Abstract
Members of the interleukin-6 (IL-6) family of cytokines exert their biological effects via binding to their cognate ligand-binding receptor subunit on a target cell. The subsequent recruitment of the common signal transducer glycoprotein 130 and activation of the JAK/STAT and SHP-2/Ras/mitogen-activated protein kinase (MAPK) pathways are responsible for the majority of cellular responses elicited by IL-6 cytokines. Several types of experiments suggest that the Src family of kinases (SFK) also participates in IL-6 family cytokine-mediated signaling events. SYF cells, which lack expression of SFKs Src, Yes, and Fyn, were used to determine the role of SFKs in IL-6 family cytokine signaling and gene induction. SYF and wild type (WT) control fibroblasts displayed similar activation of signaling intermediates following stimulation with leukemia inhibitory factor (LIF). LIF-stimulated tyrosine phosphorylation of SHP-2 and subsequent activation of MAPK in SYF cells were identical to that seen in LIF-stimulated WT cells. Both LIF-stimulated tyrosine phosphorylation of STAT1 and STAT3, as well as LIF-stimulated DNA binding activity of STAT-containing nuclear complexes were indistinguishable when compared in SYF and WT cells. In addition, the phosphatidylinositol 3-kinase-sensitive Akt kinase and p38 MAPK were activated by LIF in both SYF and WT cells. Furthermore, LIF-stimulated expression of c-fos, egr-1, and suppressor of cytokine signaling-3 was retained in SYF cells. The IL-6 family cytokine oncostatin M was also capable of activating MAPK, STAT3, STAT1, Akt, and p38 in both WT and SYF cells. These results demonstrate that IL-6 family cytokines can activate a full repertoire of signaling pathways and induce gene expression independent of SFKs.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Nucleus / metabolism
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Cells, Cultured
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Cytokines / metabolism
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Early Growth Response Protein 1
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Electrophoresis, Polyacrylamide Gel
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Enzyme Activation
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Fibroblasts / metabolism
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Growth Inhibitors / metabolism
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Growth Inhibitors / physiology*
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Humans
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Immediate-Early Proteins*
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Immunoblotting
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Interleukin-6 / metabolism
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Leukemia Inhibitory Factor
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Ligands
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Lymphokines / metabolism
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Lymphokines / physiology*
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MAP Kinase Signaling System
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism
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Oncostatin M
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Peptides / metabolism
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Phosphorylation
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Precipitin Tests
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Protein Binding
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-fos / metabolism
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction*
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Time Factors
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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p38 Mitogen-Activated Protein Kinases
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src-Family Kinases / metabolism*
Substances
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Cytokines
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DNA-Binding Proteins
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EGR1 protein, human
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Early Growth Response Protein 1
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Egr1 protein, mouse
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Growth Inhibitors
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Immediate-Early Proteins
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Interleukin-6
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LIF protein, human
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Leukemia Inhibitory Factor
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Lif protein, mouse
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Ligands
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Lymphokines
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OSM protein, human
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Osm protein, mouse
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Peptides
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-fos
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat1 protein, mouse
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Stat3 protein, mouse
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Trans-Activators
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Transcription Factors
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Oncostatin M
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src-Family Kinases
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases