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)

We report on a patient with Klinefelter's syndrome who underwent successful syngeneic peripheral blood stem cell transplantation (PBSCT) for chronic myelogenous leukemia (CML). A-46-year-old man was given a diagnosis of chronic phase CML in May 1994 on the basis of findings of leukocytosis (54,000/microliter) and bone marrow chromosomal abnormalities [47, XXY, t(9; 22; 14) (q34; q11; q24)]. Hydroxyurea and interferon alpha were administered. In August 1996, a syngeneic transplant was performed following myeloablative therapy, using peripheral blood stem cells collected from the patient's identical twin brother, who had been pretreated with rhG-CSF. Following transplantation (4.0 x 10(6) CD34+ cells/kg) and the subsequent administration of rhG-CSF, the patient rapidly achieved normal tri-lineage hematopoiesis. A post-transplant chromosomal analysis of the patient's bone marrow cells detected the 47, XXY karyotype. Although the major BCR-ABL gene had been detected in bone marrow by RT-PCR methods prior to the syngeneic PBSCT (August 1996), it was not detected after PBSCT (January 1997). In March 1998, interphase fluorescence in situ hibridization (FISH) procedures disclosed XXY signal patterns in peripheral blood lymphocyte samples from the patient and donor, at frequencies of 96% and 97%, respectively. Both the patient and donor had high levels of serum FSH and LH and low levels of serum testosterone.
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PMID:[Syngeneic peripheral blood stem cell transplantation for chronic myelogenous leukemia associated with Klinefelter's syndrome]. 1022 29

The granulocyte/macrophage colony-stimulating factor (GM-CSF)/interleukin-3 (IL-3)/IL-5 receptors are a family of heterodimeric transmembrane proteins expressed by myeloid lineage cells. Each receptor has a unique ligand-binding alpha chain and they share a common beta chain (beta c chain). Binding of GM-CSF activates at least one receptor-associated tyrosine kinase, JAK2, and rapidly induces tyrosine phosphorylation of the GMR beta c chain (GMR beta), but not the GMR alpha chain (GMR alpha). Mutation of each of the 8 tyrosine residues in the cytoplasmic domain of the human GMR beta to phenylalanine (GMR beta-F8) reduced tyrosine phosphorylation of GMR beta, SHP2 and SHC, but not JAK2 or STAT5. Interestingly, GMR beta-F8 was still capable of inducing at least short-term proliferation and enhancing viability. The role of each individual tyrosine residue was explored by replacing each mutated phenylalanine with the wild-type tyrosine residue. Tyrosine 577 was found to be sufficient to regenerate GM-CSF-dependent phosphorylation of SHC, and any of Y577, Y612, or Y695 were sufficient to regenerate GM-CSF-inducible phosphorylation of SHP2. Next, a series of four internal deletion mutants were generated, which deleted small sections from aa 518 to 626. One of these, deleting residues 566-589 was profoundly defective in signaling and supporting viability, and may identify an important viability signaling domain for this receptor family. Overall, these results indicate that GMR beta tyrosine residues are not necessary for activation of the JAK/STAT pathway, or for proliferation, viability, or adhesion signaling in Ba/F3 cells, although tyrosine residues significantly affect the magnitude of the response. However, internal deletion mutant studies identify critical domains for viability and proliferation.
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PMID:Signaling domains of the beta c chain of the GM-CSF/IL-3/IL-5 receptor. 1037 32

ERYTHROPOIETIN (EPO): Erythropoietin (EPO) is a hormone that promotes the proliferation and differentiation of erythroid progenitor cells and regulates the number of erythrocytes in peripheral blood. EPO is produced mainly by the kidneys, and transcription of the EPO gene is promoted by a reduction in the oxygen concentration in the blood. The existence of EPO was suggested near the end of the 19th century by the discovery that hypoxia increases the production of red blood cells. EPO was identified as a serum factor in the 1950s, and in 1970 Miyake and coworkers succeeded in purifying it by using the urine of patients with aplastic anemia as a starting material. The human EPO gene was cloned in 1985 using a partial amino acid sequence from this purified EPO, and it is well known that recombinant EPO is currently used as a drug to treat anemia associated with chronic renal failure and other illnesses. ACTION OF EPO: When human bone marrow cells are cultured in a semisolid medium containing EPO, they form small erythroblast colonies in five to seven days, and by day 10 large erythroblast colonies appear that resemble fireworks ("burst" colonies). The original cells in the former colonies are called colony forming units-erythroid (CFU-E) or late-stage erythroblast progenitor cells and in the latter colonies they are called burst forming units-erythroid (BFU-E) or early-stage erythroblast progenitor cells. As shown in Figure 1, red blood cells are produced through differentiation from stem cells to BFU-E, CFU-E, and erythroblasts. Although EPO acts on both BFU-E and CFU-E cells, CFU-E cells show greater sensitivity to EPO, and other factors such as stem cell factor (SCF), interleukin (IL)-3, IL-4, and granulocyte macrophage colony-stimulating factor (GM-CSF) must be present together with EPO for BFU-E cell proliferation. In erythroblasts beyond the CFU-E stage, sensitivity to EPO decreases as the cells mature. THE EPO RECEPTOR AND THE CYTOKINE RECEPTOR FAMILY: The EPO receptor gene was cloned by D'Andrea and coworkers in 1989 from murine erythroleukemia cells [1]. It became clear that the EPO receptor belongs to the cytokine receptor family that comprises receptors for the various interleukins, GM-CSF, granulocyte colony-stimulating factor (G-CSF), growth hormone and prolactin. The special characteristic of this family of receptors is that they are switched on (i.e., the receptor is activated) and transduce signals to the interior of the cell by the formation of homo- or hetero-oligomers (dimers or trimers). Moreover, hetero-oligomers of these receptors share a common receptor subunit. As shown in Figure 2, the IL-3, IL-5 and GM-CSF receptors have a common &bgr; subunit, and their ligand specificity is determined by the &agr; subunit. In the same manner, the IL-6, LIF and oncostatin M (OSM) receptors all share gp130, which is the &bgr; subunit of the IL-6 receptor. The IL-2, IL-4 and IL-7 receptors all share the &ggr; subunit of the IL-2 receptor. All the above receptors are activated by the formation of hetero-oligomers, but the G-CSF receptor, EPO receptor, and growth hormone receptor are activated by the formation of homodimers of the same types of molecules [2]. We can see that groups of cytokines such as the interleukins that affect a relatively wide range of cells and have redundant biological activity create this redundancy through the common use of a single receptor subunit. On the other hand, EPO and G-CSF act with high specificity on a relatively limited range of cells, so it was probably unnecessary for their receptors to share one of the subunits. EPO RECEPTOR AND JAK2 KINASE: The signal for cellular proliferation and differentiation into erythroblasts is thought to originate at the EPO receptor. The cytoplasmic domain of the EPO receptor can be divided into two major regions. Roughly half of the cytoplasmic domain, the part lying nearest the plasma membrane, is required for generating the signals for proliferation and differentiation such as the induction of globin synthesis [3, 4]. The remaining half is not required for this signaling, and, conversely, it acts to dampen the signals. It is known that a tyrosine kinase called JAK2 associates with the region near the plasma membrane, undergoes autophosphorylation, and phosphorylates the EPO receptor, and a transcription factor called a STAT [5]. It is thought that JAK2 plays an important role in promoting cellular proliferation. The STAT is activated by the phosphorylation, and it then translocates to the nucleus, recognizes a specific base sequence in the promoter region of its target gene, and initiates transcription. At present, we know that the STAT whose activation is mediated by the EPO receptor is STAT5, and the target genes are CIS [6], which has an SH2 domain (a molecular structure that recognizes a phosphorylated tyrosine) and OSM [7], which is a pleiotropic cytokine. However, activation of STAT5 and activation of the target genes are not unique to the EPO receptor, and they also occur with the IL-2 and IL-3 receptors. Moreover, the JAK2 substrate that is directly linked to cellular proliferation is still unknown. At present, studies are under way to determine the transcription factors specific to EPO and their target genes, as well as the substrates of JAK2. RECEPTOR PHOSPHORYLATION AND CESSATION OF THE SIGNAL: On the other hand, tyrosine phosphorylation of the receptor is necessary at the cytoplasmic tail region far from the plasma membrane, and the signal transduction pathway that originates with this phosphorylated tyrosine and is mediated by proteins with SH2 domains becomes activated. First, a GTP/GDP exchange factor called SOS, which is mediated by Shc and Grb2, migrates to the plasma membrane and converts a ras protein to its GTP form. The activated ras protein then activates the Raf-MAP kinase kinase-MAP kinase cascade, and ultimately initiates the transcription of oncogenes such as c-fos and c-jun. An enzyme called PI3 kinase binds to the tyrosine phosphorylation site of the receptor and a second messenger is born. It is known that this pathway is a requirement for DNA synthesis in certain types of fibroblasts. However, these signal transduction pathways are not unique to the EPO receptor, and they are also activated by most growth factor receptors, so they are not necessarily required for EPO-induced proliferation. Conversely, the tyrosine phosphatase SH-PTP1 (also called HCP) that has an SH2 domain and is specific to blood cells associates with the tyrosine phosphorylation site of the receptor and promotes the dephosphorylation of JAK2. In other words, the role of SH-PTP1 is to stop generation of the signal [8]. Therefore, in mutations lacking this cytoplasmic tail region of the receptor far from the plasma membrane, the receptors do not undergo tyrosine phosphorylation, JAK2 activation continues for a longer period of time, and thus the signal is generated more efficiently. In fact, in one patient with a mild case of familial erythrocytosis a mutation was discovered in which the C-terminus of the EPO receptor was missing 70 amino acids [9]. This was a dominant genetic trait, and the patient's erythroblasts showed an increased sensitivity to EPO. In this family the impairment was not severe enough to be called an illness, and in fact it is said that this patient was proficient enough athletically to compete for a gold medal at the Olympics. More specifically, the reason that athletes undergo training at high altitudes is to boost EPO production because of the lower oxygen partial pressure, and this brings about the desired effect of sustained athletic capability due to a resultant increase in red blood cells. However, the same effect has occurred naturally in this athlete thanks to accelerated receptor capability.
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PMID:Physician Education: The Erythropoietin Receptor and Signal Transduction. 1038 12

