Janus Family Kinase

Janus family kinases (JAKs) are a subgroup of non-receptor protein tyrosine kinases comprising four members (Ghoreschi et al., 2009; Hsu and Armstrong, 2014):

  • JAK1
  • JAK2
  • JAK3
  • TYK2.

These are involved in a variety of processes, including immunity, with different cytokines signalling through different JAK members to modulate immune responses in different ways (Ghoreschi et al., 2009).

When specific cytokines bind to cell-surface JAK receptors, JAK proteins are activated, and phosphorylation produces docking sites for intracellular Signal Transducer and Activator of Transcription (STAT) molecules (Coskun et al., 2013; Shaui and Liu 2003). Docked STATs are activated and translocate to the cell nucleus where they can activate or repress gene transcription (Coskun et al., 2013; Shaui and Liu, 2003).

Video 3. Animation of cytokine-specific JAK/STAT activation (Coskun et al., 2013; Ghoreschi et al., 2009; Shaui and Liu 2003; Thomas et al., 2015).

There are seven STATs and a range of JAK–STAT pairings, which enable signalling via many different cytokines (Hodge et al., 2016), and this can influence immunity in IBD pathology (Coskun et al., 2013). JAK signalling is involved in IBD in several ways, and inhibition of this may be a potential therapeutic target (Coskun et al., 2013).

 JAK involvement in IBD pathology: rationale for inhibition (Coskun et al., 2013).

Figure 11. JAK involvement in IBD pathology: rationale for inhibition (Coskun et al., 2013). IBD, Inflammatory bowel disease; JAK, Janus family kinases; Th2, T helper 2 cell; UC, Ulcerative colitis.

In contrast to therapies such as monoclonal antibodies, which have a single specific target, inhibition of JAK signalling may influence several cytokine-induced inflammatory pathways (Nielsen et al., 2016).