The suppressors of cytokine signaling (SOCS) proteins: Important feedback inhibitors of cytokine action

While positive effecters of cytokine signaling pathways are relatively well defined, negative regulation can be just as important but is poorly unders tood. The recently discovered suppressor of cytokine signaling (SOCS) famil y of proteins has been implicated in the negative regulation of several cyt okine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (AK/STAT) pathways of transcript ional activation. Biochemical studies revealed that inhibition can occur vi a a variety of mechanisms. SOCS proteins bind to tyrosine-phosphorylated re sidues of target proteins via their SH2 domains, then inhibit JAK activity through their N-terminal domains, and are thought to induce degredation of bound molecules through a conserved SOCS-box motif that interacts with the proteasome, SOCS protein expression is induced by a wide variety of cytokin es with each member displaying varying kinetics of induction. Gene modifica tion studies in mice have demonstrated that SOCS-1 has a clear role in the negative regulation of interferon-gamma signaling, while other SOCS family members have also been shown to be involved in the regulation of T cell, gr owth hormone, and erythropoietin signaling sa stems. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.