Inhibition of IL-6 family cytokines by SOCS3

• SOCS3 is the primary feedback inhibitor of IL-6 family signalling.
• SOCS3 controls the duration of IL-6 signalling and shapes the cells response to it.
• SOCS3 binds to gp130, the shared IL-6 family co-receptor.
• SOCS3 directly inhibits JAK1, JAK2 and TYK2 but not JAK3.
• SOCS3 targets gp130/JAK complexes.

IL-6 a multi-functional cytokine with important effects in both inflammation and haematopoiesis. SOCS3 is the primary inhibitor of IL-6 signalling, interacting with gp130, the common shared chain of the IL-6 family of cytokines, and JAK1, JAK2 and TYK2 to control both the duration of signalling and the biological response. Recent biochemical and structural studies have shown SOCS3 binds to only these three JAKs, all of which are associated with IL-6 signalling, and not JAK3. This specificity is determined by a three residue “GQM” motif in the kinase domain of JAK1, JAK2 and TYK2. SOCS3 binds to JAK and gp130 simultaneously, and inhibits JAK activity in an ATP-independent manner by partially occluding the kinase's substrate binding groove with its kinase inhibitory region. We therefore propose a model in which each of gp130, JAK and SOCS3 are directly bound to the other two, allowing SOCS3 to inhibit IL6 signalling with high potency and specificity.