[HTML][HTML] Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL‐6 signal transduction

SE Nicholson, TA Willson, A Farley, R Starr… - The EMBO …, 1999 - embopress.org
SE Nicholson, TA Willson, A Farley, R Starr, JG Zhang, M Baca, WS Alexander, D Metcalf…
The EMBO journal, 1999embopress.org
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 …
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 in 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.
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