Our discovery of a family of negative regulators of cytokine signalling (the Suppressors of Cytokine Signalling, SOCS) was based on a screen that allowed the M1 myeloid leukaemic cell line to continue to grow in the presence of interleukin 6.

The expression of various SOCS proteins is induced by cytokine activation of the JAK/STAT pathway and they then act as feedback inhibitors to terminate the pathway. Biochemical studies have revealed that the SH2 domains of SOCS proteins bind phosphorylated tyrosines on selected substrates and that the C-terminal SOCS box recruits elonginsB/C and cullin 5 to form an E3 ubiquitin ligase that ubiquitinates the bound substrates and targets them for proteasomal degradation.

Two members of the family, SOCS1 and SOCS3, display an additional inhibitory mechanism that involves direct inhibition of the kinase activity of JAKs. Recent structural and biochemical studies have revealed the precise mechanism by which this occurs. Genetic deletion studies in mice have revealed how overactivity of cytokine action and specificity of action are regulated by SOCS proteins and how these relate to the molecular mechanism of action. Very recently we have used the same M1 assay described above to discover a second family of inhibitors of cytokine signalling- the MARCH proteins. These proteins are integral membrane proteins that also display E3 ubiquitin ligase activity and have been previously shown to regulate the expression at the cell surface of a number of immunoregulatory receptors. We now show that some of these proteins also specifically down-regulate the cell surface expression of cytokine receptors like those for interleukin 6 and render cells unresponsive to the cytokine.