The goal of this study was to investigate how bacterial LPS affects macrophage responsiveness to the activating factor IFN-gamma. Pretreatment of macrophages with LPS for <2 h increased the transcriptional response to IFN-gamma. In contrast, simultaneous stimulation with IFN-gamma and LPS, or pretreatment with LPS for >4 h, suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and transcriptional activity in response to IFN-gamma. Consistently, the induction of MHCII protein by IFN-gamma was antagonized by LPS pretreatment. Neutralizing Abs to IL-10 were without effect on LPS-mediated suppression of Stat1 activation. Decreased IFN-gamma signal transduction after LPS treatment corresponded to a direct induction of suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the same conditions socs1, socs2, and cis genes were not transcribed. In transfection assays, SOCS3 was found to suppress the transcriptional response of macrophages to IFN-gamma. A causal link of decreased IFN-gamma signaling to SOCS3 induction was also suggested by the LPS-dependent reduction of IFN-gamma-mediated Janus kinase 1 (JAK1) activation. Further consistent with inhibitory activity of SOCS3, LPS also inhibited the JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the deactivating effect of chronic LPS exposure on macrophages with its ability to induce SOCS3.
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PMID:Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. 1045 4

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains the viability of the mouse interleukin-3-dependent cell line BA/F3 expressing the hGM-CSF receptor. Analysis of the antiapoptosis activity of GM-CSF receptor betac mutants showed that box1 but not the C-terminal region containing tyrosine residues is essential for GM-CSF-dependent antiapoptotic activity. Because betac mutants, which activate Janus kinase 2 but neither signal transducer and activator of transcription 5 nor the MAPK cascade sustain antiapoptosis activity, involvement of Janus kinase 2, excluding the above molecules, in antiapoptosis activity seems likely. GM-CSF activates phosphoinositide-3-OH kinase as well as Akt, and activation of both was suppressed by addition of wortmannin. Interestingly, wortmannin did not affect GM-CSF-dependent antiapoptosis, thus indicating that the phosphoinositide-3-OH kinase pathway is not essential for cell surivival. Analysis using the tyrosine kinase inhibitor genistein and a MAPK/extracellular signal-regulated kinase (ERK) kinase 1 inhibitor, PD98059, indicates that activation of either the genistein-sensitive signaling pathway or the PD98059-sensitive signaling pathway from betac may be sufficient to suppress apoptosis. Wild-type and a betac mutant lacking tyrosine residues can induce expression of c-myc and bcl-x(L) genes; however, drug sensitivities for activation of these genes differ from those for antiapoptosis activity of GM-CSF, which means that these gene products may be involved yet are inadequate to promote cell survival.
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PMID:Two distinct signaling pathways downstream of Janus kinase 2 play redundant roles for antiapoptotic activity of granulocyte-macrophage colony-stimulating factor. 1056 83

