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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR); 20150902-20150905; Bremen; DOCFA.33 /20150901/
    Publication Date: 2015-09-02
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; DENSITY ; PROTEIN ; cell line ; ACTIVATION ; LIGAND ; IMPACT ; DOMAIN ; BINDING ; ACID ; ACIDS ; MUTANT ; MEMBRANE ; MUTATION ; REQUIRES ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; INTERFACE ; CONSTITUTIVE ACTIVATION ; AMINO-ACIDS ; mutagenesis ; point mutation ; DIMERIZATION ; MEMBRANE PROTEIN ; MEMBRANE-PROTEIN ; LIGAND-BINDING ; COILED COILS ; signaling ; SEGMENT ; RECEPTOR ACTIVATION ; PATTERN ; LEADS ; INFECTED-CELLS ; FUNCTIONAL-CHARACTERIZATION ; AMINO-ACID ; GLYCOPHORIN-A ; VIRUS GP55 GLYCOPROTEIN
    Abstract: Structural and functional studies recently indicated that the erythropoietin receptor exists as a preassembled homodimer whose activation by ligand binding requires self-interaction of its transmembrane segment. Here, we probed the interface formed by the transmembrane segments by asparagine-scanning mutagenesis in a natural membrane. We show that this interface is based on a leucine zipper-like heptad repeat pattern of amino acids. The strongest impact of asparagine was observed at position 241, suggesting the highest packing density around this position, which is in agreement with results obtained upon mutation to alanine. Interestingly, the same face of the transmembrane helix had previously been shown to enter a heterophilic interaction with the transmembrane segment of gp55-P, a viral membrane protein that leads to ligand-independent receptor activation in infected cells. Further, functional characterization of an erythropoietin receptor mutant with asparagine at position 241 in a hematopoietic cell line showed that this protein could still be activated by erythropoietin yet was not constitutively active. This suggests that forced self-interaction of the transmembrane segments does not suffice to induce signaling of the erythropoietin receptor
    Type of Publication: Journal article published
    PubMed ID: 14602718
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; proliferation ; BLOOD ; CELL ; KINASE ; PATHWAY ; PATHWAYS ; liver ; DISTINCT ; PROTEIN ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSPLANTATION ; BINDING ; PROTEIN-KINASE ; SIGNAL ; DELETION ; FUSION ; DNA-BINDING ; SIGNALING PATHWAY ; STEM-CELLS ; CONSTITUTIVE ACTIVATION ; RECEPTORS ; HEMATOPOIETIC-CELLS ; ERYTHROPOIETIN ; STAT5A(-/-)5B(-/-) MICE ; C-KIT ; signaling ; HEMATOPOIESIS ; stem cells ; progenitor ; USA ; SELF-RENEWAL ; STEM ; MYELOPROLIFERATIVE DISORDERS ; TYROSINE KINASE JAK2 ; ERYTHROID PROGENITORS ; FETAL ; myeloid cells ; STEM-CELL-FACTOR ; STRESS ERYTHROPOIESIS
    Abstract: Erythropoiesis requires erythropoietin (Epo) and stem cell factor (SCF) signaling via their receptors EpoR and c-Kit. EpoR, like many other receptors involved in hematopoiesis, acts via the kinase Jak2. Deletion of EpoR or Janus kinase 2 (Jak2) causes embryonic lethality as a result of defective erythropoiesis. The contribution of distinct EpoR/Jak2-induced signaling pathways (mitogen-activated protein kinase, phosphatidylinositol 3-kinase, signal transducer and activator of transcription 5 [Stat5]) to functional erythropoiesis is incompletely understood. Here we demonstrate that expression of a constitutively activated Stat5a mutant (cS5) was sufficient to relieve the proliferation defect of Jak2(-/-) and EpoR(-/-) cells in an Epo-independent manner. In addition, tamoxifen-induced DNA binding of a Stat5a-estrogen receptor (ER)* fusion construct enabled erythropoiesis in the absence of Epo. Furthermore, c-Kit was able to enhance signaling through the Jak2-Stat5 axis, particularly in lymphoid and myeloid progenitors. Although abundance of hematopoietic stem cells was 2.5-fold reduced in Jak2(-/-) fetal livers, transplantation of Jak2(-/-)-cS5 fetal liver cells into irradiated mice gave rise to mature erythroid and myeloid cells of donor origin up to 6 months after transplantation. Cytokine-and c-Kit pathways do not function independently of each other in hematopoiesis but cooperate to attain full Jak2/Stat5 activation. In conclusion, activated Stat5 is a critical downstream effector of Jak2 in erythropolesis/myelopoiesis, and Jak2 functionally links cytokine- with c-Kit-receptor tyrosine kinase signaling
    Type of Publication: Journal article published
    PubMed ID: 18239084
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  • 4
