Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of red blood cells is tightly regulated by erythropoietin (Epo). The phosphoinositide 3-kinase (PI 3-kinase) pathway was previously shown to be activated in response to Epo. We studied the role of this pathway in the control of Epo-induced survival and proliferation of primary human erythroid progenitors. We show that phosphoinositide 3 (PI 3)-kinase associates with 4 tyrosine-phosphorylated proteins in primary human erythroid progenitors, namely insulin receptor substrate-2 (IRS2), Src homology 2 domain-containing inositol 5'-phosphatase (SHIP), Grb2-associated binder-1 (Gab1), and the Epo receptor (EpoR). Using different in vitro systems, we demonstrate that 3 alternative pathways independently lead to Epo-induced activation of PI 3-kinase and phosphorylation of its downstream effectors, Akt, FKHRL1, and P70S6 kinase: through direct association of PI 3-kinase with the last tyrosine residue (Tyr479) of the Epo receptor (EpoR), through recruitment and phosphorylation of Gab proteins via either Tyr343 or Tyr401 of the EpoR, or through phosphorylation of IRS2 adaptor protein. The mitogen-activated protein (MAP) kinase pathway was also activated by Epo in erythroid progenitors, but we found that this process is independent of PI 3-kinase activation. In erythroid progenitors, the functional role of PI 3-kinase was both to prevent apoptosis and to stimulate cell proliferation in response to Epo stimulation. Finally, our results show that PI 3-kinase-mediated proliferation of erythroid progenitors in response to Epo occurs mainly through modulation of the E3 ligase SCF(SKP2), which, in turn, down-regulates p27(Kip1) cyclin-dependent kinase (CDK) inhibitor via proteasome degradation.
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PMID:Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. 1250 11

Cytokine growth factors regulate the normal proliferation of hematopoietic cells but can also override irradiation-induced growth arrest checkpoints through activation of a phosphoinositide 3-kinase (PI3K) signaling pathway. In the present study, we assessed the effect that erythropoietin and interleukin-3 have on cisplatin-treated hematopoietic cells. When cultured in the presence of cytokine, cisplatin-treated 32D cells transiently accumulated in a G(2)-M phase arrest and ultimately died by a nonapoptotic mechanism. By comparison, reduction of cytokine-induced PI3K activity, either through cytokine receptor mutation or direct inhibition with LY294002, caused cisplatin-treated cells to enter a biphasic G(1) and G(2)-M arrest. The arrest of these cells coincided with an absence of cyclin-dependent kinase (Cdk)1 and Cdk2 activity and significantly reduced cell death during cisplatin treatment. Indeed, LY294002 treatment during cisplatin exposure allowed the recovery of a viable, proliferating cell population after removal of cisplatin. In contrast, Cdks remained active in the G(2)-M-arrested population of cisplatin-treated cells with continuous cytokine activation of PI3K, and even transient exposure to cisplatin resulted in death of the entire population. These data suggest that cytokine activation of PI3K signaling pathways overrides cisplatin-induced growth arrest checkpoints, thereby sensitizing hematopoietic cells to DNA damage-induced death.
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PMID:Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death. 1261 19

Circulating bone marrow-derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34(+)/CD45(+) circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% +/- 31%; week 8, 308% +/- 40%; both P <.01 versus baseline) as well as in healthy subjects (week 8, 194% +/- 15%; P <.05 versus baseline). The effect on EPCs was already observed with an rhEPO dose of about 30 IU/kg per week. Administration of rhEPO increased the number of functionally active EPCs by differentiation in vitro in a dose-dependent manner, assessed in cell culture and by tube formation assay. Furthermore, rhEPO activates the Akt protein kinase pathway in EPCs. Erythropoietin increases the number of functionally active EPCs in humans. Administration of rhEPO or EPO analogs may open new therapeutic strategies in regenerative cardiovascular medicine.
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PMID:Erythropoietin regulates endothelial progenitor cells. 1452 88

Interferon (IFN)-gamma is a survival factor for mature erythroid progenitor cells. To elucidate related survival mechanisms, we compared the role of phosphatidylinositol 3-kinase (PI3-kinase) in the survival signals of IFN-gamma and erythropoietin (EPO). Human erythroid colony-forming cells (ECFCs) purified from peripheral blood were used, and Ly294002 was used as a PI3-kinase inhibitor. Treating ECFCs with a high concentration of Ly294002 (50 micromol/L) in the presence of EPO and/or IFN-gamma reduced cell viability by inducing apoptosis. However, treating cells with a lower concentration of Ly294002 (10 micromol/L) did not affect the antiapoptotic function of IFN-gamma and abolished the antiapoptotic effect of EPO. Adding IFN-gamma or EPO induced Bcl-x expression in ECFCs, as determined by Western blotting, and expression was suppressed in the presence of Ly294002. We also examined the phosphorylation of the protein kinase Akt, the downstream target of PI3-kinase. EPO stimulation significantly increased the level of Akt phosphorylation, but IFN-gamma did not. These results suggest that IFN-gamma plays a role in preventing the apoptosis of erythroid progenitor cells by affecting Bcl-x expression, thereby reducing the disruption of the mitochondrial transmembrane potential via PI3-kinase pathways that are related to but distinct from the EPO pathway.
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PMID:The signaling pathways of erythropoietin and interferon-gamma differ in preventing the apoptosis of mature erythroid progenitor cells. 1470 34

