Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primitive chronic myeloid leukemia cells display a unique autocrine interleukin 3 (IL-3)/granulocyte-colony-stimluating factor (G-CSF) mechanism that may explain their abnormal proliferation and differentiation control. Here we show that BCR-ABL transduction of primitive Sca-1(+) lin(-) mouse bone marrow (BM) cells causes immediate activation of IL-3, G-CSF, and granulocyte macrophage-colony-stimulating factor (GM-CSF) expression in these cells. Their autocrine IL-3-mediated growth dependence is thus demonstrable only in clonal cultures where paracrine effects are reduced. Interestingly, upon continued culture, these cells produce large populations of rapidly proliferating mast cells in which only the IL-3 autocrine mechanism is consistently maintained, together with evidence of hyperphosphorylation of p210(BCR-ABL) and STAT5 and retention of a multilineage but attenuated in vivo leukemogenic potential characterized by a prolonged latency. BCR-ABL transduction of IL-3(-/-) Sca-1(+) lin(-) BM cells initially activates GM-CSF and G-CSF production, factor independence, and the ability to generate phenotypically indistinguishable populations of mast cells. However, maintenance of factor independence, and p210(BCR-ABL) and STAT 5 activation beyond 4 to 6 weeks, requires rescue with an IL-3 transgene. The cultured BCR-ABL-transduced IL-3(-/-) cells also lack leukemogenic activity in vivo. These findings provide new evidence that IL-3 production is a rapid, sustained, and biologically relevant consequence of BCR-ABL expression in primitive hematopoietic cells with multilineage leukemogenic activity.
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PMID:Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo. 1239 60

1. Inducible nitric oxide (iNOS) is thought to involve in host defence and tissue damage in inflammatory loci. In previous study, we have found that the endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from cell death induced by bacterial lipopolysaccharide. This action is through the interruption with signalling pathways for NF-kappa B and AP-1 activation, and thus iNOS expression. In this study we have addressed the effects of ATA on JAK-STAT signalling pathways. 2. In murine RAW 264.7 macrophages, IFN-gamma-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3-100 micro M ATA. 3. IFN-gamma-induced STAT1 activation, as assessed from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA response element and evoked IRF-1 reporter gene assay, were concomitantly inhibited by ATA. However, ATA did not alter IFN-gamma binding to RAW 264.7 cells. 4. The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signalling in response to IFN-gamma, were also reduced by ATA. 5. Moreover, IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5 and/or STAT6 in macrophages were diminished by the presence of ATA. 6. Taken together, we conclude that ATA can interfere JAK-STAT signalling pathways in response to cytokines. This action contributes to the inhibition of IFN-gamma-induced iNOS expression.
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PMID:Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid. 1242 73

This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropoiesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydrate content (52% vs 40%), a longer plasma half-life, the amino acid sequence differs from that of native human EPO at five positions, and has been reported to maintain hemoglobin levels just as effectively in patients with chronic renal failure as rHuEPO at less frequent dosing. The use of rHuEPO and darbepoetin to enhance athletic performance is officially banned by most sports-governing bodies because the excessive erythrocytosis can lead to increased thrombogenicity and can cause deep vein, coronary, and cerebral thromboses.
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PMID:Erythropoietin: physiology and pharmacology update. 1252 67

Neutrophils from patients with myelodysplastic syndrome (MDS) show a disturbed differentiation pattern and are generally dysfunctional. To study these defects in more detail, we investigated reactive-oxygen species (ROS) production and F-actin polymerization in neutrophils from MDS patients and healthy controls and the involvement of N-formyl-L-methionyl-L-lucyl-L-phenylaline (fMLP) and granulocyte macrophage-colony-stimulating factor (GM-CSF)-stimulated signal transduction pathways. Following fMLP stimulation, similar levels of respiratory burst, F-actin polymerization, and activation of the small GTPase Rac2 were demonstrated in MDS and normal neutrophils. However, GM-CSF and G-CSF priming of ROS production were significantly decreased in MDS patients. We subsequently investigated the signal transduction pathways involved in ROS generation and demonstrated that fMLP-stimulated ROS production was inhibited by the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002, but not by the MAPK/ERK kinase (MEK) inhibitor U0126. In contrast, ROS production induced by fMLP stimulation of GM-CSF-primed cells was inhibited by LY294002 and U0126. This coincides with enhanced protein kinase B (PKB/Akt) phosphorylation that was PI3K dependent and enhanced extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation that was PI3K independent. We demonstrated higher protein levels of the PI3K subunit p110 in neutrophils from MDS patients and found that though the fMLP-induced phosphorylation of PKB/Akt and ERK1/2 could also be enhanced by pretreatment with GM-CSF in these patients, the degree and kinetics of PKB/Akt and ERK1/2 phosphorylation were significantly disturbed. These defects were observed despite a normal GM-CSF-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation. Our results indicate that the reduced priming of neutrophil ROS production in MDS patients might be caused by a disturbed convergence of the fMLP and GM-CSF signaling routes.
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PMID:Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia. 1252 94

To investigate whether ABL specific tyrosine kinase specific inhibitor STI571 can restore beta1 integrin mediated negative effect on Ph(+) chronic myeloid leukemia(CML), the inhibitory effect of beta 1 integrin activator (beta1 integrin activating antibody 8A2, cytokines such as GM-CSF, G-CSF and SCF) and/or FN on the granulocyte-macrophage colony forming unit (CFU-GM) from 16 patients with Ph(+)CML and 13 normal individuals were examined; the bone marrow mononuclear cells (BMMNC) before and after ABL kinase specific inhibitor STI571 pretreatment (0.1 micro mol/L for 30-60 minutes) were target cells in this study. The roles which VLA4 and VLA5 played in this process were evaluated through blocking assay. The results showed: (1) beta1 integrin activator(s) or FN alone have no effect on CFU-GM from CML or normal bone marrow mononuclear cells before or after STI571 pretreatment, nor STI571 pretreatment itself. (2) The inhibitory effect of beta1 integrin activator(s) plus FN on CML CFU-GM are significantly lower than that on normal CFU-GM. (3) The inhibitory effect of beta1 integrin activator(s) plus FN on CML CFU-GM after STI571 pretreatment is comparable to that on normal CFU-GM. (4) Monoclonal antibody to VLA4 and VLA5 or to total beta1 integrins almost completely abrogate the above effect of STI571. The results suggested enhancing beta1 integrin mediated negative effect on myeloid progenitors in Ph(+)CML is one of the therapeutic mechanisms of STI571 on Ph(+)CML.
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PMID:[Low Concentrations of STI571 Enhances beta1 Integrin Mediated Inhibitory Effect on Proliferation of Myeloid Progenitors in Ph(+)Chronic Myeloid Leukemia] 1257 90

According to our previous experiments, Ph(+) chronic myeloid leukemia (CML) cell line K562 cells have defects in beta 1 integrin activation. In order to search the same regularity in Ph(+) CML bone marrow cells, bone marrow mononuclear cells (BMMNC) from 12 cases of Ph(+) CML and 10 cases of normal individuals were studied. Their expression rate of 9EG7 epitope on beta1 integrin post treatment by 8A2 or GM- or G-CSF and cell adhesion ability with soluble fibronectin (FN) were evaluated by flow cytometry; in addition, the effects of CGP57148B, a highly specific ABL tyrosine kinase inhibitor, were observed. Our results showed that 9EG7 expression rate and FN binding rate were very low in all the inactivated cells. The parameter increased markedly post 8A2 activation in both NBMMNCs and CMLBMMNCs, but the degree of increase in CMLBMMNCs was significantly lower than that in NBMMNCs; GM-CSF or G-CSF could significantly increase the parameters in NBMMNCs while had no effects on that in CMLBMMNCs. CGP57148B could increase the beta1 integrin activation potential of CMLBMMNCs but had no effects on that of NBMMNCs. The results indicate that decreased activation potential of beta1 integrin in CMLBMMNCs is the major cause of adhesion defects of Ph(+) CML cells; beta1 integrin functional insufficiency in CMLBMMNCs could not be directly reversed by ABL tyrosine kinase inhibitor CGP57148B.
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PMID:[beta1 Integrin Dysfunction in Adult Chronic Myeloid Leukemia Bone Marrow Cells] 1257 92

A functional hybrid receptor associating the common gamma chain (gammac) with the granulocyte/macrophage colony-stimulating factor receptor beta (GM-CSFRbeta) chain is found in mobilized human peripheral blood (MPB) CD34+ hematopoietic progenitors, SCF/Flt3-L primed cord blood (CB) precursors (CBPr CD34+/CD56-), and CD34+ myeloid cell lines, but not in normal natural killer (NK) cells, the cytolytic NK-L cell line or nonhematopoietic cells. We demonstrated, using CD34+ TF1beta cells, which express an interleukin (IL)-15Ralpha/beta/gammac receptor, that within the hybrid receptor, the GM-CSFRbeta chain inhibits the IL-15-triggered gammac/JAK3-specific signaling controlling TF1beta cell proliferation. However, the gammac chain is part of a functional GM-CSFR, activating GM-CSF-dependent STAT5 nuclear translocation and the proliferation of TF1beta cells. The hybrid receptor is functional in normal hematopoietic progenitors in which both subunits control STAT5 activation. Finally, the parental TF1 cell line, which lacks the IL-15Rbeta chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15alpha/gammac/TRAF2 complex that triggers nuclear factor kappaB activation. The lineage-dependent distribution and function of these receptors suggest that they are involved in hematopoiesis because they modify transduction pathways that play a major role in the differentiation of hematopoietic progenitors.
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PMID:Detection of a functional hybrid receptor gammac/GM-CSFRbeta in human hematopoietic CD34+ cells. 1264 4

