Schematic outlining the IL-6 JAK-STAT signalling pathway and regulation
The JAK proteins are constitutively associated with the GP130 receptor. IL-6 binds IL6RA and GP130, allowing the JAKs to come into close proximality to one another. The JAKs are then activated by transphosphorylation, and subsequently phosphorylate nearby tyrosine residues including those found on the GP130 receptor tail. The four distal phosphotyrosine sites act as docking sites for STATs. Activated STATs then translocate to the nucleus where they bind to specific regions on target DNA and up-regulate gene transcription. These changes in gene transcription dictate the response the cell has to the initial cytokine binding. There are several proteins involved in the regulation of JAK-STAT signalling, including the SOCS proteins and phosphatases which control ubiquitination and dephosphorylation of the proteins, respectively. Additionally, drugs such as JAK and IL-6 inhibitors have been developed as therapeutics to block signalling via the JAK-STAT signalling pathway.