INTRODUCTION
Janus kinases are a key component of the molecular machinery
involved in signal transduction through various cytokine
receptors.1 Janus kinases, which are associated with the cytoplasmic domain of cytokine receptors, become activated
when a cytokine binds to its receptor (Figure 1, panel a).2-4 Activation of JAKs leads to the phosphorylation of the cytokine receptor (Figure 1, panel b), and this event creates docking sites for proteins known as signal transducers and activators of transcription
(STATs) (Figure 1, panel c). Binding of a STAT to the cytokine receptor results in its phosphorylation by JAKs (Figure 1, panel d). The phosphorylated STAT dissociates from the cytokine
receptor and forms a dimer with another phosphorylated STAT (Figure 1, panels e - f), and the dimer translocates to the nucleus, where it modulates transcription of genes involved in cell growth, proliferation, and differentiation.2-5
Functional Domains of JAKs
Four subtypes of JAKs (JAK1, JAK2, JAK3, and Tyrosine kinase 2 [Tyk2]) have been identified, with seven functional domains common to all subtypes (Figure 2).4-6 The targeted deletion of genes for each subtype of JAK has provided information on their functions (Table 1).1,7,8 Both JAK1 and JAK2 genes are necessary
for survival, as mice without JAK1 die perinatally and mice without JAK2 die as embryos on day 12.1,7 Mice lacking JAK3 do not die but develop severe combined immunodeficiency
(SCID).8 Also, mice without JAK3 are defective in T, B, and NK cells.9,10 Finally, mice without Tyk2 show increased viral
susceptibility.11 Studies have further investigated animals deficient in JAK3 and Tyk2 and identified the effects of these deficiencies on signaling through various cytokines (Table 1).
Limited Distribution of JAK3
While JAK1, JAK2, and Tyk2 are expressed in most tissues, a unique feature of JAK3 is that it is mainly expressed in hematopoietic
cells and mediates signaling only through cytokines whose receptors contain a gc-subunit.12 Thus, JAK3 participates in signaling
through IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21. These cytokines are involved in the development, differentiation, proliferation, and survival of multiple cell types (T-cells, B cells, NK cells, mast cells, and dendritic cells) of the innate as well as adaptive immune systems.
12 Because JAK3 is expressed mainly in the immune system, its inhibition should only affect this system without affecting any other organ systems.6,13,14 This attribute of JAK3 makes it a good target to develop therapies for inflammation, allergy, autoimmune
disease, and organ transplant rejection. However, it has not been possible to develop completely selective inhibitors of JAK3; previous inhibitors claiming to be JAK3 selective have been found to have some affinity for other JAK subtypes as well.
