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)

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

One of the principal functions of erythropoietin (EPO) is to stimulate the maturation of erythroid precursors. Yet EPO has recently been shown to modulate a host of cellular signal transduction pathways in pluripotent stem cells to perform multiple functions other than erythropoiesis. The production of EPO is tightly modulated by the loss of oxygen and the hypoxia-inducible factor 1. Once generated, EPO becomes a robust stimulus which regulates endothelial cell proliferation and migration as well as erythropoiesis and vascular resistance. Further downstream in the signal transduction cascade, EPO engages diverse cellular pathways--such as those involving Janus kinase 2, signal transducers and activators of transcription (STATs), mitogen-activated protein kinases (MAPKs), Bcl-x(L), protein kinase B, protein kinase C, and cysteine proteases--to provide "plasticity" to vascular systems through highly conserved mechanisms. EPO also has recently been demonstrated to inhibit the induction of apoptosis through two distinct components that involve the maintenance of the integrity of genomic DNA and the preservation of cellular membrane asymmetry. Recognition of the multipotential attributes of EPO for vascular systems may further the progress of the development of therapeutic strategies to delay the onset of degenerative diseases.
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PMID:Angiogenesis and plasticity: role of erythropoietin in vascular systems. 1259 Jul 1

A major problem hampering effective stem cell-based therapies is the absence of a clear understanding of the human hematopoietic stem cell (HSC) pool composition. The severe combined immunodeficiency (SCID) repopulating cell (SRC) xenotransplant assay system provides a powerful tool for characterizing the frequency, cell surface markers, cell cycle status, homing and response to cytokine stimulation of human HSCs. Clonal tracking of retrovirally transduced SRCs and transplantation of specific subpopulations revealed SRC classes with distinct repopulation potentials. However, all HSC repopulation assays are based on intravenous injection, a complex process that requires circulation through blood, recognition and extravasation through bone marrow vasculature, and migration to a supportive microenvironment. Thus, some classes of HSCs may remain undetected. By direct intrafemoral injection, we identified rapid SRCs (R-SRCs) within the Lin-CD34+CD38loCD36- subpopulation. R-SRCs rapidly generate high levels of human myeloid and erythroid cells within the injected femur, migrate to the blood and colonize individual bones of non-obese diabetic (NOD)-SCID mice within 2 weeks after transplantation. Lentivector-mediated clonal analysis of individual R-SRCs revealed heterogeneity in their proliferative and migratory properties. The identification of a new HSC class and an effective intrafemoral assay provide the tools required to develop more effective stem cell-based therapies that rely on rapid reconstitution.
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PMID:Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells. 1279 74

BCR-ABL oncogene, the molecular hallmark of chronic myelogenous leukemia (CML) arises in a primitive hematopoietic stem cell with both differentiation and self-renewal ability. To study the phenotypic effects of BCR-ABL in a clonal in vitro self-renewal and differentiation model, we have introduced BCR-ABL in the ES cell line CCE. The major effect of BCR-ABL expression was the persistence of primitive morphology of ES cells despite LIF deprivation, correlated with a constitutive activation of STAT3, the major self-renewal factor of ES cells, but no evidence of activation of STAT5. The enforced expression of BCR-ABL in an ES cell line, engineered to express a tetracycline-inducible dominant-negative form of a STAT3, triggered ES cell differentiation with an increased generation of hematopoietic cells expressing erythroid and megakaryocytic phenotypes. RT-PCR analysis for Oct4, Brachyury and beta-globin expression confirmed a delay of differentiation in BCR-ABL expressing clones, which could be entirely reversed upon activation of the dominant-negative form of STAT3. To study the possible relevance of STAT3 activation by BCR-ABL in human CML, Western blot analyses performed on the CD34+ cells, purified from CML patients at different stages of their disease, also demonstrated increased levels of STAT3 proteins phosphorylated both on tyrosine and serine residues. These results represent to our knowledge the first functional link between BCR-ABL oncogene and a self-renewal in the context of ES cells through constitutive activation of STAT3. Thus, the BCR-ABL embryonic stem cell model that we developed as well as the results obtained in human CML samples suggests a role for STAT3 in the pathogenesis of human CML.
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PMID:Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. 1282 44

