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 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Carrier Proteins / chemistry
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Carrier Proteins / genetics*
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Carrier Proteins / physiology*
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Cell Differentiation
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Cell Line
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Cytokines / physiology
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DNA-Binding Proteins*
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Growth Inhibitors / physiology*
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Interleukin-6 / physiology*
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JNK Mitogen-Activated Protein Kinases
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Leukemia Inhibitory Factor
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Lymphokines / physiology*
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Mice
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Mitogen-Activated Protein Kinases*
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Mutation*
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Phosphorylation
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Proteins / chemistry
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Proteins / genetics
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Proteins / physiology
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Repressor Proteins*
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Signal Transduction
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators*
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Transcription Factors*
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Transfection
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Tyrosine / metabolism
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src Homology Domains / genetics
Substances
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Carrier Proteins
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Cytokines
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DNA-Binding Proteins
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Growth Inhibitors
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Interleukin-6
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Leukemia Inhibitory Factor
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Lif protein, mouse
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Lymphokines
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Proteins
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Repressor Proteins
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Socs1 protein, mouse
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Socs2 protein, mouse
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Tyrosine
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases