Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction
- Author(s)
- Nicholson, SE; Willson, TA; Farley, A; Starr, R; Zhang, JG; Baca, M; Alexander, WS; Metcalf, D; Hilton, DJ; Nicola, NA;
- Details
- Publication Year 1999-01-15,Volume 18,Issue #2,Page 375-385
- Journal Title
- EMBO JOURNAL
- Publication Type
- Journal Article
- Abstract
- SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts, Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction, Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity irt vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways, Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.
- Publisher
- OXFORD UNIV PRESS
- Keywords
- TYROSINE KINASE; ACTIVATION; STAT3; CIS; SH2; PHOSPHORYLATION; DIFFERENTIATION; EXPRESSION; BINDING; PATHWAY
- Publisher's Version
- https://doi.org/10.1093/emboj/18.2.375
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 1999-01-15 12:00:00