Signals provided by the erythropoieitin receptor (EpoR) are required for erythroid development beyond the erythroid colony-forming unit (CFU-e) stage and are propagated via the EpoR-tethered Janus kinase, JAK2. JAK2 functions, in part, to phosphorylate 8 conserved EpoR phosphotyrosine (PY) sites for the binding of a diverse set of signaling factors. However, recent studies in transgenic and knock-in mice have demonstrated substantial bioactivity for PY-null EpoR forms. Presently, the activities of a PY-null EpoR-HM form in primary progenitor cells from knock-in mice were further assessed using optimized Epo dose-dependent proliferation, survival, and differentiation assays. As compared with the wild-type (wt)-EpoR, EpoR-HM activity was compromised several-fold in each context when Epo was limited to physiologic concentrations. Possible compensatory increases in serum growth factor levels also were investigated, and as assayed using embryonic stem (ES) cell-derived erythroid G1E2 cells, activities in serum from EpoR-HM mice were substantially elevated. In addition, when challenged with phenylhydrazine-induced anemia, EpoR-HM mice failed to respond with efficient splenic stress erythropoiesis. Thus, the function of this JAK2-coupled but minimal PY-null EpoR-HM form appears to be attenuated in several contexts and to be assisted in vivo by compensatory mechanisms. Roles normally played by EpoR PY sites and distal domains therefore should receive continued attention.
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PMID:Attenuated signaling by a phosphotyrosine-null Epo receptor form in primary erythroid progenitor cells. 1286 13

Erythropoietin (EPO) is the principal hormone regulating the proliferation of erythroid precursors and their differentiation into erythrocytes. Binding of ligand to the cell-surface EPO-R (EPO receptor) induces dimerization and JAK2 (Janus kinase 2)-mediated tyrosine phosphorylation of the receptor. Less than 1% of the EPO-Rs are displayed on the cell surface; most of the receptor molecules are retained in intracellular compartments, including the ER (endoplasmic reticulum). Using pervanadate (PV) as a potent tool to inhibit cellular PTPs (protein tyrosine phosphatases), we demonstrated previously the accumulation of mature (endoglycosidase H-resistant) tyrosine-phosphorylated EPO-R [Cohen, Altaratz, Zick, Klingmuller and Neumann (1997) Biochem. J. 327, 391-397]. In the present study, we investigated the participation of the ER-associated PTP1B in the dephosphorylation of intracellular EPO-R. We demonstrate tyrosine phosphorylation of EPO-R in BOSC-23T cells co-expressing EPO-R and the 'substrate-trapping' mutant form of PTP1B, PTP1B D181A (referred to as PTP1BD). In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly. Endoglycosidase H resistance of tyrosine-phosphorylated EPO-R in cells expressing PTP1BD suggested that mature EPO-R is dephosphorylated by PTP1B. Stimulation with EPO of cells co-expressing EPO-R and either PTP1BD or PTP1B resulted in an increase or decrease respectively in phosphotyrosine EPO-R. We thus suggest that PTP1B dephosphorylates EPO-stimulated EPO-R and participates in the down-regulation cascade of EPO-mediated signal transduction.
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PMID:Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling. 1452 37

Formin homology proteins with FH1 and FH2 domains are signaling effectors for assembly and polarization of actin filaments. FH1 is the binding domain for Profilin, SRC, EMS1/Cortactin, FNBP1, FNBP2, FNBP3, FNBP4 and WBP4/Fbp21, while FH2 is the actin-filament modification domain. Here, we identified and characterized a novel member of Formin-homology gene family, Diaphanous homology 3 (DIAPH3), by using bioinformatics. DIAPH3 isoform 1, corresponding to 3'-truncated FLJ34705 cDNA and 5'-divergent IMAGE5265490 cDNA, encodes full-length DIAPH3 protein (1112 aa), while DIAPH3 isoform 2, identical to NM_030932.2 cDNA, encodes N-terminally truncated DIAPH3 protein (849 aa). DIAPH3 isoform 1, consisting of exons 1-27, was expressed in lymph node, erythroid progenitor cells as well as in pancreatic cancer. DIAPH3 isoform 2, consisting of exons 1b and 8-27, was expressed in testis. DIAPH3 gene at human chromosome 13q21.2 was found to encode two isoforms due to alternative splicing of the alternative promoter type. Full-length human DIAPH3 protein, consisting of FDD, FH1 and FH2 domains, showed 51.3% total-amino-acid identity with DIAPH1, and 57.3% total-amino-acid identity with DIAPH2. FMNL1/FMNL, FMNL2/FHOD2, FMNL3/WBP3, DAAM1, DAAM2, DIAPH1, DIAPH2 and DIAPH3 were classified as the FDD-type Formin homology proteins, while GRID2IP/Delphilin, FHOD1, Fmn1 and Fmn2 were classified as the non-FDD-type Formin homology proteins. This is the first report on identification and characterization of human DIAPH3 gene.
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PMID:Identification and characterization of human DIAPH3 gene in silico. 1476 82