CC chemokine receptor 1 (CCR1) has been implicated in inflammation. The present study examined the signaling mechanisms that mediate GM-CSF/IL-10-induced synergistic CCR1 protein expression in monocytic U937 cells. GM-CSF alone markedly increased both the mRNA and protein expression of CCR1. IL-10 augmented GM-CSF-induced CCR1 protein expression with no effect on mRNA expression. PD098059 and U0126 (two MEK inhibitors), and LY294002 (a PI3K inhibitor) inhibited GM-CSF/IL-10-induced CCR1 gene and protein expression. PD098059, U0126, and LY294002 also attenuated chemotaxis of GM-CSF/IL-10-primed U937 cells in response to MIP-1alpha. Immunoblotting studies show that GM-CSF alone induced ERK2 phosphorylation; whereas, IL-10 alone induced p70(S6k) phosphorylation in U937 cells. Neither cytokine when used alone induced PKB/Akt phosphorylation. Combined GM-CSF/IL-10 treatment of U937 cells induced phosphorylation of ERK2, p70(S6k), and PKB/Akt. PD098059 and U0126 completely abrogated ERK2 phosphorylation; whereas, LY294002 completely blocked PKB/Akt and p70(S6k) phosphorylation. Our findings indicate that IL-10 may potentiate GM-CSF-induced CCR1 protein expression in U937 cells via activation of PKB/Akt and p70(S6k).
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PMID:IL-10 synergistically enhances GM-CSF-induced CCR1 expression in myelomonocytic cells. 1271 32

HEK-293T cells transiently transfected with ovine (o) GH receptor (GHR) and prolactin receptor (PRLR) constructs respectively tagged downstream with cyan or yellow fluorescent proteins were used to study ovine placental lactogen (oPL)-stimulated heterodimerization by fluorescence resonance energy transfer (FRET) microscopy. The oPL-stimulated transient heterodimerization of GHR and PRLR had a peak occurring 2.5-3 min after oPL application, whereas oGH or oPRL had no effect at all. The results indicate none or only little dimerization occurring before the hormonal stimulation. The effect of heterodimerization was studied by comparing activation of Janus kinase 2, signal transducer and activator of transcription (STAT)1, STAT3, STAT5, and MAPK in Chinese hamster ovary cells stably transfected with chimeric genes encoding receptors consisting of cytosolic and transmembrane parts of oGHR and oPRLR, extracellular domains of human granulocyte and macrophage colony-stimulating factor (hGM-CSF) receptor alpha or beta, and cells transfected with the two forms (alpha or beta) of PRLR and GHR. Functionality of those proteins was verified by hGM-CSF-induced phosphorylation of both intracellular PRLR and GHR domains and hGM-CSF-induced heterodimerization was documented by chimeric receptor coimmunoprecipitation. Homodimerization or heterodimerization of PRLRs and GHRs had no differential effect on activation of STAT5 and MAPK. However, heterodimerization resulted in a prolonged phosphorylation of STAT1 and in particular STAT3, suggesting that the heterodimerization of alpha-oGHR and beta-oPRLR is able to transduce a signal, which is distinct from that occurring on homodimeric associations.
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PMID:Ovine placental lactogen-induced heterodimerization of ovine growth hormone and prolactin receptors in living cells is demonstrated by fluorescence resonance energy transfer microscopy and leads to prolonged phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. 1286 35

Granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibits Fas-induced apoptosis of neutrophils. However, the exact step in the apoptotic pathway blocked by GM-CSF remained unclear. Here, we found that pretreatment of neutrophils with GM-CSF inhibits the recruitment of Fas-associated protein with death domain (FADD) to Fas, abolishing the formation of the death-inducing signaling complex required for Fas-induced apoptosis. Two-dimensional electrophoresis revealed that GM-CSF modifies the ratio of FADD subspecies. These GM-CSF-triggered changes were abrogated, and Fas-induced apoptosis was restored by an inhibitor of classical protein kinase C (PKC), Go6976, and by the combination of a phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002, and an inhibitor of mitogen-activated protein kinase kinase (MEK)1, PD98059. Go6976 blocked GM-CSF-elicited phosphorylation of Akt/PKB and extracellular signal-regulated kinase (ERK)1/2. These results indicated that GM-CSF suppresses Fas-induced neutrophil apoptosis by inhibiting FADD binding to Fas, through redundant actions of PI-3K and MEK1-ERK1/2 pathways downstream of classical PKC.
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PMID:Short-term delay of Fas-stimulated apoptosis by GM-CSF as a result of temporary suppression of FADD recruitment in neutrophils: evidence implicating phosphatidylinositol 3-kinase and MEK1-ERK1/2 pathways downstream of classical protein kinase C. 1532 34


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