Abstract
Down-regulation of interleukin (IL)-6-type cytokine signaling has been shown to occur, among other mechanisms, via induction of the feedback inhibitor SOCS3 (suppressor of cytokine signaling 3). Binding of SOCS3 to the phosphorylated Tyr(759) in the cytoplasmic region of gp130, the common signal transducing receptor chain of all IL-6-type cytokines, is necessary for inhibition of Janus kinase-mediated signaling. In the present study, we analyzed the effect of SOCS3 on signal transduction by the proinflammatory cytokine oncostatin M (OSM), which signals through a receptor complex of gp130 and the OSM receptor (OSMR). OSM leads to a much stronger and prolonged induction of SOCS3 in HepG2 hepatoma cells and murine embryonal fibroblasts (MEF) compared with IL-6. A negative effect of SOCS3 on OSM signaling was confirmed using MEF cells lacking SOCS3. We can show that the OSMR-mediated signaling is inhibited by SOCS3 to a similar extent as previously described for gp130. However, the inhibition occurs independent of tyrosine motifs within the OSMR. Instead, SOCS3 interacts directly with JAK1 in a stimulation-dependent manner, a mechanism so far only known for SOCS1.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Blotting, Western
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Carcinoma, Hepatocellular / pathology
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Transformation, Viral
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Cytokine Receptor gp130 / genetics
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Cytokine Receptor gp130 / metabolism
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Cytokines / pharmacology
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Fibroblasts / metabolism
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Gene Expression Regulation*
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Genes, Reporter
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Humans
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Interleukin-6 / metabolism
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Janus Kinase 1
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Leupeptins / pharmacology
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Liver Neoplasms / pathology
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Luciferases / metabolism
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Mice
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Oncostatin M
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Precipitin Tests
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Protein Binding
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Protein-Tyrosine Kinases / metabolism
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Receptors, Amino Acid / metabolism*
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Receptors, Cytokine / genetics
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Receptors, Cytokine / metabolism*
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Receptors, Oncostatin M
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Signal Transduction*
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / metabolism*
Substances
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Antineoplastic Agents
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Cytokines
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Interleukin-6
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Leupeptins
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OSM protein, human
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Osm protein, mouse
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Receptors, Amino Acid
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Receptors, Cytokine
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Receptors, Oncostatin M
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SOCS3 protein, human
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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tyrosine receptor
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Oncostatin M
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Cytokine Receptor gp130
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Luciferases
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Jak1 protein, mouse
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Janus Kinase 1
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde