Suppressor of cytokine signaling proteins

CYP cytochrome P450 GH growth hormone GHR GH receptor HNF hepatocyte nuclear factor 3MC 3-methylcholanthrene MSG monosodium glutamate SOCS suppressor of cytokine signaling protein STAT signal transducer and activator of transcription. 

Suppressors of cytokine signaling are a family of cytokine-inducible proteins that inhibit JAK kinases. 

Zhang, J. G., et al.. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc Nad Acad Sci USA, 1999, 96(5), 2071-6. 

Alexander WS, Hilton DJ. 2004. The. role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Ann Rev Immunol. 22 503-529. 

Anderson, K.V., Bokla, L., Nusslein-Volhard, C. Establishment of dorsal-ventral polarity in the Drosophila embryo-, the induction of polarity by the Toll gene product. Cell 42 (1985) 791-798. Baetz, A., Frey, M., Heeg, K., Dalpke, A.H. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. J Biol Chem 279 (2004) 54708-54715. 

Protein kinase C-mediated phosphorylation of the EGF receptor on Ser/Thr residues located on the cytoplasmic domain results in inhibition of its tyrosine kinase activity and in inhibition of EGF binding to the extracellular domain. This phosphorylation appears to provide a negative feedback mechanism for control of receptor activity. In another negative control mechanism, inhibitory proteins like SOCS (suppressor of cytokine signaling) bind via their SH2 domains to phosphotyrosine residues in the tyrosine kinase domain of the receptor and directly inhibit the RTK activity. 

The pathway is negatively regulated by protein tyrosine phosphatases and by feedback inhibition through STAT-mediated expression of suppressors of cytokine signaling (SOCs). Agonists for cytokine receptors are currently used to stimulate red blood cell maturation in anemia (erythropoietin) and to stimulate the immune system (interferons). The cascade nature of the cytokine pathway lends itself to future agents that specifically target components of the pathway. 

Fig. 44.16. C54okine signaling through the JAK/STAT pathway. 1. Cytokine binding to receptors initiates dimerization and activation of the JAK kinase, which phosphorylates the receptor on tyrosine residues. 2. STAT proteins bind to the activated receptors and are themselves phosphorylated. 3. Phosphorylated STAT proteins dimerize, travel to the nucleus, and initiate gene transcription. 4. One of the proteins whose s5mthesis is stimulated by STATs is SOCS (suppressor of cytokine signaling), which inhibits further activation of STAT proteins (circle 5) by a variety of mechanisms.

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