The role of cyclic AMP (cAMP) as second messenger in erythropoiesis has been suggested in the early 1980s. However, careful analysis showed that cAMP is not generated in direct response to the main erythropoiesis-controlling cytokines such as erythropoietin (Epo). As a result, cAMP disappeared from the central stage in research of erythropoiesis. Instead, other signal transduction pathways, including the Ras/extracellular regulated kinase (ERK)-pathway, the phosphatidylinositol 3-kinase (P13K) and the signal transducer and activator of transcription (STAT5)-pathways, have been found and explored. In concert, these signaling pathways control the transcriptional machinery of erythroid cells. Although cAMP is not directly generated in response to Epo stimulation, it has recently been demonstrated that increased cAMP-levels and in particular the cAMP-dependent protein kinase A (PKA) can modulate erythroid signal transduction pathways. In some cases, like the ERK-signaling pathway, PKA affects signal transduction by regulating the balance between specific phosphatases and kinases. In other cases, such as the STAT5 pathway, PKA enhances Epo signaling by inducing recruitment of additional co-regulators of transcription. In addition to STAT5, PKA also activates other transcription factors that are required for erythroid gene expression. This review discusses the impact of cAMP/PKA on Epo-mediated signaling pathways and summarizes the role of cAMP in malignant erythropoiesis.
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PMID:cAMP/PKA-mediated regulation of erythropoiesis. 1473 40

Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.
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PMID:Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity. 1500 87

Stimulation of the erythropoietin (EPO) receptor triggers a cascade of signaling events. We reported that EPO upregulates c-myc expression through 2 pathways in BaF3-EpoR cells--a phosphatidylinositol 3-kinase (PI3K) pathway operating on transcriptional initiation and a Raf-1-mitogen-activated protein kinase (MAPK) pathway affecting elongation. We now show that EPO induces phosphorylation of Raf-1 at serine 338 and within the carboxy-terminal domain, resulting in an electrophoretic mobility change (hyperphosphorylation). Importantly, MEK 1 inhibitor PD98059 blocked only the hyperphosphorylation of Raf-1 but not the phosphorylation at serine 338. This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity. Deletion of the first 184 amino acids of Raf-1, which are involved in its interaction with Ras, had no effect on EPO-induced phosphorylation. Introducing the dominant-negative N17Ras or GAP had no effect on EPO-induced kinase activity of Raf-1 and ELK activation. N17Ras failed to inhibit ELK activation in another cell line-Rauscher murine erythroleukemia- which expresses the EPO receptor endogenously and differentiates in response to the hormone. These results indicate the presence of a Ras-independent mechanism for Raf-1 and MEK activation in these cells.
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PMID:Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. 1502 17

Erythropoietin is protective against cardiac ischemia, but the underlying mechanisms are unknown. We determined whether erythropoietin (0.5 - 10.0 U/ml) confers acute cardioprotection in infant rabbit hearts and the contribution of protein kinases, nitric oxide synthase and potassium channels to the underlying mechanism. Hearts from normoxic infant New Zealand White rabbits (n=8/group) were isolated and perfused in the Langendorff mode. Biventricular function was recorded under steady-state conditions prior to 30 min global no-flow ischemia and 35 min reperfusion. Administration of erythropoietin for 15 min immediately prior to ischemia resulted in a concentration-dependent increase in recovery of left and right ventricular developed pressure in rabbit hearts following myocardial ischemia and reperfusion. The optimal concentration of erythropoietin that afforded maximum recovery of developed pressure was manifest at 1.0 U/ml. Erythropoietin (1.0 U/ml) treatment resulted in phosphorylation of PKC, p38 MAP kinase and p42/44 MAP kinase. The cardioprotective effects of erythropoietin were abolished by the protein kinase inhibitors SB203580 (p38 MAP kinase), PD98059 (p42/44 MAP kinase) and chelerythrine (PKC) as well as the potassium channel blockers glibenclamide, HMR 1098, 5-HD and Paxilline. Nitrite and nitrate release from hearts before (2.3 +/- 0.9 nmol/min/g) and after (2.4 +/- 1.9 nmol/min/g) 15 min treatment with erythropoietin (1.0 U/ml) were not different. L-NAME and L-NMA did not block the cardioprotective effect of erythropoietin. We conclude the rapid activation of potassium channels and protein kinases by erythropoietin represents an important new mechanism for increasing cardioprotection.
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PMID:Acute cardioprotective effects of erythropoietin in infant rabbits are mediated by activation of protein kinases and potassium channels. 2751 2

Myeloproliferative disorders (MPD) represent a subcategory of hematological malignancies and are characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leucocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). At present, these four disorders are referred to as 'classic' MPD and are distinguished from a spectrum of other MPD-like clinicopathologic entities that are operationally classified as 'atypical' MPD. The oncogenic mutations(s) in classic MPD are unknown except for CML, which is associated with an activating mutation (Bcr/Abl) of the gene encoding for the Abl cytoplasmic protein kinase (PTK). In the last 3 months, a somatic point mutation of JAK2 (JAK2(V617F)), the gene encoding for another cytoplasmic PTK was reported in the majority of patients with PV and approximately half of those with either ET or MMM. The same mutation was also found in a small number of patients with either atypical MPD or the myelodysplastic syndrome but not in normal controls, germline tissue including T lymphocytes, and patients with secondary erythrocytosis. In vitro, JAK2(V617F) was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell lines. In vivo, murine bone marrow transduced with a retrovirus containing JAK2(V617F) induced erythrocytosis in the transplanted mice. Taken together, these observations suggest that JAK2(V617F) is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD.
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PMID:JAK2 in myeloproliferative disorders is not just another kinase. 1597 Jul 5

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction.
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PMID:EPO: renoprotection beyond anemia correction. 1695 90


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