Suppressors of cytokine signaling as tumor repressors. Silencing of SOCS3 facilitates tumor formation and growth in lung and liver

Abstract

The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Eight SOCS (SOCS1-SOCS7 and CIS /cytokine-inducible SH2-domain) proteins with similar structures have been identified. Cytokines bind to specifi c sites on the extracellular domains of their cognitive receptor, causing receptor dimerization. This allows the recruitment of JAKs to the receptors, which then cross-phosphorylate each other before phosphorylating the receptor on key tyrosine residues. STAT molecules bind to these phosphorylated docking sites, are in turn phosphorylated, dimerized, and enter the nucleus where they initiate transcription. Some of the genes transcribed by these factors include the SOCS genes. The SOCS proteins then act to negatively regulate activated receptor complexes by inactivating JAKs or blocking recruitment sites for STATs and also may target signaling complexes for ubiquitination and degradation. Lung cancer and hepatocellular carcinoma (HCC) are associated with abnormalities of the JAK/STAT pathway. In conclusion, determining the importance of SOCS family in health and disease will no doubt aid to the development of novel therapeutic strategies in human carcinogenesis.