Regulation of survival, expansion, and differentiation of erythroid progenitors requires the well-controlled activity of signaling pathways induced by erythropoietin (Epo) and stem cell factor (SCF). In addition to qualitative regulation of signaling pathways, quantitative control may be essential to control appropriate cell numbers in peripheral blood. We demonstrate that Bruton's tyrosine kinase (Btk) is able to associate with the Epo receptor (EpoR) and Jak2, and is a substrate of Jak2. Deficiency of Btk results in reduced and delayed phosphorylation of the EpoR, Jak2, and downstream signaling molecules such as Stat5 and PLCgamma1 as well as in decreased responsiveness to Epo. As a result, expansion of erythroid progenitors lacking Btk is impaired at limiting concentrations of Epo and SCF. In addition, we show that SCF induces Btk to interact with TNF-related apoptosis-inducing ligand (TRAIL)-receptor 1 and that lack of Btk results in increased sensitivity to TRAIL-induced apoptosis. Together, our results indicate that Btk is a novel, quantitative regulator of Epo/SCF-dependent expansion and survival in erythropoiesis.
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PMID:Btk is required for an efficient response to erythropoietin and for SCF-controlled protection against TRAIL in erythroid progenitors. 1500 95

Polycythemia vera (PV) is a myeloproliferative disorder arising in a multipotent hematopoietic stem cell. The pathogenesis of PV remains poorly understood; however, the biologic hallmark of this disease is the presence of erythropoietin (Epo)-independent colony formation (endogenous erythroid colony [EEC]) and cytokine hypersensitivity. We have developed a simple liquid culture from CD34+ cells to study PV erythroid differentiation. PV erythroid differentiation was characterized in this culture system by two types of abnormalities: 1) an increased proliferation of progenitors in response to cytokines, associated with strict cytokine dependency for preventing apoptosis; and 2) Epo-independent terminal erythroid differentiation in the presence of stem cell factor and interleukin-3 as evidenced by the acquisition of glycophorin A. The level of Epo-independent terminal differentiation correlates in PV patients with the number of EEC. Epo-independent terminal differentiation as well as normal Epo-induced differentiation were repressed by inhibitors of JAK2 (AG490), PI3K (LY294002), and the Src family kinases (PP2). In contrast, an inhibitor of the ERK/MAP kinase pathway (PD98059) had no effect on Epo-independent terminal differentiation. These signaling abnormalities were not mediated by a decreased expression or activity of the membrane tyrosine phosphatase CD45, which dephosphorylates JAK2 and Src family kinases. This study demonstrates that early steps of PV erythroid differentiation are strictly cytokine dependent. In contrast, late erythroid differentiation is an Epo-independent phenomenon that is mediated by signaling pathways identical to those in Epo-induced differentiation.
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PMID:Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. 1510 79

Erythropoietin (EPO) activates many distinct signal transduction cascades on engagement of its receptor. Deletion of the EPO, EPO receptor (EPO-R), or JAK2 genes in mice results in embryonic lethality due to a fatal anemia. EPO activates signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a/b transcription factors in erythroid cell lines. Studies have focused on STAT5 as the primary target of EPO-dependent JAK2 activation. However, STAT5a/b(-/-) mice are viable, displaying a nonfatal anemia during embryogenesis, and delayed differentiation in adult erythropoiesis. Importantly, EPO-R cytoplasmic tyrosines are dispensable for viability in vivo. Interestingly, no cytoplasmic tyrosines are required for phosphorylation of STAT1. This led us to examine whether STAT1-deficient mice have altered erythropoiesis. A shift in erythropoiesis was observed in STAT1(-/-) mice, with reduced bone marrow-derived erythroid colony-forming units (CFU-Es) and a compensatory increase in splenic burst-forming units (BFU-Es) and CFU-Es. Both types of splenic-derived cells displayed EPO hyperresponsiveness. A 1.6-fold reduction in total CFU-Es was observed in STAT1-deficient mice, whereas total BFU-Es were comparable. Flow cytometry of STAT1-deficient erythroid cells revealed a less differentiated phenotype, associated with increased apoptosis of early erythroblasts. STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and protein kinase B (PKB)/Akt. These results illustrate that STAT1 plays an important role in the regulation of erythropoiesis.
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PMID:A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution. 1521 94


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