Following the identification of the JAK kinase family in the late 1980s, the novel enzyme group was colloquially known as “just another kinase.”1,2
Since then, these tyrosine kinases have defied that reputation amid abundant evidence showing that they transmit a variety of signals into the cell with many biological consequences.
Dysregulation of the JAK pathway plays a role in the development of numerous tumor types; it is particularly central to the pathophysiology of myelofibrosis (MF) and has long been recognized as a potentially valuable therapeutic target in that malignancy. Ruxolitinib (Jakafi), the first JAK inhibitor to gain FDA approval, has become a centerpiece in the treatment of patients with MF. JAK inhibition has not proved effective in other tumor types, and thus far, no other JAK-targeting therapies have become available.
That picture, however, may be changing. A better understanding of the complexities of JAK signaling in normal and cancerous cells and the design of rational drug combinations, are poised to expand the use of JAK inhibitors in anticancer therapy for hematologic, and possibly solid, tumors. Ruxolitinib continues to be explored in multiple malignancies, and several promising novel agents are being evaluated in clinical trials (TABLE).
Table. Clinical Trials Targeted the JAK Pathway
A Diverse Family With Multiple Roles
JAKs are now known as the Janus kinases, after the 2-faced Roman god of the same name, in recognition of their most striking feature: the presence of 2 near-identical kinase domains. There are 4 known members of the JAK family: JAK1, JAK2, JAK3, and TYK2, all sharing 7 conserved JAK homology (JH) domains within their protein structures.
At one end of the protein are JH1 and JH2, which comprise the 2 kinase domains. The first has tyrosine kinase activity, while the second is a pseudokinase domain with no catalytic activity that is thought to negatively regulate the first.3,4 At the other end, 3 of the JH domains collectively make up a larger FERM domain through which the JAKs are recruited to and bound by the cell-surface receptors that activate JAK signaling. A third domain, SH2, facilitates signal transducer and activator of transcription (STAT) signaling (FIGURE 1).3,5
Figure 2. Broad Outlines of the JAK Signaling Pathway
Cytokines and their receptors are among the most significant activators of the JAK pathway. Unlike tyrosine kinase receptors, cytokine receptors have no catalytic activity and are reliant upon the JAKs to perform kinase functions for them. JAKs bind to the part of the cytokine receptor that protrudes into the cell via their FERM domain. When the cytokine receptor is activated, it pairs up with another receptor molecule and this brings 2 JAKs close enough that they are able to phosphorylate and activate one another.
Activated JAKs then phosphorylate other target proteins, including the cytokine receptor to which they are bound, forming a binding platform for proteins containing an SH2 domain, primarily STAT proteins. Once they dock to the cytokine receptor, the STATs themselves are phosphorylated by the JAK proteins and become activated (FIGURE 2).
Figure 1. Domain structure of JAK Kinases
Activated STATs subsequently disengage from the cytokine receptor, pair up with one another and move into the nucleus, where they attach to specific sequences within the DNA to either activate or, less commonly, repress the transcription of a host of target genes. In this way, the interaction between JAKs and STATs transmits a signal from outside of the cell into the nucleus to coordinate a response to the signal.
Although this at first appears to be a relatively simple signaling cascade, the activity is complicated by the fact that there are 7 STATs. The diversity of possible JAK-STAT pairings, in addition to the range of different ligands and receptors that can activate JAKs upstream, allows for the multiplicity of biological effects coordinated by this pathway.