Differential inhibition of IL-6-type cytokine-induced STAT activation by PMA.
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.
Institut für Biochemie, Linikum der RWTH Aachen, Pauvelsstr, 30, 52057 Aachen, Germany.
L
L
Terstegen
B G
BG
Maassen
S
S
Radtke
I
I
Behrmann
F
F
Schaper
P C
PC
Heinrich
L
L
Graeve
P
P
Gatsios
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053649:Receptors, Interleukin-5; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015848:Interleukin-5; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D053683:Oncostatin M; D010455:Peptides; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C507837:LIF protein, human; C507840:LIFR protein, human; C508351:OSM protein, human; C106644:SOCS3 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C507904:JAK1 protein, human; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human