Biology and significance of the JAK/STAT signalling pathways

Abstract

Since its discovery two decades ago, the activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway by numerous cytokines and growth factors has resulted in it becoming one of the most well-studied intracellular signalling networks. The field has progressed from the identification of the individual components to high-resolution crystal structures of both JAK and STAT, and an understanding of the complexities of the molecular activation and deactivation cycle which results in a diverse, yet highly specific and regulated pattern of transcriptional responses. While there is still more to learn, we now appreciate how disruption and deregulation of this pathway can result in clinical disease and look forward to adoption of the next generation of JAK inhibitors in routine clinical treatment.

Figure 1. Non-redundant JAK/STAT signalling in mice

Schematic showing the preferential cytokine/growth factor usage of different JAKs and STATs, as based on gene-targeting studies in mice. Emphasis in bold indicates the dominant JAK of the pair and colour coding links the individual cytokine/growth factors with their requisite STAT/s. See text for references.

Figure 2. JAK and STAT domain organisation

Schematic showing the domain organisation of JAK and STAT proteins. The valine 617 commonly mutated in JAK2 in myeloproliferative neoplasms is shown. NT: N-terminal region, DBD: DNA binding domain, TAD: transcriptional activation domain.