Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130

Sandra E. Nicholson(Walter and Eliza Hall Institute of Medical Research), David P. De Souza(Walter and Eliza Hall Institute of Medical Research), Louis Fabri(Walter and Eliza Hall Institute of Medical Research), Jason Corbin(Walter and Eliza Hall Institute of Medical Research), Tracy A. Willson(Walter and Eliza Hall Institute of Medical Research), Jian‐Guo Zhang(Walter and Eliza Hall Institute of Medical Research), Anabel Silva(Walter and Eliza Hall Institute of Medical Research), Maria Asimakis(Walter and Eliza Hall Institute of Medical Research), Alison Farley(Walter and Eliza Hall Institute of Medical Research), Andrew D. Nash(Walter and Eliza Hall Institute of Medical Research), Donald Metcalf(Walter and Eliza Hall Institute of Medical Research), Douglas J. Hilton(Walter and Eliza Hall Institute of Medical Research), Nicos A. Nicola(Walter and Eliza Hall Institute of Medical Research), Manuel Baca(Walter and Eliza Hall Institute of Medical Research)
Proceedings of the National Academy of Sciences
May 30, 2000
10.1073/pnas.100135197
Cited by 465Open Access

Abstract

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.

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