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 cytokin e stimulation through different types of receptors to transduce intrac ellular responses. We have previously reported that leukemia inhibitor y factor (LIF) induces the activation of Janus kinase signal transduce r and activator of transcription (JAK-STAT) and mitogen-activated prot ein (MAP) kinase pathways through glycoprotein (gp) 130 in cardiac myo cytes, However, whether PI 3-kinase is involved in regulation of gp130 signaling and the activation mechanisms by which it associates with o ther tyrosine-phosphorylated proteins remain unknown. We found that LI F induced the activation of PI 3-kinase in cardiac myocytes, Moreover, JAK1 binds to PI 3-kinase, and LIF stimulation increases the PI 3-kin ase 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 wer e inhibited by wortmannin and rapamycin. Both inhibitors failed to app reciably affect the phosphorylation of STAT3. In conclusion, PI 3-kina se is activated with LIF in cardiac myocytes, and JAK1 is found to ass ociate with this enzyme. PI 3-kinase provides a crucial link between g p130, MAP kinase, protein kinase B, and p70 S6 kinase in cardiac myocy tes.