Abstract
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.
Highlights
A large number of studies have shown that cytokines share signaling pathways involving activation of protein tyrosine kinases which are required for subsequent cellular responses [1,2,3]
We have recently demonstrated that Janus kinase (JAK) signal transducer and activator of transcription (STAT) and mitogen-activated protein (MAP) kinase pathways are present at downstream of gp130 in cardiac myocytes and are rapidly activated by leukemia inhibitory factor (LIF) both in vivo and in vitro [12]
We found that treatment of cardiac myocytes with LIF caused a substantial increase in the PI 3-kinase activity that immunoprecipitated with either anti-phosphotyrosine or anti-PI 3-kinase antibody (Fig. 1A, upper panel)
Summary
A large number of studies have shown that cytokines share signaling pathways involving activation of protein tyrosine kinases which are required for subsequent cellular responses [1,2,3]. A specific inhibitor of PI 3-kinase, wortmannin, inhibited the LIF-induced activation of MAP kinase, protein kinase B (PKB), p70 S6 kinase, protein synthesis, and c-fos mRNA expression in cardiac myocytes. Our study suggests that maximal stimulation of the protein kinase cascade by LIF requires the activation of PI 3-kinase, which may be an important mediator of LIF-induced signal transduction in cardiac myocytes.
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