    Keywords: RECEPTOR ; CELL ; Germany ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; NETWORKS ; SYSTEM ; SYSTEMS ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; FAMILY ; REDUCTION ; BIOLOGY ; SIGNAL ; STIMULATION ; DESIGN ; PLASMA ; MEMBRANE ; PLASMA-MEMBRANE ; RECRUITMENT ; PROGENITOR CELLS ; sensitivity ; systems biology ; ERYTHROPOIETIN RECEPTOR ; ORDER ; FAMILIES ; INCREASE ; intensity ; CANDIDATE ; ENGLAND ; PREDICT ; AGREEMENT ; quantitative ; QUANTITATIVE DATA ; VALUES ; IDENTIFIABILITY ANALYSIS
    Abstract: Background: The amplification of signals, defined as an increase in the intensity of a signal through networks of intracellular reactions, is considered one of the essential properties in many cell signalling pathways. Despite of the apparent importance of signal amplification, there have been few attempts to formalise this concept. Results: In this work we investigate the amplification and responsiveness of the JAK2-STAT5 pathway using a kinetic model. The recruitment of EpoR to the plasma membrane, activation by Epo, and deactivation of the EpoR/JAK2 complex are considered as well as the activation and nucleocytoplasmic shuttling of STAT5. Using qualitative biological knowledge, we first establish the structure of a general power-law model. We then generate a family of models from which we select suitable candidates. The parameter values of the model are estimated from experimental quantitative time-course data. The final model, whether it is conventional model with fixed predefined integer kinetic orders or a model with variable non-integer kinetic orders, is selected on the basis of a good agreement between simulations and the experimental data. The model is used to analyse the responsiveness and amplification properties of the pathway with sustained, transient, and oscillatory stimulation. Conclusion: The selected kinetic model predicts that the system acts as an amplifier with maximum amplification and sensitivity for input signals whose intensity match physiological values for Epo concentration and with duration in the range of one to 100 minutes. The response of the system reaches saturation for more intense and longer stimulation with Epo. We hypothesise that these properties of the system directly relate to the saturation of Epo receptor activation, its low recruitment to the plasma membrane and intense deactivation as predicted by the model
    Type of Publication: Journal article published
    PubMed ID: 18439261
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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; CELL ; Germany ; GENERATION ; INFORMATION ; NETWORK ; NETWORKS ; SYSTEM ; validation ; ACTIVATION ; COMPLEX ; COMPLEXES ; BINDING ; IDENTIFICATION ; SIGNAL-TRANSDUCTION ; endocytosis ; SURFACE ; EPIDERMAL-GROWTH-FACTOR ; signaling ; FEATURES ; mathematical modeling ; SCIENCE ; INTERNALIZATION ; DEPLETION
    Abstract: Cell surface receptors convert extracellular cues into receptor activation, thereby triggering intracellular signaling networks and controlling cellular decisions. A major unresolved issue is the identification of receptor properties that critically determine processing of ligand-encoded information. We show by mathematical modeling of quantitative data and experimental validation that rapid ligand depletion and replenishment of the cell surface receptor are characteristic features of the erythropoietin (Epo) receptor (EpoR). The amount of Epo-EpoR complexes and EpoR activation integrated over time corresponds linearly to ligand input; this process is carried out over a broad range of ligand concentrations. This relation depends solely on EpoR turnover independent of ligand binding, which suggests an essential role of large intracellular receptor pools. These receptor properties enable the system to cope with basal and acute demand in the hematopoietic system
    Type of Publication: Journal article published
    PubMed ID: 20488988
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; SURVIVAL ; carcinoma ; TRIAL ; CANCER-PATIENTS ; HUMAN TUMOR-CELLS ; TRANSFERRIN RECEPTOR ; QUALITY-OF-LIFE ; ANEMIA ; CHRONIC HEART-FAILURE ; EPOETIN-BETA ; STIMULATING AGENTS
    Type of Publication: Journal article published
    PubMed ID: 21829709
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  • 7
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    Unknown
    German Medical Science GMS Publishing House; Düsseldorf
    In:  86. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20150513-20150516; Berlin; DOC15hnod009 /20150326/
    Publication Date: 2015-03-27
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
