RESUMEN
Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-gamma signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-gamma. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-gamma and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.
Asunto(s)
Proteínas Portadoras/fisiología , Citocinas/antagonistas & inhibidores , Proteínas Represoras , Animales , Proteínas Portadoras/genética , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de CitocinasRESUMEN
Suppressor of cytokine signaling-3 (SOCS-3) is one member of a family of intracellular inhibitors of signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain of SOCS-3 has been shown to be essential for this inhibitory activity, and we have used a quantitative binding analysis of SOCS-3 to synthetic phosphopeptides to map the potential sites of interaction of SOCS-3 with different components of the gp130 signaling pathway. The only high-affinity ligand found corresponded to the region of gp130 centered around phosphotyrosine-757 (pY757), previously shown to be a docking site for the tyrosine phosphatase SHP-2. By contrast, phosphopeptides corresponding to other regions within gp130, Janus kinase, or signal transducer and activator of transcription proteins bound to SOCS-3 with weak or undetectable affinity. The significance of pY757 in gp130 as a biologically relevant SOCS-3 docking site was investigated by using transfected 293T fibroblasts. Although SOCS-3 inhibited signaling in cells transfected with a chimeric receptor containing the wild-type gp130 intracellular domain, inhibition was considerably impaired for a receptor carrying a Y-->F point mutation at residue 757. Taken together, these data suggest that the mechanism by which SOCS-3 inhibits the gp130 signaling pathway depends on recruitment to the phosphorylated gp130 receptor, and that some of the negative regulatory roles previously attributed to the phosphatase SHP-2 might in fact be caused by the action of SOCS-3.