Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors

Abstract

Cytokines can trigger multiple signalling pathways, including Janus tyrosine kinases [JAK] and signal transducers and activators of transcription [STATS] pathways. JAKs are cytoplasmic proteins that, following the binding of cytokines to their receptors, transduce the signal by phosphorylating STAT proteins which enter the nuclei and rapidly target gene promoters to regulate gene transcription. Due to the critical involvement of JAK proteins in mediating innate and adaptive immune responses, these family of kinases have become desirable pharmacological targets in inflammatory diseases, including ulcerative colitis and Crohn's disease. In this review we provide an overview of the main cytokines that signal through the JAK/STAT pathway and the available in vivo evidence on mutant or deleted JAK proteins, and discuss the implications of pharmacologically targeting this kinase family in the context of inflammatory diseases.

Keywords: Janus tyrosine kinase; cytokine signalling; inflammatory bowel disease.

Figure 1.

Schematic of Janus kinase proteins structure. Janus kinases comprise the FERdomain [JH6-JH7] and the SH2 domain [JH3-JH5], both mediating receptor interactions, the pseudokinase domain [JH2] with regulatory function, the catalytic domain [JH1], and the kinase domain.

Figure 2.

Overview of cytokine signalling through the Janus kinase pathway. Cytokines bind to homodimeric or heterodimeric receptors, after ligand stimulation receptors undergo conformational changes and bring JAKs into proximity which each other. JAKs trans/auto phosphorylate each other and the receptor, allowing STATS to bind to the receptor. Subsequently JAKs phosphorylate STATS, allowing them to dimerise and translocate to the nucleus to regulate gene transcription.

Figure 3.

Schematic representation of cytokine and receptor Janus kinase pathway. The four JAKs [JAK1, JAK2, JAK3, and TYK2] are selectively bound to and therefore mediate signalling for various cytokine and hormone receptors. Scheme representing all JAK pathway cytokines and with whom JAKs are associated. TYK2 [shown in dark blue] where there is evidence of its catalytic activity playing an essential role. TYK2 [in light blue] when it plays a scaffolding function. *The cytokine IL-31 does not signal through gp130 because of sharing the subunit [OSMRβ] with OSM, which belongs to the IL-6 receptor family.