Limiting cytokine action: Suppressors Of Cytokine Signalling (SOCS) Proteins
Many cytokines are a double-edged sword - having beneficial effects in the body’s fight against infection, yet playing a role in the onset and development of inflammatory disease. This implied to us that the body must have mechanisms by which it keeps the effects of cytokines under strict control. Using an expression cloning approach we discovered a family of SH2 domain containing proteins, which we named the Suppressors Of Cytokine Signalling or SOCS proteins, that have proven to be the major negative regulators of cytokine action. Studies in collaboration with the Division of Cancer and Haematology and many other laboratories have established that SOCS proteins are expressed rapidly following stimulation of the JAK/STAT pathway by cytokines. Once produced, SOCS proteins terminate JAK/STAT signalling by binding to signalling complexes. Inhibition of signal transduction occurs both through interaction of the SH2 domain of SOCS proteins with key phosphotyrosine residues in activated signalling components and the recruitment of ubiquitin ligase machinery via a conserved 40 amino acid motif that we named the SOCS Box. This leads to polyubiquitylation of signalling proteins and their degradation by the proteasome.
The JAK/STAT pathway
In order to understand the physiological role of the SOCS proteins we have generated or obtained null alleles of all eight family members. Six of these have been created in collaboration with Professor Warren Alexander in the Division of Cancer and Haematology, one was obtained from Prof. James Ihle and one was obtained using a TILLING approach. Analysis of these mice has yielded important and surprising insights into the specificity of SOCS proteins. SOCS1 for example plays a crucial role in limiting the production and action of IFNγ, SOCS2 controls body size through regulation of growth hormone action and SOCS3 acts as a feedback inhibitor of the LIF/IL6 group of cytokines and of G-CSF. In contrast, the roles of SOCS4, SOCS5, SOCS6 and SOCS7 have been more difficult to define. Our current studies are focussed on understanding the redundancy in this system, by generating and analysing mice that lack two or more functional SOCS genes.