Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytes.
Phosphatidylinositol (PI) 3-kinase is known to be activated by cytokine stimulation through different types of receptors to transduce intracellular responses. We have previously reported that leukemia inhibitory factor (LIF) induces the activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein (MAP) kinase pathways through glycoprotein (gp) 130 in cardiac myocytes. However, whether PI 3-kinase is involved in regulation of gp130 signaling and the activation mechanisms by which it associates with other tyrosine-phosphorylated proteins remain unknown. We found that LIF induced the activation of PI 3-kinase in cardiac myocytes. Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kinase activity in JAK1 immunoprecipitates. Activation of MAP kinase and protein kinase B by LIF was attenuated by wortmannin. LIF-induced p70 S6 kinase activation, protein synthesis, and c-fos mRNA expression were inhibited by wortmannin and rapamycin. Both inhibitors failed to appreciably affect the phosphorylation of STAT3. In conclusion, PI 3-kinase is activated with LIF in cardiac myocytes, and JAK1 is found to associate with this enzyme. PI 3-kinase provides a crucial link between gp130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocytes.
Oh
H
H
Department of Medicine III, Osaka University Medical School, Suita, Osaka 565, Japan.
Fujio
Y
Y
Kunisada
K
K
Hirota
H
H
Matsui
H
H
Kishimoto
T
T
Yamauchi-Takihara
K
K
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016762:Genes, fos / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6; D053613:Janus Kinase 1; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D000077191:Wortmannin
D000730:Androstadienes; D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D015850:Interleukin-6; D053613:Janus Kinase 1; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; D019893:Ribosomal Protein S6 Kinases; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000077191:Wortmannin; C494201:Il6st protein, rat; C494088:Stat3 protein, rat; C507906:Jak1 protein, rat