Activation of Phosphatidylinositol 3-Kinase through Glycoprotein 130 Induces Protein Kinase B and p70 S6 Kinase Phosphorylation in Cardiac Myocytes

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.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 (1-3). Recent reports revealed that interleukin-6 related cytokines including interleukin-6, leukemia inhibitory factor (LIF), 1 ciliary neurotrophic factor, oncostatin M, and cardiotrophin-1 activate Janus kinase (JAK)/Tyk family kinases by the formation of homodimers or heterodimers of gp130 (4 -7). gp130 functions as a common cytokine signal transducer for the interleukin-6 family, and is reported to lead to cardiac hypertrophy. These signals might be essential in the physiologic regulation of myocardium by these cytokines (8,9). LIF is also a member of multifunctional cytokines, and induces one to one heterodimerization between the LIF receptor and gp130 (10,11). We have recently demonstrated that 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 LIF both in vivo and in vitro (12).Activation of cell proliferation by several different cytokines has been shown to correlate with the intracellular activation of common protein kinase cascades. This may be explained by the functional pleiotropy and redundancy of cytokine receptor systems (13). It is very intriguing that growth factors (e.g. plateletderived growth factor and angiotensin II) and cytokines work through the JAK/Tyk and MAP kinases and lead to the activation of the same or different sets of signal transduction pathways.It is generally accepted that the tyrosine kinases of growth factor receptors and oncogene products specific...

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

“…[1][2][3][4] Moreover, the recent demonstration of a direct SERCA-2 upregulation in Akt-over- Akt and calcium handling A Cittadini et al expressing mice 11 is in part supported by our data demonstrating a significant increase of SERCA-2 protein in Ad.Akt-infected rats. This finding, which was also observed in rats following exogenous GH administration, 24 provides potential molecular underpinnings for the contractility and Ca 2+ handling changes observed in the current study.…”

“…Myocardial oxygen consumption was evaluated as MVO 2 . Dobutamine doses titrated to achieve a similar .…”

“…interleukin-6), and estrogens. [1][2][3][4] Akt phosphorylation occurs primarily through phosphoinositide 3-kinase (PI3K) activation, translocating the kinase to the membrane. 4 The relevant downstream effectors of Akt are less clear, but include glycogen synthase kinase 3 (GSK-3), tuberus sclerosis complex 1-2, and members of the apoptotic cascade.…”

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

“…Thus, STAT3, a major mediator of LIF function (Auernhammer and Melmed, 2000;Metcalf, 2003), is activated by IGF-I during lung development (Zong et al, 2000). Conversely, LIF induces phosphorylation of insulin receptor substrates, and activation of both MAPK and PI3K/Akt pathways (Argetsinger et al, 1995;Oh et al, 1998;Turnley and Bartlett, 2000). Activation of the Ras/MAPK pathway induces LIF synthesis and activation of JAK/STAT3 in lung carcinoma cells (Park et al, 2003).…”

Akt Promotes Survival of Cardiomyocytes In Vitro and Protects Against Ischemia-Reperfusion Injury in Mouse Heart

“…For example, CT-1 19 and LIF 25 can activate Akt in a wortmannin-sensitive manner, 26 but the role of Akt in gp130-mediated survival has yet to be demonstrated. It might also be relevant that insulin administered with glucose and potassium (GIK therapy) can slow the rate of ischemic cell death after acute myocardial infarction, thereby reducing patient mortality.…”