Negative regulation of cytokine signaling

Abstract

Cytokines use complex signaling cascades to elicit their biological effects, many of which involve phosphorylation as a mechanism of activation. Rapid and efficient attenuation of cytokine signals is crucial to maintaining regulation of these processes and to preventing toxic side effects. Phosphatases have been shown to be involved in these regulatory processes, but more recent research has seen the discovery of two new families of negative regulators, the suppressor of cytokine signaling (SOCS) and protein inhibitors of signal transducer and activator of transcription (STAT) (PIAS) protein families. SOCS proteins are induced by and inhibit many cytokine-signaling systems in a classic negative-feedback loop, and the generation of transgenic and knockout models has greatly increased our understanding of their physiological functions. PIAS proteins interact with the transcriptional mediators of cytokine action, the STATs, to suppress their DNA-binding activity. These three classes of molecules form what is now emerging as an integrated system for deactivating cytokine signaling at a number of levels, from the receptor to the transcription factor.