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains viability of the mouse interleukin (IL)-3 dependent lymphoid cell line BA/F3 expressing the hGM-CSF receptor. Caspase-3 like enzyme activity and DNA fragmentation were augmented by depletion of this factor from the cell, and exposure to gamma irradiation accelerated kinetics of these events. Anti gamma irradiation-induced apoptosis occurred through various mutant GM-CSF receptors and only the box1 region was essential while the C terminal region, including tyrosine residues which are required for MAPK cascade activation, was dispensable. Consistent with this notion, the addition of PD98059 had no effect on this activity thereby indicating that activation of MAPK is not essential for the activity. As expected, gamma irradiation increased p53 protein and bax mRNA levels and the presence of hGM-CSF dramatically modulated bax/bcl-X(L) ratio. The PI-3K specific inhibitor wortmannin did not affect hGM-CSF dependent anti gamma irradiation induced apoptosis nor bcl-X(L) induction, thus bcl-X(L) but not PI-3K pathway seems to be involved in hGM-CSF dependent anti gamma irradiation-induced apoptosis. It is well documented that the boxl region is essential for GM-CSF dependent activation of JAK2 and JAK2 specific inhibitor AG490 suppressed anti gamma, irradiation-induced apoptosis by hGM-CSF. An artificial JAK2 activating molecule in which extracellular and the transmembrane of beta(c) fused with whole JAK2 can sustain BA/F3 cells survival and proliferation mIL-3 independently, but these cells are susceptible to gamma irradiation. Furthermore GyrB/Jak2, which can activate STAT5 but not the MAPK cascade nor survival of BA/F3 cells, also could not prevent gamma irradiation-induced apoptosis. Although JAK2 is essential for hGM-CSF dependent anti gamma irradiation-induced apoptosis, it appeared that JAK2 does not seem sufficient for the activity.
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PMID:Analysis of mechanisms involved in the prevention of gamma irradiation-induced apoptosis by hGM-CSF. 1069 27

Granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-3 (IL-3) and Interleukin-5 (IL-5) have overlapping, pleiotropic effects on hematopoietic cells, including neutrophils, eosinophils, monocytes and early progenitor cells. The high-affinity receptors for human GM-CSF, IL-3, and IL-5 share a common beta-subunit (hbeta(c)), which is essential for signalling and plays a major role in recruiting intracellular signalling molecules. While activation of the cytoplasmic tyrosine kinase JAK2 appears to be the initiating event for signalling, the immediate events that trigger this are still unclear. We have isolated a number of activated mutants of hbeta(c), which can be grouped into classes defined by their state of receptor phosphorylation, their requirement for alpha subunit as a cofactor, and their activities in primary cells and cell lines. We discuss these findings with regard to the stoichiometry, activation, and signalling of the normal GM-CSF/IL-3/IL-5 receptor complexes. Specifically, this work has implications for the role of the ligand-specific alpha-subunits in initiating the signalling through the beta-subunit, the role of beta subunit dimerization as a receptor trigger, and the function of receptor tyrosine phosphorylation in generating growth and survival signals. Based on the properties of the activated mutants and the recent structures of erythropoietin receptor (Epo-R) complexes, we propose a model in which (1) activation of hbeta(c) can occur via alternative states that differ with respect to stoichiometry and subunit assembly, but which all mediate proliferative responses, and (2) each of the different classes of activated mutants mimics one of these alternative states.
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PMID:A model for assembly and activation of the GM-CSF, IL-3 and IL-5 receptors: insights from activated mutants of the common beta subunit. 1072 Jun 88

There is currently no satisfactory model allowing analysis of dose-effect relationships of BCR-ABL proteins in human hematopoietic cells. To study comparatively the proliferative, differentiative and anti-apoptotic actions of different levels of BCR-ABL proteins in the context of the same cellular background, we have introduced the BCR-ABL gene into the GM-CSF-dependent pluripotent human cell line UT-7. Individual clones expressing BCR-ABL were analyzed by Western blots. After normalization to equivalent levels of endogenous ABL protein, 14 clones always grown in GM-CSF were found to express low but variable levels of BCR-ABL whereas two clones selected in the absence of GM-CSF expressed very high levels of BCR-ABL. All low-level BCR-ABL expressing clones exhibited a behavior similar to that of the GM-CSF-dependent parental cells as they ceased to proliferate upon growth factor deprivation and showed a strong proliferative response upon GM-CSF addition. One out of 14 clones showed progressive GM-CSF independence during culture over several weeks and was found to have a significant increase of BCR-ABL expression at that time. The resistance of this clone (E8-2) to different apoptotic stimuli was found to be increased as compared to its low BCR-ABL-expressing counterpart (E8-1) and similar to that observed in clones with very high levels of BCR-ABL (UT-7/9 and UT-7/11) which were totally resistant to apoptotic stimuli. When injected into nude mice, parental UT-7 cells and clones with low-level of BCR-ABL were not tumorigenic over 10 weeks of observation whereas UT-7 clones with high levels of BCR-ABL (UT-7/9, UT-7/11 and UT-7/E8-2) induced aggressive tumors in 2-4 weeks with a significant correlation between the amount of BCR-ABL protein and the rate of tumor growth. In conclusion, the establishment of an in vitro and in vivo CML model using UT-7 cells suggests for the first time in human cells, that the fully transformed phenotype induced by BCR-ABL requires high levels of BCR-ABL expression. These findings suggest that variable levels of BCR-ABL in primary patient cells could also be responsible for the different phenotypic features seen in chronic and acute phases of CML, such as the differentiation ability induced by growth factors.
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PMID:Biological effects induced by variable levels of BCR-ABL protein in the pluripotent hematopoietic cell line UT-7. 1076 52

