Fig. 3

Illustration of the JAK/STAT pathway. After binding to their receptor, cytokines such as IL-6 activate an associated Janus Kinase (JAK), which upon phosphorylation of its tyrosine residues recruits and phosphorylates the STAT3 transcription regulator. Phosphorylated STAT3 in turn forms homo- or heterodimers which translocate into the nucleus and impact the transcription of cytokine-responsive genes. In STAT3 GOF, the signaling pathway can lead to increased phosphorylation, altered dimer formation, as well as changes in gene expression. Targeting molecules which are part of the STAT3 pathway leads to improved STAT3 GOF disease control, e.g., disruption of the IL-6/IL-6R interaction via the anti-IL-6R monoclonal antibody tocilizumab. Another strategy is the inhibition of JAK by jakinibs such as ruxolitinib