Abstract
Prior activation of mitogen-activated protein kinases by phorbol 13-myristate 12-acetate (PMA) results in an inhibition of interleukin (IL)-6-induced activation of the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway which is most likely mediated by the induction of suppressor of cytokine signaling-3 and requires the specific SHP2 binding site Y759 of the IL-6 signal transducer gp130. In this study, we demonstrate that PMA inhibits STAT activation by IL-6 and the related cytokine leukemia inhibitory factor (LIF) but not by oncostatin M (OSM). Since the LIF receptor also contains an SHP2 recruitment site whereas the OSM receptor lacks such a module, we propose that two SHP2 binding modules within a homo- or heterodimeric receptor are necessary to mediate the PMA inhibitory effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Motifs
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Animals
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Antigens, CD / chemistry
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Binding Sites
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Cell Line
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Cytokine Receptor gp130
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DNA-Binding Proteins / metabolism*
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Dimerization
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Enzyme Activation / drug effects
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Growth Inhibitors / antagonists & inhibitors
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Growth Inhibitors / pharmacology
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Humans
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Interleukin-5 / pharmacology
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Interleukin-6 / antagonists & inhibitors*
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Interleukin-6 / pharmacology
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Intracellular Signaling Peptides and Proteins
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Janus Kinase 1
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Lymphokines / antagonists & inhibitors
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Lymphokines / pharmacology
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MAP Kinase Signaling System / drug effects*
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Oncostatin M
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Peptides / pharmacology
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Receptors, Cytokine / chemistry
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Receptors, Cytokine / metabolism
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Receptors, Interleukin / chemistry
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Receptors, Interleukin / genetics
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-5
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Receptors, OSM-LIF
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Receptors, Oncostatin M
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Tetradecanoylphorbol Acetate / pharmacology*
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Trans-Activators / metabolism*
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Transcription Factors*
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Transfection
Substances
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Antigens, CD
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DNA-Binding Proteins
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Growth Inhibitors
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IL6ST protein, human
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Interleukin-5
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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LIF protein, human
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LIFR protein, human
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Leukemia Inhibitory Factor
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Leukemia Inhibitory Factor Receptor alpha Subunit
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Lymphokines
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Membrane Glycoproteins
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OSM protein, human
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Peptides
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Proteins
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Receptors, Cytokine
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Receptors, Interleukin
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Receptors, Interleukin-5
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Receptors, OSM-LIF
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Receptors, Oncostatin M
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Recombinant Fusion Proteins
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Repressor Proteins
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SOCS3 protein, human
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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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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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Oncostatin M
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Cytokine Receptor gp130
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Protein-Tyrosine Kinases
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JAK1 protein, human
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Janus Kinase 1
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Mitogen-Activated Protein Kinases
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Tetradecanoylphorbol Acetate