We analyzed the expression of IL-12Rbeta1 and IL-12Rbeta2 and the role of IL-12 in the activation of monocyte-derived dendritic cells (DCs) via IL-12Rbeta1-mediated signaling events. Flow cytometric analysis revealed that IL-12Rbeta1 was expressed in T cells, Con A blasts, and monocyte-derived DCs, but not in monocytes, while its transcript was detected in all of these cell types. Transcriptional expression of IL-12Rbeta2 was observed in T cells, Con A blasts, and monocyte-derived DCs, but not monocytes. The ligation of DCs as well as Con A blasts by IL-12 induced the production of GM-CSF, IL-1beta, IL-6, TNF-alpha, and IFN-gamma at the transcription levels. Furthermore, stimulation of DCs with IL-12 induced IL-12p40 transcript, but not IL-12p35 transcript, whereas this stimulation caused the expressions of both transcripts in Con A blasts. Stimulation of DCs with IL-12 caused a tyrosine phosphorylation of several intracellular proteins, and the pattern of these events were distinct from those of IL-12-stimulated Con A blasts. IL-12 also induced tyrosine phosphorylation of IL-12Rbeta1 as well as recruitment of several tyrosine-phosphorylated proteins to IL-12Rbeta1 in DCs and Con A blasts. Receptor engagement of DCs as well as Con A blasts by IL-12 resulted in activation of Janus kinase 2 and Tyk2 kinases and Stat3 and Stat4 transcription factors and the association of these proteins to IL-12Rbeta1. Stimulation with IL-12 caused a tyrosine phosphorylation and enzymatic activity of a family of mitogen-activated protein kinases, p38mapk. These results suggest that IL-12 acts directly on DCs to induce their functional activation via IL-12Rbeta1-mediated signaling events.
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PMID:IL-12 responsiveness and expression of IL-12 receptor in human peripheral blood monocyte-derived dendritic cells. 1086 Oct 35

Human GM-CSF (hGM-CSF) induces proliferation and sustains the viability of a mouse IL-3-dependent lymphoid cell line BA/F3 that expresses the functional hGM-CSF receptor (hGMR). To reveal an antiapoptotic mechanism of hGM-CSF, we analyzed various apoptotic markers of BA/F3 cells in various conditions. Within 24 hours of factor depletion, caspase 3-like, but not caspase 1-like, enzyme activity and DNA fragmentation were augmented. Analysis with the tyrosine kinase inhibitor (genistein) and an MEK1 inhibitor (PD98059) on antiapoptosis activity indicates that the activation of either the genistein-sensitive signaling pathway or the PD98059-sensitive signaling pathway of the betac subunit may be sufficient to suppress apoptosis through hGMR. Because hGMR mutants (which activate JAK2 but neither STAT5 nor the MAPK cascade) have antiapoptotic activity in BA/F3 cells, the involvement of JAK2, excluding the molecules mentioned earlier, for antiapoptosis activity seems likely. Because the JAK2 inhibitor AG-490 suppressed the antiapoptotic activity of hGM-CSF, the essential role for JAK2 activation to maintain the viability is considered. Interestingly, hGMR mutants, which lack MAPK cascade activation, require a higher dose of hGM-CSF than that for wild-type hGMR. Because the expression level and affinity to hGM-CSF among wild-type hGMR and mutant hGMR are the same, we speculated that biologic response is determined by a combination of strength of various signaling events.
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PMID:Analysis of antiapoptosis activity of human GM-CSF receptor. 1088 29


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