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

• DOI: 10.1073/pnas.100135197
• Publication Date: 2002-07-26T14:41:48Z
• Authors: Sandra E. Nicholson; David De Souza; Louis J. Fabri; Jason Corbin; Tracy A. Willson; Jian-Guo Zhang; Anabel Silva; Maria Asimakis; Alison Farley; Andrew D. Nash; Donald Metcalf; Douglas J. Hilton; Nicos A. Nicola; Manuel Baca
• Keywords: Glycoprotein 130; Cytokine receptor; HEK 293 cells

Suppressor of cytokine signaling-3 (SOCS-3) is one member a family intracellular inhibitors signaling pathways initiated by cytokines that use, among others, the common receptor subunit gp130. The SH2 domain SOCS-3 has been shown to be essential for this inhibitory activity, and we have used quantitative binding analysis synthetic phosphopeptides map potential sites interaction with different components gp130 pathway. only high-affinity ligand found corresponded region centered around phosphotyrosine-757 (pY757), previously docking site tyrosine phosphatase SHP-2. By contrast, corresponding other regions within gp130, Janus kinase, or signal transducer activator transcription proteins bound weak undetectable affinity. significance pY757 in as biologically relevant was investigated using transfected 293T fibroblasts. Although inhibited cells chimeric containing wild-type domain, inhibition considerably impaired carrying Y→F point mutation at residue 757. Taken together, these data suggest mechanism which inhibits pathway depends on recruitment phosphorylated receptor, some negative regulatory roles attributed SHP-2 might fact caused action SOCS-3.