    Keywords: RECEPTOR ; CELL ; Germany ; MODEL ; DENSITY ; VOLUME ; GENE ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; DOMAIN ; BIOLOGY ; MOLECULAR-BIOLOGY ; signal transduction ; SIGNAL ; MUTANT ; AMPLIFICATION ; SIGNAL-TRANSDUCTION ; EFFICIENT ; LOCALIZATION ; PROGENITOR CELLS ; CELL-SURFACE ; point mutation ; DIMERIZATION ; DOMAINS ; ERYTHROPOIETIN ; ERYTHROPOIETIN RECEPTOR ; LAYER ; OLIGOMERIZATION ; signaling ; molecular biology ; molecular ; RE ; VARIANT ; RESPONSIVENESS ; analysis ; MUTANTS ; TRANSMEMBRANE DOMAIN ; USA ; correlation ; SET ; NOV ; correlates ; modeling ; response ; erythrocytosis ; FUNCTIONALITY ; biological ; MEMBRANE-PROTEINS ; PRIMARY FAMILIAL POLYCYTHEMIA
    Abstract: The formation of signal-promoting dimeric or oligomeric receptor complexes at the cell surface is modulated by self-interaction of their transmembrane (TM) domains. To address the importance of TM domain packing density for receptor functionality, we examined a set of asparagine mutants in the TM domain of the erythropoietin receptor (EpoR). We identified EpoR-T242N as a receptor variant that is present at the cell surface similar to wild-type EpoR but lacks visible localization in vesicle-like structures and is impaired in efficient activation of specific signaling cascades. Analysis by a molecular modeling approach indicated an increased interhelical distance for the EpoR-T242N TM dimer. By employing the model, we designed additional mutants with increased or decreased packing volume and confirmed a correlation between packing volume and biological responsiveness. These results propose that the packing density of the TM domain provides a novel layer for fine-tuned regulation of signal transduction and cellular decisions
    Type of Publication: Journal article published
    PubMed ID: 18855427
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  • 9
    Keywords: CANCER ; DISEASE ; PROTEIN ; DYNAMICS ; DOWN-REGULATION ; systems biology ; ENDOPLASMIC-RETICULUM ; ERYTHROPOIETIN RECEPTOR ; EPIDERMAL-GROWTH-FACTOR ; DRUG DISCOVERY ; KINASE INHIBITORS ; TRANSMEMBRANE DOMAIN ; ACTIVATING MUTATION ; C-MET
    Abstract: Reliable inter- and intracellular communication is central to both the development and the integrity of multicellular organisms. Key mediators of these processes are cell surface receptors that perceive and convert extracellular cues to trigger intracellular signaling networks and ultimately a phenotypic response. Deregulation of signal transduction leads to a variety of diseases, and aberrations in receptor proteins are very common in various cancer types. Therefore, cell surface receptors have been established as major targets in drug discovery. However, in order to efficiently apply therapeutics, it is crucial to gain knowledge about design principles of receptor signaling. In this chapter, we will discuss signal transduction at the receptor level for examples from different receptor classes
    Type of Publication: Journal article published
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  • 10
    Keywords: CANCER ; SURVIVAL ; lung cancer ; ACTIVATION ; cytokines ; inactivation ; systems biology ; ERYTHROPOIETIN RECEPTOR ; PROTEIN-PHOSPHORYLATION ; SINGLE CELLS ; transcriptome ; hematology ; CELL BIOLOGY ; IDENTIFIABILITY ; TO-CELL VARIABILITY
    Abstract: Abstract.  Bachmann J, Raue A, Schilling M, Becker V, Timmer J, Klingmüller U (German Cancer Research Center, Heidelberg; BIOSS Centre for Biological Signalling Studies, Freiburg; and University of Freiburg, Freiburg; Germany). Predictive mathematical models of cancer signalling pathways (Key Symposium). J Intern Med 2012; 271:155-165. Complex intracellular signalling networks integrate extracellular signals and convert them into cellular responses. In cancer cells, the tightly regulated and fine-tuned dynamics of information processing in signalling networks is altered, leading to uncontrolled cell proliferation, survival and migration. Systems biology combines mathematical modelling with comprehensive, quantitative, time-resolved data and is most advanced in addressing dynamic properties of intracellular signalling networks. Here, we introduce different modelling approaches and their application to medical systems biology, focusing on the identifiability of parameters in ordinary differential equation models and their importance in network modelling to predict cellular decisions. Two related examples are given, which include processing of ligand-encoded information and dual feedback regulation in erythropoietin (Epo) receptor signalling. Finally, we review the current understanding of how systems biology could foster the development of new treatment strategies in the context of lung cancer and anaemia.
    Type of Publication: Journal article published
    PubMed ID: 22142263
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