email:

osheajo@mail.nih.gov

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Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2004/5/12/253

Published:

30 November 2004

The Janus kinases (Jaks)

Summary

The Janus kinase (Jak) family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (Stat) family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes. Through the generation of Jak-deficient cell lines and gene-targeted mice, the essential, nonredundant functions of Jaks in cytokine signaling have been established. Importantly, deficiency of Jak3 is the basis of human autosomal recessive severe combined immunodeficiency (SCID); accordingly, a selective Jak3 inhibitor has been developed, forming a new class of immunosuppressive drugs.

Frontiers

Despite intensive studies during the past decade that have generated the model shown in Figure 2, the exact molecular mechanisms of Jak activation have largely remained elusive. It is clear that much more detailed structural information pertaining to Jaks and the Jak-cytokine-receptor complex is needed to enhance our understanding of the mechanism of Jak activation. Also, the exact mechanism and functional relevance of autophosphorylation at different sites in Jaks is not known but will be an interesting area for future research.

Another important topic for future studies is to define the mechanisms of crosstalk between Jaks and other pathways. For instance, the receptor Notch has been reported to promote Stat3 activation, and the Notch effectors Hes1 and Hes5 have been found to associate directly with Jak2 and Stat3 [53]. Evidence for cooperation between the Jak/Stat and Notch pathways has also been provided by work from Drosophila [54] and genetic screens in Drosophila have identified additional potential modifiers of the Jak/Stat pathway [55]. Jaks have also been reported to be activated by a variety of structurally diverse receptors, beyond the cytokine receptors. Examples include receptor tyrosine kinases, death receptors (such as CD40) and G-protein-coupled receptors (such as chemokine receptors). Many of the studies have employed overexpression or putatively specific inhibitors to implicate the Jaks, but we now know that these inhibitors are not specific, so the essential function of Jaks for non-cytokine receptors remains uncertain. This is clearly another critical area for future work.

Finally, because of the crucial role of Jak3 in cytokine signaling through γc and because of its limited tissue expression, the inhibition of Jak3 activity has emerged as a promising strategy for immunosuppression. A highly selective and potent Jak3 inhibitor (CP-69O, 550) has recently been developed that has nanomolar potency against Jak3 in vitro, with much less potency against other Jak family members. Consequently, CP-690, 550 was both very efficacious and well-tolerated in animal models of organ transplantation [56]. One might anticipate that this drug will help to overcome the unwarranted side effects often seen in patients under current immunosuppressive therapy. Thus, the drug could be useful in blocking transplant rejection and in the treatment of autoimmune diseases. Conceivably, it might also be useful in treating those hematological malignancies that exhibit constitutive Jak3 activation. Targeting Tyk2 with specific drugs would also be logical, given its restricted role; presumably a Tyk2 inhibitor would be useful in some immune-mediated diseases. Whether a Jak2 inhibitor would be useful in malignancies is also worthy of consideration.

A schematic representation of the primary structure of Janus kinases (Jaks), which are made up of FERM, SH2-like, pseudokinase and kinase domains

An overview of cytokine signaling