Jeff Babon-Projects

Jeff Babon-Projects



Understanding the molecular function of SOCS3

The protein SOCS3 is a powerful regulator of interleukin 6 (IL-6) signalling. IL-6 is a cytokine that helps to orchestrate our immune responses as well as controlling development and maintenance of our haematapoietic (blood) system. Our biochemical and structural studies have elucidated some aspects of the SOCS3 mechanism and shown that it binds to a complex of the IL-6 receptor and JAK the enzyme responsible for initiating the intracellular signaling cascade. However, there is much still to learn, for example it is unclear whether SOCS3 inhibits JAK in cis or in trans. Further it is unclear whether the position of the SOCS3 binding site within the IL-6 receptor is important. Is it possible to widen the repertoire of cytokines inhibited by SOCS3 by engineering SOCS3 binding sites into other receptors? This project aims to elucidate such molecular details of SOCS3 action.

Project references: 
Kershaw, NJ, Murphy, JM, et al. SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nature Structural & Molecular Biology. 2013 Apr;20(4):469-476. PMID: 23454976.
Babon, JJ, Kershaw, NJ, et al. Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity. 2012 Feb 24;36(2):239-250. PMID: 22342841.


A novel family of interleukin-6 inhibitors

Interleukin-6 (IL6) is a pleiotropic cytokine that has important roles in immunity and inflammation and in some cancers. It can have both pro- and anti-inflammatory activities. Blockade of IL-6 signalling is used to treat both rheumatoid arthritis and Castleman’s Disease. In order to signal, IL6 binds to a specific receptor (IL6-R) found on the surface of target cells. Recently, we have identified a novel protein that controls the levels of this receptor found expressed on the cell surface. This project aims to understand the molecular basis of IL-6 receptor down-regulation and the biological consequences on the immune system. Since the centrality of IL6 to several human diseases has been demonstrated by the approval of IL6 inhibitors for clinical use, understanding the mechanism of inhibition by this novel family of IL6 inhibitors may point to new therapeutic approaches to treating these diseases.